Posted on Authorea 30 Dec 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160937136.67710116/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. motn oei h ouaino erlectblt n ahgnsso plpy ayhsaiereceptor histamine Many epilepsy. of an pathogenesis plays and system excitability nervous neural central evidence of the modulation of in the histamine shreds in Recently, that the role suggest seizures, from important neurons. researches results GABAergic preclinical epileptic epilepsy and inhibitory spontaneous that clinical and available supports and from neurons theory Traditional glutamate repeated excitatory medication. by of current characterized by imbalance controlled disorder well not neurological is common which a is Epilepsy epilepsy Abstract in histamine of Roles title: Running 143 6077 references: legend): of figure Number and reference abstract, (excluding count Word address: Email +86-571-88208228. Fax: & Tel Chen Zhong Prof. to: *Correspondence China PR 3 China PR Zhejiang, Hangzhou, University, China PR Zhejiang, Hangzhou, University, 2 Medical Chinese Zhejiang Science, maceutical 1 eta itmnri inln,Nua xiaiiyadEpilepsy Yang and Lin Excitability Neural Signaling, and Histaminergic animal Central from the findings on perspectives the provide focusing studies. further summarizes are we future Importantly, review insights for epilepsy. This New directions in receptor which research and epilepsy. histamine trials. possible among and excitability treat clinical some histamine models, brain neural and on in of epilepsy control of effect role the animal to anti-epileptic modulation on in researches receptors good the clinical histamine response a in researches shown of positive role has preclinical action show important even potential and ligands pitolisant an clinical receptor antagonist plays available histamine H3R system from Many the nervous well evidence epilepsy. central not of of the glutamate is shreds excitatory pathogenesis in which Recently, of histamine imbalance seizures, the that epileptic neurons. from spontaneous suggest GABAergic results epilepsy and inhibitory that repeated and supports by theory neurons Traditional characterized medication. disorder current neurological by controlled common a is Epilepsy Abstract 2020 30, December 1 Yang Epilepsy Lin and Excitability Neural Signaling, Histaminergic Central hjagCieeMdclUniversity Medical Chinese Zhejiang nttt fPamclg oiooy olg fPamcuia cecs colo eiie Zhejiang Medicine, of School Sciences, Pharmaceutical of College Toxicology, & Pharmacology of Institute plpyCne,Scn ffiitdHsia,Sho fMdcn,Zein nvriy aghu Zhejiang, Hangzhou, University, Zhejiang Medicine, of School Hospital, Affiliated Second Center, Epilepsy e aoaoyo erpamclg n rnltoa eiieo hjagPoic,Cleeo Phar- of College Province, Zhejiang of Medicine Translational and Neuropharmacology of Laboratory Key 1 iWang Yi , 1 iWang Yi , [email protected] 1,2 hn Chen Zhong , 1 n hn Chen Zhong and , 1,2,3 * 1 1 Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h itmnri erni h ansuc fhsaiepouto nteban hs oai located is soma whose brain, the in production histamine of source main the is neuron brain histaminergic the The in receptors histamine and Histamine future 2.1 on excitability perspectives neural provides and further of Histamine and role 2. epilepsy, the summarizes and review excitability This neural 2016). hi- directions. in to Stark, of research discovered & receptors temporal decline Jalal been its mesial have Sadeq, A and pharmacoresistant ligands Saad, 2008). histamine (Sadek, H3R with Selbach, treatment several patients & epileptic Indeed, of the Sergeeva 2016). neocortex target al., (Haas, (Ba˜nuelos-Cabrera temporal from et brain (MTLE) in isolated epilepsy demonstrated the found firstly have lobe in been studies was neurotransmitter several has Histamine then content a understood. Since stamine as 1943). least (Kwiatkowski, acts the 1943 histamine been in that Kwiatkowski has by histamine cortex them, brain (Meller, the Among epileptogenesis and 2018). ictogenesis Huo, L the & and & acetylcholi- excitability Klein and neural of 5-HT, Theilmann, histamine, modulation Brandt, the including in neurontransmitters, participating other of also that target ne, indicated designed have evidence the of are Pieces which the of to glutamatergic both AEDs. results excitatory due neurotransmission, of epilepsy the be that most on GABAergic may focus supports inhibitory mainly theory clinical Traditional researches and Classically, in understood. excitability. neurotransmission challenge neural fully of not et therapeutic imbalance is (Engel, Schaper the Above epilepsy 2018; preferred from of limited. (Kaeberle, mechanism patients are treatment is the of epilepsy effects that there for fact 1% anti-epileptic used worse, than vagus but therapy, also What’s 2020), less thermal are so, interstitial al., modification, but laser Even dietary (DBS), patients. therapy and stimulation ultimate many brain stimulation patients. deep nerve the of most as is such control for (Trinka, treatments, surgery Alternative choice (L seizure worldwide 2018). DRE, (DRE) first people improper For epilepsy the million drug-resistant to 2013). are become 70 Schmidt, lead patients (AEDs) to AEDs of drugs up one-third of Anti-epileptic approximately affecting effects disease, 2019). adverse neurologic Dash, the common & of Lee kind Kwan, one is Epilepsy Introduction type wide 1. tuberomammillary WT, TMN, strychnine; transporter-2; STR, monoamine cortex; Vesicular phosphokinase VMAT-2, granular PKC, nucleus; retrosplenial A; RGC, phosphokinase and pentylenetetrazole; PKA, Disorders PTZ, A2; Neurological phospholipase C; of PLA2, Institute Health; National electroshock of NINDS/NIH, maximal Institutes epilepsy; MES, Stroke/National lobe kinase; temporal protein recep- mesial mitogen-activated MTLE, H4 MAPK, seizure; histamine stimulation; H4R, low-frequency receptor; LFS, H3 H1R, out; histamine H3R, N-methyltransferase; receptor; IP H2 histamine tor; histamine HNMT, H2R, ki- receptor; signal-regulated stimulation; H1 deep histamine extracellular high-frequency DBS: ERK, HFS, diacylglycerol; like; DAG, histidine-decarboxylase; epilepsy element-binding; EL, epilepsy; response GSK3 drugs; nase; drug-resistant cAMP anti-epileptic DRE, CREB, AEDs, stimulation; monophosphate; system; brain guanosine cyclase; cyclic nervous adenylate cGMP, central Program; AC, Screening CNS, Anticonvulsant duration; ASP, afterdischarge seizure; audiogenic ADD, AGS, acid; arachidonic AA, Abbreviations further action studies. and we Importantly, potential future animal epilepsy. for the from in directions findings on Keywords: receptor research the histamine focusing possible summarizes and are some histamine review insights on brain This perspectives New of epilepsy. provide role even treat the trials. pitolisant on and antagonist clinical researches control H3R in clinical to the effect receptors which anti-epileptic among histamine of models, good epilepsy a animal shown in has response positive show ligands 3 hshtdlioio-,5bpopae A ancai;K,Kuhnk-ookn;K,knock KO, Krushinski-Molodkina; KM, acid; Kainic KA, 5-biphosphate; inositol-4, phosphatidyl , β, plpy itmn,hsaiercpo,cnrlnrossystem nervous central receptor, histamine histamine, epilepsy, lcgnsnhs iae3 kinase synthase glycogen shr 09 uiae kb,Nra asi 00 ho i,Ce,Li Chen, Lin, Zhao, 2020; Matsui, & Nariai Okubo, Sugitate, 2019; ¨ oscher, β· C,hproaiainatvtdcci uloiegtd HDC, nucleotide-gated; cyclic hyperpolarization-activated HCN, 2 shr ltar,Tya & Twyman Klitgaard, ¨ oscher, Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. epneeeetbnig(RB rti.Smlrt 1,tedsrbto fHRi h ri swide, is brain the in Then H2R cAMP. of messenger distribution second the cAMP a H1R, as form such to targets, to Similar downstream cyclase protein. phosphorylates cou- adenylyl turn (CREB) is in activates element-binding H2R which turn (PKA), response The receptor in A 1995). coupled phosphokinase which Ruat, G-protein activates G-protein, 7-transmembrane & cAMP Schwartz encoding Gs Souil, 5, to Tardivel-Lacombe, chromosome pled Vizuete, on (Traiffort, located amino-acids) is (359 cervical gene H2R superior human in The depolarization excitability potential neural and membrane H2R to 2.3 K led KCNQ/M antagonist inhibiting via H1R neurons Similarly, K ganglion 1997). of excitability K activation cell 2007). Haas, the decreases Pfaff, through H1R & & and neurons Kow instance, For area, pyramidal Zhang, excitability. Devidze, tegmental hippocampal neuronal Lee, the ventral of Zhou, dif- regulate 2002; and ventromedial negatively Brown, on the also nigra & depending H1R Haas in substantia However, (Korotkova, neurons, excitability that of both in in neuronal involved in effects elicits histamine is channel neurons histamine of side H1R, GABAergic response the through and inhibitory for example, hypothalamus or For corresponding excitatory regions. mainly either brain ferent mediates is raphe H1R H1R of forebrain, central Most basal The cortex, cerebellum. nucleus thalamus, and as including accumbens, drugs. well nucleus antihistamine brain, monophosphate corelus, as the guanosine locus solitaries in cyclic hippocampus, tractus amygdala, and distributed nuclei, (AA) widely septal hypothalamus, acid is nuclei, The arachidonic H1R 2012). of The al., formation et (cGMP). to pro- (Yamamoto mitogen-activated leads plasticity induces subsequently synaptic activation turn neuron in in IP involves which and which (PKC), DAG activation, C diacylglycerol (MAPK) phosphokinase messenger, kinase G- activates second tein DAG 7-transmembrane, form 1994). the to (IP Schwartz, phospho- of 5-biphosphate 5-biphosphate & and member inositol-4, phosphatidyl-4, protein a phosphatidyl hydrolyses Gq/11 and encodes turn with (DAG) which in coupled is which 3, H1R C, chromosome amino-acids). lipase on (486-491 located family receptor is protein-associated gene H1R is human It The located. excitability neural postsynaptically H1R neurons. and and H4R). in H1R and presynaptically expressed H3R, 2.2 is both H2R, H4R (H1R, was receptors whether H3R H4 that receptors and located, controversial histamine H3, still postsynaptically four H2, are were H1, 2016).There histamine H2R Stark, brain: & and the Jalal in Sadeq, identified Saad, learning processes, attention, (Sadek, been on have pathological regulation, so neuroendocrine and and locomotion, physiological epilepsy intake, memory, several food and and modulates water histamine cycle, tele-methyhistamine sleep-wake Brain into including (Fig.1). metabolized B is oxidase which monoamine cleft, postsynaptic the 1996). histamine Weihe, by into & by Eiden catalyzed release Bonner, histamine was Schafer, release into (Erickson, neuronal histamine transporter depolarization packaged evokes Then neuron acid release was histaminergic the calcium L-amino histamine upon and vesicles (VMAT-2), by Neuronal from transporter-2 neurons decarboxylation. monoamine vesicular into by through up histamine vesicles taken into L-histidine (HDC) acid histidine-decarboxylase amino dietary histamine The of sources secretion. Distinct acid brain. Fig.1. gastric response. the regulate in enter immune to can shown with cells histamine are associated mast of histamine conditions, closely release tissue, pathological is the some connective which to under still rise Interestingly, peripheral basophils, give is and the also cells cells In cells endothelial mast enterochromaffin-like synthesize 2000). cerebrovascular Stomach from could al., in released et also histamine and Yamakami synthesized microglia of 1999; is cultured production al., the that et (Haas, while found varicosities (Karlstedt 2001), axon study controversial in widely al., one especially et are neurons, and (Katoh fibers somata Besides histamine cell neuron 2008). in histaminergic Selbach, stored The is & histamine hypothalamus. Sergeeva Neuronal the brain. of the in (TMN) distributed nucleus tuberomammillary the in 3 N rmt acu ees rmteedpamcrtclmit h yols.I diin H1R addition, In cytoplasm. the into reticulum endoplasmic the from release calcium promote mtytaseae(NT n hndgae into degraded then and (HNMT) -methyltransferase + hne Lu hn,Wn,Zag&Zag 2008). Zhang, & Zhang Wang, Zhang, (Liu, channel 3 3) Lus riot rag advlLcme Ruat Tardivel-Lacombe, Arrang, Traiffort, (Leurs, + hnesb nraeo Ca of increase by channels N l mtyiiaoeaei cdby acid acetic -methylimidazole 2+ Slah Brown (Selbach, + Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h xiaoygi fD-xrsigmdu pn ern nncesacmescr yHRdependent reduces H3R histamine by that core noted accumbens be to nucleus needs in It neurons neuron 2006). spiny G inhibitory Zhou, medium through & reticulate D1-expressing depression LeDoux pars long-term Savage, of to Zhao, nigra gain & Xu, potentials substantia Zhou, excitatory Hamilton field and 2016; the Rosenberg, postsynaptic neurons al., (Varaschin, excitatory histaminergic et cells fast Luca TMN granule (De of the Watan- gyrus coupling inhibits Rhee, dentate the and (Jang, hippocampal 2014), reduces neurons H3R of hypothalamic ventromedial spikes 2001). of population Akaike, excitability neurotrans- ven- the & to targeted Akaike modulate the may projecting abe, this terminals on Ca and nerve P/Q-type depending H3R presynaptic presynaptic excitability, to inhibiting from neural by release of neurons GABA hypothalamic modulation spontaneous tromedial the inhibits in & Histamine also role (Ellenbroek H3R mitter. 2 complex reported and a been 1 plays receptor has H3R dopamine it with location, colocalized presynaptic activates ganglia from 1999), basal 2014). Apart al., in Ghiabi, et location 2016). (Lovenberg postsynaptic Stark, on cAMP & present form Jalal dopamine, to Sadeq, and AA Saad, noradrenaline, synthesis 3 Sadek, inhibits GABA, kinase the also synthase glutamate, inhibits H3R Akt/glycogen which including The MAPK, 2016), neurotransmitters, serotonin. al., inwardly-rectifying other and et the and acetylcholine, Luca activates histamine (De and of depolarization 2010), release nerve Tabarean, chan- calcium heteroreceptor blocking & the as channels Klaus inhibits acts autore- activation potassium and Ghochani, the H3R neurons Sanchez-Alavez, as histaminergic neurons. identified (Lundius, the in non-histaminergic is nels in histamine as presynaptically neurotransmitters of well located other release mainly as regulate found and H3R to synthesis neurons, been The has the histaminergic it cells. regulate cortex, of Additionally, endothelial to varicosities cerebral 2001). on ceptor and Haas, located in hypothalamus. & is dendrites, found Brown and H3R axon, Eriksson, been that (Stevens, hippocampus, soma, neurons has the nigra, non-histaminergic H3R on of substantia axon of located and distribution is tubercles H3R The olfactory The striatum, 1983). G Schwartz, accumbens, encoding & nucleus 20, Garbarg chromosome on (Arrang, located acids) is gene H3R 2013). human Wang, The excitability & neural Zhu and and Peng, H3R H1R 2.4 Zhuang, In through Yu, 2018). cortex (Zhang, entorhinal al., rat H2R et 2017). the Zhuang to Na Na+-Ca in activating 2013; linked by by transmission Wang, H2R HCN action GABAergic & excitatory facilitates and Zhu histamine postsynaptic H1R Wu, Additionally, strong Wu, to induces Zhuang, coupled histamine 2006; exchangers neurons, M Zhou, nuclear & H2R & vestibular and Jones LeDoux medial H1R Pegna, Zhao, postsynaptic Fort, via Xu, Khateb, neurons Zhou, 2018; nucleus cholinergic al., vestibular basalis inferior et and neurons, and nucleus (Ji pallidum D1 ventral neurons, histamine neurons, GABAergic dopamine nuclear neurons, co-mediates vestibular excites projection projection H2R superior inhibitory histamine spiny reticulate and instance, pars medium nigra For H1R substantia GABAergic neurons, neurons. postsynaptic striatal of both receptor-expressing kinds of D2 several activation in that excitability confirmed induced-neuron nucleus have vestibular studies lateral nucleotide-gated Many cyclic the linked-hyperpolarization-activated in H2R K the response and by 2000), excitatory channels co-mediated Wang, elicits is (HCN) & which Zuo histamine Yung, rats, Li, Wang, Additionally, Wen, in (Chen, Tian, 2005). neurons pathway 2011; signaling Chow, al., PKA & et (AC)- through cyclase Qin cells Chan G-protein-adenylate 2005; Purkinje intracellular Chow, cerebellar to & as linked well Chan which as Yung, response Wang, neurons, excitatory nucleus (Chen, induced dentate receptors Histamine area. cerebellar H2 histamine. and tegmental by neurons ventral elicited pallidus and excitability globus H2R nigra in neuronal substantia and the nuclei, mediates H1R raphe mainly The H2R coeruleus, hypothalamus. locus and hippocampus, thalamus, in amygdala, colocalized hippocampus, are ganglia, basal cortex, including + + emal aincanl n niiigiwr etfirK rectifier inward inhibiting and channels cation permeable hnes(ie l,2016). al., et (Li channels βγ - Akt/GSK3 β (GSK3 β inln aha Mn,Bce,Gutr&Gutr 2020). Grueter, & Grueter Becker, (Manz, pathway signaling β hehlr 95 eg hag e h ag 2013; Wang, & Zhu He, Zhuang, Peng, 1995; uhlethaler, ¨ n hshlps 2(L2 Goann ta. 2003; al., et (Giovannini (PLA2) A2 phospholipase and ) 4 i/o poenculdrcpo 3645amino- (326-445 receptor coupled -protein 2+ hnesvaaGpoencoupled G-protein a via channels + hnes(iz&Lei, & (Cilz channels ² + Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ol ofimta h ffc fcnrlHRo 2 nepilepsy. that on evidence H2R direct not or are H1R findings central these overall of However, the effect seizure. of the in risk compared that seems seizures the seizure confirm of It affect with could Garc´ıa risk not Rodr´ıguez, 2016). patients might increased & 8605 study antagonist including an H2R Nagy cohort which (S´aez,that with Gonz´alez-P´erez, Johansson, status, observational controls associated Einsiedel, epilepsy Gaist, larger not 40000 by (von was stratified a with manic discontinued cohorts antagonist epilepsy. However, presented the was H2R affects 2002). or then of famotidine population also Bergemann, pain, use the antagonist the gastric & after that H2R for Mundt showed seizures uptake antagonist) Sartor, generalized after (H2R Diebold, two patient famotidine Roesch-Ely, developed with the and treated antagonist, patient symptoms H1R a antagonist of H1R example, action For the the overtaking. that of for demonstrated Hirose, re- case Yokoyama, Except findings mental in 2018; above especially mild Erkonen, The effect, and & pro-seizure 2012). epilepsy Virk a Kimura, localization-related has Thomas, & by Greene, Iinuma followed Haginoya, Meulmester, encephalopathy Uematsu, (Labarinas, the toxic infancy dysrhythmias taking even and overdose in seriously, seizures or tardation tonic-clonic More teenager, epilepsy generalized 2013). a developed generalized Curatolo, ketotifen in idiopathic & or developed develop or Castro diphenhydramine who who antagonist Lo pattern child- dermatitis, infancy, H1R Roberto, In pathological atopic old El-Malhany, 1998). treat electroencephalogram months (Cerminara, to Kobayashi, typical 5 desloratadine later & antagonist with and Harada H1R Ochi, seizure 4 uptake (Yasuhara, two that absence ketotifen indicated in antagonist report observed adminis- case H1R been after ren, taking discharges has after Onodera, epileptic evidence spasm & of similar tonic Sakurai Watanabe, number then, Yanai, the Iinuma, Since (Yokoyama, increased antagonist) 1993). “excitation- boy (H1R d-chlorpheniramine 5-years-old of of a imbalance summarized tration the reported are the Yokoyama and that studies 1993, trials to clinical preclinical In not due in in epilepsy is epilepsy mainly on in it receptor that receptors excitability, 1. histamine its Table the epilepsy neuronal and in targeting the histamine in ligands of related regulating role action of in the effect a address receptors play we its Next, would the and inhibition”. histamine investigate histamine to that the epilepsy applied for mentioned surprise research mainly also clinical we were 2017). in Galeotti, As mice receptors & KO Masini its H4R Thurmond, and Ghelardini, years, Histamine (Sanna, Recently Masini 3. function Borgonetti, 2019). neural Sanna, its al., phenotypes 2017; and et disease Mattioli, phenotype and Zhou & behavioral behavioral some 2020; Gianlorenco in Serafim, Galeotti, H4R Fernandes, of & function antago- 2019; the or Serafim, assess Agonists excitability. to & neuron neuron used (Fernandes kinase (Fernandes vestibular commonly vestibular in signal-regulated are cortex inhibit involves H4R antagonists prefrontal extracellular H4R target suggests H4R nists downstream and 2012), 2018). vermis the al., Galeotti, et inactivates cerebellar & (Desmadryl and activity Masini the Mello, targets in (Sanna, H4R CREB pathway Also, is (ERK)-CREB of which 2019). inhibition 2004). other 2012), Serafim, to Hidalgo, to Dartt, & leads & Similar & Kemmerling H4R 2018). Jaimovich, Hodges of (Carrasco, Silberstein, Shatos, Activation excitability & Carozza, synaptic (Yuan (Li, neuron cortex release & regulating G cerebral Schneider calcium for distributed to and crucial was 2009; increases coupled H4R is hippocampus, al., H4R which brain, et ganglia, receptors, H3R, the (Connelly to histamine root In similar not dorsal 2001). 18, or Galizzi, the chromosome & neurons on in (Cog´e, Boutin located on Gu´enin, is receptor Rique, is gene coupled present, H4R H4R At protein human of nervous 1994). The central expression Schulman, the 2016). & the in Seifert, Kosinski microglia Fayvilevich, whether in Lenahan, controversial located Raible, is mainly 2009; is it al., which et decades, (Connelly last (CNS) the system in discovered recently is H4R The Neumann excitability (Schneider, brain neural the and in H4R receptors 2002). 2.5 these (Szczepanska, al., of ligands function et these Toyota knock the of H1R/H2R/H3R study 2014; discovery to or Seifert, used H1R/H2R/H3R drug & commonly target the are antagonists on mice or (KO) focus Agonists out research 2018). of Kiec-Kononowicz, kinds & are Kuder there discovery, H3R Since 5 i/o - Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ltmt n AAlvl nteTNE-einlso as(i ta. 07.Mroe,i a enfound been has it Moreover, 2007). found al., et been changing (Jin has tonic-clonic rats without 2017; lesion generalized hypothalamus, also Hu, E2-region and MES-induced striatum TMN & brainstem in the and He in observed hippocampus, hippocampus levels Chen, been cortex, GABA in Chen, and the has histamine glutamate in Zhang, phenomenon 2020; of decreased similar 2014; al., change histamine A et Mehndiratta, no seizures: 2006). (Alachkar & while hypothalamus al., Pillai 2006), et and Singh, Li, thalamus, (Szyndler 2012; & hippocampus, accompa- Hu, Ma the seizure & Zhang, in induced Zhang PTZ histamine that Ren, of found Chen, decrease studies a most seizures, by models myoclonic nied animal generalized epilepsy PTZ-induced in in the signaling ligands In histaminergic related central histamine of of change effect The therapeutics 4.1 the genetic Fig.2. and and in researches. receptor showed animal 3), histamine (Table in are and review epilepsy epilepsy epilepsy in to histamine on interventions attention of ligands other electrically-induced pay change as related also well and The receptors we as Moreover, chemically histamine animal, of 2). genetic-edited or across (Table findings especially histamine models interventions, in summarize of animal we expression effect other Next, therapeutic as receptor well cases. the histamine as some models, or in animal level together epilepsy use histamine of combined in indication are chemical changes methods vestibular and stimulation, induction electrical audiogenic chemical as the (L and such seizure for models, febrile seizure-induced except hyperthermia-induced other and Besides, are stimulation there seizure. animals, of normal method in commonly seizures are induction kindling electrical transauricular and as stimulation used 6-Hz and to kindling, agonists), (PTZ), amygdaloid ways receptors (MES), Pentylenetetrazole common glutamate seizure induction. electroshock (KA, two acid chemical kainic usually and (STR), (GABA are strychnine induction picrotoxin mice, agonist), there receptor DBA/2 electrical latter, M as animals: or (Ach have such the normal pilocarpine includes epilepsy, epilepsy seizure, For it in reflex of in former, animals. seizures with the models receptor (KM) For induce animals models. The Krushinski-Molodkina its and animal seizures, agents. and and acquired recurrent and antiepileptic GEPR, histamine spontaneous models new with of animal mice genetic of role into transgenic development classified indispensable causal preclinical be an the can have the seizures seizures investigating in epileptic of instrumental of advancement models been Animal the researches. in epilepsy clinical for to role limitations studies many to animal are needs in There subtypes, receptors receptor its histamine and of Histamine histamine change the 4. distribution how However, the studies. or clinical from brain, and epilepsy further. subdivide in H2R, validate H4R H1R, the of especially in role ligands, clinical the change receptor-related that under content histamine about available ligands of known most antagonists effect is present, Little At the H3R 2020). H3R. on Fasinu, other for & focus several (Harwell Commission Masnou, mainly epilepsy are researches European not Genton, There clinical but Trenit´e, the early Parain, indications 2016. by target Kasteleijn-Nolst in March other approved in for model 2016; generalized development was narcolepsy concept the (WakixR) al., of pitolisant of suppressed et treatment Currently, pitolisant proof the Dutilleul 2013). and photosensitivity Hirsch, (Collart the II & trials phase in Schwartz clinical patients in clinical. in II epilepsy response effects all phase positive anti-epileptic of the good received response shows pitolisant patients photoparoxysmal discuss antagonist, of latter will H3R The we third The antagonists. which affinity. Many One non-imidazole-based studies, attention. and and preclinical of selectivity imidazole-based in lot into high epilepsy a classified has on receive are effect antagonists H3R needed. protective of H3R is Antagonists good the studies later. a H3R, clinical show of the from ligands activity identifying antagonist constitutive evidence on H3R high direct focus specific More the studies epilepsy. protective on Most in potential Based 2016). antagonist with the al., H2R (Ba˜nuelos-Cabrera patients suggests protein et or which MTLE Gai/o that H1R H3Rs cortex, in of epilepsy. reported of histamine temporal role efficacy in literature and in high receptor H3R histamine and one of of its hippocampus, only contents the role and in is tissue histamine function low there H3R of with the present, activation role in At reduction the a limited. for showed are MTLE evidence studies direct more related provide However, could reports Autopsy A eetratgns)aecmol sdceia usac oidc ezr.Maximal seizure. induce to substance chemical used commonly are antagonist) receptor 6 shr 01 osha 02.Atal,teelectrical the Actually, 2012). Potschka, 2011; ¨ oscher, Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ayn&Toit,21;Vngaoa htkv umso 07.Teersace ugs preventing epilepsy. suggest against researches and protect These rats effectively 2007). KM Tuomisto, could in & degradation Shatskova AGS histamine Vinogradova, Kuznetsova, by Midzyanovskaya, Birioukova, 2012; induced (Samotaeva, Tuomisto, rats convulsions addition, & WAG/Rij Bazyan clonic-tonic in In discharge of Kaki- 2004). wave rats Ishizawa, severity spike Nakano, the (Kamei, and kindling & suppressed stimulation duration Murashima amygdala vestibular Watanabe, the in Nakagawa, the decreased Tanaka, after stage Yawata, metoprine mice 1998; seizure epileptic-like Fukunaga, facilitated the in & L-histidine decreased onset noki (thus seizure of metoprine HNMT the the treatment content), delayed inhibiting by forelimb daily histamine and Ligands affect however, bilateral 1996). brain be Koshino, of ADD, the will & onset Nakamura and histidine increasing the Shiraishi, of stages (Wada, to action development seizure latency the seizure that the the the fact prolonged changing the L-histidine without rats to example, kindling clonus, due For amygdaloid be dosage. in reported may (ADD) administration Yoshida This duration However, its 2000). afterdischarge histamine. Tsuru, and & ranks of Noguchi seizure effect Kakinoki (Yoshida, reduce anti-seizure Ishizawa, not Kamei, medicates did L-histidine 2006; H1R that and Kamei, suggesting diphenhydramine & pyrimidine, 1998), antagonist, Rahman Fukunaga, H1R Ashequr & by Fain- Matsumoto, Watanabe, attenuated Ishikawa, Nakagawa, & is Tanaka, (Ago, (Yawata, Randall effect chlorpheiramine mice Naritoku, this Feng, like 2004), 2000; epilepsy Nakano, Faingold, stimulation & kindling & Fukunaga, vestibular Murashima amygdala (Feng & rhythmic in rats Kakinoki and seizure Ishizawa, GEPR-9s Zhang, 2001), Kamei, inhibit in 2002; gold, 2006; Wei, (AGS) histamine Kamei, & seizure and & Shen audiogenic histidine Zhu, Rahman Similarly, 1998), Li, Ashequr 2004). (Chen, Matsumoto, Ishikawa, Chen, jerks (Ago, myoclonic & seizu- rats delay, to Zhao onset latency Hu, seizure prolonging by Jin, as indicating Shen, well rat animal kindling as precursor, PTZ decrease, in histamine on stage The effect epilepsy. epilepsy re protective in a histamine on showed of histidine receptors effects and protective carnosine histamine the investigating studies and several are histamine There are targeting researches ligands more H4R. of epilepsy, and times effect under mode H2R sampling therapeutics especially receptor different receptors, The histamine by histamine 4.2 of caused of be changes expression the may the elucidate studies For Tuomisto, to two regions. & needed nucleus former (Midzyanovskaya grey, brain rats the Sallmen, central WAG/Rij different between (Lintunen, colliculus, epilepsy-prone and outcome area superior genetic difference in CA1 the The increases in hippocampal 24 2003). density nuclei & the hippocampal and H1R pontine Lintunen the then 12 the and in (Jin, and Likewise, 6, loop interpositus amygdala model 2005). intracellular injection Panula, and third KA KA & full-length cortex the (after a Karlstedt piriform in with mRNA transiently by isoforms nuclei KA the followed H3R geniculate of CA3, that and mRNA and mRNA reported thalamus, The brain posterior, increase research increases ventral model. and posterior, hours) another the decrease epilepsy ventral However, transiently and in firstly the 2005). loop areas change in Panula, intracellular week midline found third full-length 1 the been a after with have in isoforms H3R decreases H3R of and epilepsy. transiently expression of H1R H1R stage epilepsy. only different of of level, the expression in process receptor change pathological focal histamine content across the histamine In regions in how brain involves unclear many histamine still in Sallmen, that is observed (Lintunen, suggesting it content later However, seizures, histamine hours the of generalized 6 in reduction and injection fibers The seizure KA nerve 2005). after immunoreactive Panula, striatum temporal histamine & and KA-induced and Karlstedt the hippocampus histamine in amygdala, brain However, cortex, re- midbrain, increases 1992). piriform epilepsy amygdala, immediately Airaksinen, than KA lower & hippocampus, Tacke epilepsy, significantly Saboory, Tuomisto, were striatum, lobe (Onodera, rats (Gholipoor, the rats KM rats Wistar epilepsy-prone in blood infant sistant genetically of levels of in decrease been hypothalamus Histamine convulsion has a and 2013). hyperthermia-induced level thalamus And Fereidoni, histamine that 2003). of & found Tarhanen, decrease & stimulation been Roshan-Milani a Freeman 6-Hz has mice, and Sturman, DBA/2 level 2006), (Tuomisto, audiogenic Chen, histamine hypothalamus the & the Zhou In histamine Zhu, in 2017). brain Liu, Vohora, detected of (Li, & reduction rats Pillai kindling a (Jahan, transauricul l 7 Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. u o 1 naoitprlmn Aaha ta. 09.Mroe,teHRnptaeederivatives naphthalene H3R the Moreover, 2019). al., first the et to (Alachkar latency pyrilamine R-( prolonging antagonist agonist and mice H3R H1R rate KA by survival not blocked pilocarpine in the in was but CREB effect effect increasing protective this seizures and by shows and behavioral indicating also (Ser473) seizure, E177, rat reduced phospho-Akt antagonist epilepticus Guo, and H3R caspase-3, Zhang, statue seizure Another cleaved Yan, induced of 2014). Song, Bax, Vohora, onset 2016; & of delayed Stark, Saini expression ABT-239, (Bhowmik, & antagonist, Walter altered Weizel, 2018a; H3R restored Schwed, al., Saad, and 2020). et Sadek, et (Alachkar Deng, Sadek 2016; & model 2018; al., seizure Zhou Sadek, Kie´c-Kononowicz et & MES-induced Wiecek, Sadek Shafiullah, and H3R 2014a; Abdulrazzaq, STR non-imidazole al., Bastaki, novel PTZ, 2018b; of in al., effects found et Nakano, Alachkar anticonvulsant been & thiop- and have Murashima antiepileptic antagonist pyrilami- ligands Watanabe, of H3R Nakagawa, antagonist antagonist Tanaka, degree mice, (Yawata, H1R different like seizure Furthermore, by epilepsy of 2004). reversed stimulation is induction vestibular was action the rhythmic decreased the model the eramide suggesting MES in Kie´c-Kononowiczc, MES-induced 2016), in Besides, & in La˙zewska Shafiullah, DL77 effect H1R-dependent. Subramanian, anticonvulsant of Haru- Saad, showed Fujii, effect (Sadek, DL77 Hirai, anticonvulsant showed antagonists Harada, ne also 2004; H3R the ligands Kamei, The and & all 2004). many seizure, Shinomiya AQ0145, Kamei, are Hirai, except & Fujii, there model, (Harada, Kurihara model, kindling model sawa, PTZ amygdala MES to Chen, in in Similar Zhang, effect 2004). stage VUF5515 2003; protective Chen, seizure VUF5514, al., & decreased clobenpropit, Zhao AQ0145, et VUF4929 iodophenpropit, Hu, Zhang and thioperamide, Jin, 2020; including Shen, al., ligand, Zhang, antagonist clonic et 2013; H3R and (Alachkar Ding, jerks thiope- myoclonic model & to clobenpropit, Hu seizure latency antagonist, Chen, the PTZ-induced H3R prolonged epilepsy. in and target stage, seizure to seizure generalized onset, synthesis seizure been delayed have E177 ligands and ramide, H3R many date, urge epilepsy. to are in Up investigations H2R such systemic of AEDs, agonist, role Czuczwar, of H2R & the from properties Wielosz anticonvulsant reveal obtained Swiader, the to therapeutics Porebiak, positive affect (Swiader, chroni- potential model. not or PTZ Although did acutely in 2006). also either phenobarbital and or alone clonazepam seizure given valproate, antagonist, PTZ-induced as H2R & alter (Seeley an not amt- model cimetidine, did agonist, mice that cally H2R epilepsy reported an PTZ-induced that Another showed and 2001). study picrotoxin-induced One Sturman, in limited. antagonists seizure are clonic-tonic H1R epilepsy decreased in of H2R hamine dosage targeting ligands the the and about epilepsy, Reports in demons- antagonist findings enhanced H1R These that. of 2004). it contribute Czuczwar, effect acutely might & therapeutic the action, Wielosz controversial reduced (Swiader, biphasic the treatment, MES 7-day trate a in following the carbamazepine possessed while, of of phenobarbital ketotifen activity region and antiseizure antagonist (Kukko-Lukjanov carbamazepine CA3 of mice H1R thalamus, action immature the anticonvulsant KA-treated septum, Interestingly, the the the 2010). in in (RGC) al., cortex damage et granular antagonist, neuronal retrosplenial H1R and and another Additionally, severity hippocampus, & 1996). Hirai seizures Watanabe, Harada, Tanaka, & increased epinasti- (Fujii, Onodera not triprolidine model Iinuma, kindling but Sato, amygdala diphenhydramine, Yokoyama, in and 2003; Freeman seizures ketotifen Kamei, accelerates (Sturman, pyrilamine, cetirizine, induction antagonist, and seizure H1R loratadine convulsive the ne, Nakano, the Besides, & delayed 2001). Murashima mg/kg of Quinn, Watanabe, 30 Nakagawa, & outcomes Tanaka, at (Yawata, a opposite diphenhydramine at process Similarly, diphenhydramine whereas, this mice, opposite. 2004), accelerated like the mg/kg epilepsy 15 stimulation showing 10mg/kg vestibular or of mg/kg rhythmic 5 dosage the 30 administrated in orally dose controversial manifesting dosage: large different antagonists The the H1R whereas 2012). to effect, due Kanda, has might positive rats & rats, Tamura infant infant leading Takizawa, in MES (Yamada, seizure in model (Ishikawa ketotifen accelerates of rats ketotifen seizure infant outcome the MES-induced however, weeks in 3 2004), Czuczwar, or found & mice been Wielosz adult chlorpheniramine, in Swiader, effects 2007; diphenhydramine, anti-seizure al., ketotifen, of et antazoline, degrees varying model, show seizure and cyproheptadine chlorphe- and pyrilamine MES-induced cetirizine, 8 α -ehlitmn n 2 naoitzolantidine, antagonist H2R and )-methylhistamine Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. . hti h oeo te itmn eetr nepilepsy? in behind. receptors left histamine issues re- other unsolved of histamine numerous role and still the histamine are is There that What epilepsy. supports 5.1 of studies pathogenesis preclinical the and in involves clinical ceptor available from evidence Current investigate. 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Guo, in been Zhang, DL77 Yan, has antagonists (Song, mice H3R also 2006). PTZ epilepsy in Chen, different outcome moiety in & triazole negative effects Zhou containing anti-seizure Zhu, The good Liu, show Hu, agonists Li, & antagonists/inverse models. & 2005; H3R He al., cases, Hu Chen, antagonist, deficits most et Chen, Chen, memory in H3R (Li (Zhang, Although, the Chen, seizure and H1R ameliorates Zhang, kindled not and 2006), transuricular carbamazepine but 2006; Li, chronic of H2R al., by efficacy & through anticonvulsant et induced might Ma the Jia L-histidine promotes Zhang, of Histidine 2020; 2012; effect 2017). can al., this Hu, which et and & deficits, (Alachkar 2013), memory Zhang E177 Ding, and Ren, and learning (Chen, JNJ-5207852, by L-histidine accompanied thioperamide, usually by model amygdaloid rescued seizure in be epileptic ranks induced seizure PTZ the 2000). The changing Pourhossein Tsuru, without Doostmohammadi, & ADD (Yazdi, Noguchi an- reduced (Yoshida, mice agonist/H3R Betahistine rats treated H1R kindling 2020). PTZ an and Beheshti, in induction Betahistine, & intensity seizures Majarshin tonic-clonic pitolisant. seizures generalized as clonic preventing marketed by forelimb indicating be diminishing National effect and protective the shows trials good by 13 MD, shows clinical compound accepted tagonist Rockville, This enter was (NINDS/NIH; to al., 2018). 13 ( ( Health al., possibility et La˙zewska (ASP) La˙zewska compound et model of the Program derivatives stimulation Screening Institutes Anticonvulsant naphthalene 6-Hz Stroke/National an H3R started and and the USA) Disorders PTZ that Neurological in note of seizure to Institute of needs effect It protective 2018). shows also 13 compound L ˙ esa&KecKnnwcc 06.Wa’ oe h cino 1 naoit nsiueaia model animal seizure in antagonists H1R of action the more, What’s Kie´c-Kononowiczc, 2016). La˙zewska & 9 Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nteato fHRnest dniyfrhr otg-ae o hnesicuigNa including channels ion Voltage-gated further. participating identify 5-HT to and needs acetylcholine al., H3R et GABA, of (Dai glutamate, NMDA- pathway action the signaling as the reduced cAMP/PKA such in and effectively through neurotransmitters, synthesis clobenopropit releases other neurotransmitters antagonist GABA H3R other increasing 2007).Whether the by regulates transgenic to toxicity neurons, which of neuronal innervating cortical heteroreceptor development induced cultured as or well the acts neurons The In H3R histaminergic release. optogenetic. clas- in understood. of the CamKII localized fully help as HDC-Cre, not is the considered as is histamine which such is of neurons mice, action neurons GABAergic The GABAergic or inhibitory epilepsy. glutamatergic and epilepsy? for in glutamatergic theory system excitatory sical of histaminergic of basis of novel mechanism circuit imbalance molecular the as The reveal and such to cellular specificity the technologies, spatial is (Nectow Advanced DBS and What system 5.3 temporal that tracing high seizure. viral supports provide epilepsy. novel control finding 2020), in with al., to These system combination et histaminergic approach in Xu 2008). 2020; 2017), therapeutic Nestler, al., Deisseroth, exacerbated good & & et TMN Adhikari a (Wu during of (Kim, lesions (ADD) 2008). not kindling optogenetics bilateral al., duration amygdaloid is and et afterdischarge the HFS TMN (Wu mean kindled, in model on the fully PTZ progression increased in & in seizure effect and Urade effects anticonvulsive Miura, the stage appreciable no Mikuni, seizure had no Huang, accelerated but had (Nishida, acquisition TMN TMN rats the the histamine PTZ of of of in increase LFS LFS stimulation prominent However, TMN a after 2007). with cortex accompanying Hashimoto, frontal protection the dominant in a seizure, showed release epileptic in TMN tract response on regula- positive TMN-solitary directly receive pressure receptors DBS the histamine arterial several Whether and in histamine that further. although 2017). participating Interestingly, validate reported promis- Waki, nucleus needs has an epilepsy & tract It shows regulates Maeda solitary tract projection 2006). 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Investigations many intervention. of still in epilepsy 2012). expression is investigated changes and al., epilepsy been The distribution et in have the (Desmadryl antagonists H4R especially model. excitability H3R of further, animal neuronal and report elucidate epilepsy regulating H2R to the of however, studies H1R, type autopsy model, addition, and one imal In researches in H4R. animal detected and systemic merely H2R need been receptors have histamine expression of H3R and H1R α- r,adVa-r r vial onuoa pcfi ouainwith modulation specific neuronal to available are Vgat-Cre and Cre, 10 + Ca , 2+ n K and + Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. amkY 20) plpy lcrauucueadtenceso h oiaytat cpntr in Acupuncture tract. solitary 24 the Society Acupuncture of Medical nucleus British the the and of journal electroacupuncture Epilepsy, : kainicmedicine attenuates (2006). ABT-239 1581 by YO research antagonism Cakmak Brain receptor H3 244 mice. Histamine Neurol in (2014). excitotoxicity Exp D induced matter? Vohora acid & they N, do Saini epilepsy: M, Bhowmik in circuits Neuronal (2013). mice. Anticon- EH in Bertram 2-18 (2018). 12 antagonist B therapy H3R Sadek and histamine development imidazole-based & Kie´c-Kononowicz the design, K, of M, Drug studies Wiecek toxicological M, reproductive and Shafiullah vulsant YM, Abdulrazzaq SM, Bastaki 57 human the Epilepsia in neocortex. function receptor temporal H3 and and a turnover hippocampus by histamine modifies mediated epilepsy lobe release F temporal histamine Carmona Pharmacoresistant M, brain Alonso-Vanegas 302 F, of Velasco Nature AL, Auto-inhibition Ba˜nuelos-Cabrera Cu´ellar-HerreraVelasco receptor. I, M, (1983). histamine JC of Rats. Schwartz (H3) in & class Seizures novel M, Induced Garbarg Chemically JM, and Arrang 19. Electrically sciences in molecular Antagonists of A H3R journal Lubelska Histamine International Pharmacology, A, Novel Siwek of rats. A, Effects Frank in sant G, models Latacz convulsion D, La˙zewska A, Alachkar different in 170 antagonists behavior H3R and Grybo´s histamine biochemistry, A E, non-imidazole Honkisz A, novel Lubelska A, of in Siwek Epilepticus G, Latacz Status A, Pilocarpine-Induced Alachkar on 24. E177 Switzerland) Antagonist (Basel, Receptor Molecules Kie´c-Kononowicz H3 Rats. K La˙zewska D, Histamine R, of Beiram (Basel, SK, Effects Molecules protective Ojha S, Rats. Azimullah in A, Alachkar Expression Mitigat- Protein by c-Fos Deficits and Memory 25. Neurotransmitters, imipramine- Switzerland) Associated Central of and Stress, Mechanism Oxidative R Kindling Beiram Pentylenetetrazole-Induced ing SK, (2006). Alleviates Ojha E, C receptors Adeghate Kamei M, H3 Lotfy & S, 72 Azimullah M, research A, Alachkar Epilepsy Rahman rats. Ashequr amygdala-kindled N, in Matsumoto seizures induced T, Ishikawa J, Ago interest. of conflicts no References are (81630098, there China that declare of authors Foundation The Science Natural interests National of the Conflict from grants 81821091). by and supported 82022071 was work to encouraged This the is of level role circuit the neural of even The Acknowledgments or understanding H3R therapeutics. cellular, epilepsy. precise for epilepsy molecular, A in especially in at involved transformation aspects, epilepsy unsolved. clinical are development in questions receptor AED system many the histaminergic its are central broadens and there system histamine Nevertheless, histaminergic the antagonists. central suggested mechanism. the Borm evidence molecular of (Lein, the of discovery efficiency activity investigate plenty high channels to with conclusion, way ion convenient sequencing In voltage-gated a RNA regulate al., provides single et receptor that cellular Wei its 2017), 2019; Since Linnarsson, or al., evaluation. & et histamine further Loo Whether needs van epilepsy 2014; 2014). in (Catterall, Isom, discharges & seizure Yuan of 2017; generation the to contribute channels, : 14-24. : 179-194. : : 832-837. 11 e76-80. : 129-140. : tal. et , 1-9. : tal. et , 164-168. tal. et , 21a.Atcnusn evaluation Anticonvulsant (2018a). 22) naoimo Histamine of Antagonism (2020). 21b.Suiso Anticonvul- on Studies (2018b). tal. et , : 67-74. 21) h Neuro- The (2019). tal. et , (2016). Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nmc.Eies eair:E&B JJL : Costa behavior MG, & model Valle-Dorado seizure Epilepsy A, pharmacoresistant mice. 31 a Lazarowski in in neurology overexpression S, in (P-gp) Goicoechea P-glycoprotein opinion prevent Current ME, neurosciences candidates anticonvulsant surgery. Ianni in epilepsy Trends Di of AV, receptor. place Enrique H3 current The histamine (2018). the Jr. of J, side Engel other The British (2014). excitability. B 37 Ghiabi neuron & primary BA, vestibular Ellenbroek A mammalian Saleur of 167 A, pharmacology modulators Broussy of potent C, journal Travo as A, antagonists Brugeaud receptor S, 106 Gaboyard-Niay Neuropharmacology G, autoinhibition. Desmadryl receptor-mediated 3 Baumg histamine D, through Yang neurons T, minergic Suvorava R, Luca H 588 Ohtsu De letters CL, Neuroscience Xu mice. WW, immature Hou in B, Feng seizures DC, 563 Wu pharmacology YJ, of Dai journal H the European through Timmerman neurons. excitotoxicity cortical Z, NMDA-induced cultured against Zhang in 123. pathway protect W, A to Hu kinase release cAMP/protein GABA Y, pharmacology enhances Shen of clobenpropit journal Q, agonist British Fu CNS. H, mammalian Dai the in RL Faull neurons Partial HJ, on Waldvogel Refractory expressed R, 157 functionally in Leurs is (BF2.649) N, receptor Pitolisant Lethbridge 39 H4 FC, of neuropharmacology Shenton Clinical Effect Months. WM, Antiepileptic 3 Connelly the During A Treatment human and Adjunctive Biraben the Safety as F, the of Given Semah Evaluate Seizures, L, expression Vercueil to and P, Trial Kahane Structure P, II (2001). Ryvlin 284 P, JP communications Dutilleul research Galizzi Collart biophysical Hip- & and Biochemical channels. JA, gene. K(+) Boutin H4-receptor Roles rectifier histamine H, inward cortex: Rique entorhinal and Gu´enin SP, rat channels, Cog´e F, the cation in -permeable transmission Na(+) GABAergic receptors, 27 facilitates H(2) pocampus Histamine on and histamine, (2017). H(1) S of 143 of M Lei precursor pharmacology Kato & of a Y, NI, journal histidine, Kiso Cilz British of C, brain. Effects Jin the W, in (2002). neurons Hu histaminergic EQ E, Wei neuronal Sakurai 23 on Z, & Sinica histamine Chen YJ, pharmacologica 53 Acta of research Shen effect Neuroscience rats. LJ, in Excitatory vitro. Zhu seizures in WD, pentylenetetrazole-induced (2005). receptors Li BK H2 Z, of Chow activation & Chen by YS, 41 pallidus sciences Chan globus Medical rat WH, University Yung of Zhejiang pentylenetetrazole-induced activity JJ, of on Wang Journal mycelia = K, Wuling ban Chen of xue [Effects Yi bao (2012). xue XY xue da Hu 647-652. Zhejiang & deslorata- LS, rats]. by in Zhang induced epilepsy Seizures GL, Ren 44 (2013). GF, P Neuropediatrics Curatolo Chen observations. & clinical A, antihistamine: Castro second-generation Lo a D, phar- dine, Roberto of N, review El-Malhany Annual C, drugs. Cerminara antiepileptic and expression 37 54 epilepsy, gene research toxicology inherited Biological and and channels, macology transduction cells. Sodium Signal excitable (2014). in WA (2004). stores Catterall C internal Hidalgo from release & calcium U, by Kemmerling regulated E, Jaimovich MA, Carrasco : : 191-199. 55-63. : 613-631. : : 317-338. 905-916. : 106451. re ,KjaG asHL Haas G, Kojda W, ¨ artel : tal. et , 12 95-100. tal. et , tal. et , 20) hraooia ffcso acnn on carcinine of effects Pharmacological (2004). 21) rtcieeeto ansn nfebrile on carnosine of effect Protective (2015). 20) h itmn 3rcpo ant- receptor H3 histamine The (2007). tal. et , : tal. et , 573-580. : 361-366. 21) dnicto fhista- of Identification (2016). tal. et , tal. et , 21) xlrtr Phase Exploratory (2016). : 222-224. 20) h histamine The (2009). 21) itmn H4 Histamine (2012). : tal. et , 301-309. : 701-712. : : 192-197. 188-193. : 21) New (2019). 288-297. : 102-115. : 117- : Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. i ,Lnue ,&Pnl 20) itmn ()adH3 eetr nterttaau n their and thalamus rat the in receptors H(3) 194 and neurology H(1) Experimental Histamine administration. (2005). acid kainic P mice. systemic Panula weanling after & in modulation M, kindling Lintunen E pentylenetetrazol C, by Sakurai Jin induced T, deficits Okuda mnemonic A, and 50 Xu learning Neuropharmacology H, on 34 Dai bulletin donepezil Neuroscience M, and L Receptors. Kato Yu H2 Z, F, and GABAergic Chen H1 Jia of YX, of Co-activation modulation Zhang via XC, Histaminergic Neurons Peng (2001). 534 Pallidum Ventral XY, physiology N of Zhang Akaike Journal MJ, & The clinical Ji N, neurones. & Akaike hypothalamic Fundamental ventromedial T, rat mice. Watanabe in in JS, transmission Rhee model IS, seizure Jang psychomotor behavioral 6-Hz alters in depletion 31 5-HT levels Parachlorophenylalanine-induced pharmacology neurotransmitters (2017). D brain Vohora & and KK, bulletin Pillai pharmaceutical K, & Jahan Biological rats. infant in seizure on A electroshock Murakami Update 30 maximal N, on Matsumoto Antagonists-An antagonists J, Receptor receptor Ago H1 A, Histamine-3 Rahman 7. K, Other Switzerland) Takechi (Basel, T, and Ishikawa Medicines Pitolisant Prospects. (2020). Clinical and PS Potentials findings Fasinu Therapeutic and & Methods epilepsia. V, of Harwell models 26 administra- rat pharmacology Intracerebroventricular in (2004). clinical seizures C and decreases Kamei experimental antagonists & in receptor T, H3 Kurihara selective histamine S, a Harusawa of 63 iodophenpropit, Y, tion bulletin Fujii of T, research effect Hirai Brain Inhibitory C, seizures. (2004). 88 Harada C kindled reviews Kamei amygdaloid Physiological & on K, system. antagonist, Shinomiya H3 nervous T, histamine Hirai the Y, in Fujii C, Histamine Harada (2008). O Selbach & neuroscience 1183-1241. 23 OA, of Neuroscience Sergeeva Journal for HL, The Society Haas cells. the F CA3 of Giachi hippocampal journal C, in official Bucherelli activation the E, ERK2 : histamine-elicited Baldi 29 by E&B MB, blood memory : Passani histamine fear behavior M, on & hyperthermia Efoudebe Epilepsy of MG, rats. Effect Giovannini infant (2013). in J Fereidoni behavior & convulsive H(1) S, histamine and Roshan-Milani by level E, induced activity Saboory Epileptogenic P, 991 (2003). Gholipoor research C agonist Kamei Brain receptor & rats. T, H4 amygdala-kindled Hirai 135 in Intra-vermis C, antagonists bulletin (2017). Harada research T, Brain R Tanaka Y, models. Mattioli Fujii fear-mediated in & and 52 decrease anxiety- ACL, mice. a in in Gianlorenco induces performance cortex KR, agonist impairs prefrontal receptor and Serafim vermis H4 CEM, cerebellar an Fernandes the of in injection levels Systemic pCREB seizures (2019). and kindled KR CREB 172 audiogenically Serafim neurology of & Experimental Modulation CEM, amygdala. Fernandes (2001). the CL in Faingold mechanisms & acid-related ME, in gamma-aminobutyric Randall receptors by DK, adenosine Naritoku and histamine HJ, by Feng 163 seizures neurology 93 audiogenic Experimental America of colliculus. of transporter. 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Data may be preliminary. 1rcpo.I.Sal xrsini hns ase vr el eel h neato ihtremajor three with interaction the reveals cells ovary 62 histamine hamster neurochemistry pig of Chinese Guinea Journal in (1994). pathways. expression JC Schwartz transduction Stable & signal M, era II. Ruat the J, in receptor. Tardivel-Lacombe neuroscience JM, H1 for Arrang E, transcriptomics Traiffort spatial R, of Leurs 358 promise Science The typing. (2017). cell S molecular Linnarsson of & LE, Borm Bioorganic E, evaluation. Lein pharmacological and Synthesis 26 chemistry ligands. medicinal receptor & H(3) histamine Potent of - journal derivatives official Cardiopul- : Extracorporeal 14 toxicology (2018). Toxicology G medical Medical Erkonen of of & Journal College M, American Ingestion. Virk the Diphenhydramine J, After Thomas S, Resuscitation Greene monary K, Meulmester S, 12 Labarinas discovery Drug reviews Nature development. and 20 Seizure L drugs. antiepileptic new of 102 development physiology and of Journal The tissue. L nervous in Histamine (1943). Epilepsy H mice. Kwiatkowski KA immature in Michelsen neuroprotection FR, and susceptibility Lopez-Picon 90 seizure Laur´en in research HB, receptor N, 1 consequent Jalava histamine and of M, Involvement epilepticus Lintunen status TK, to Kukko-Lukjanov susceptibility age-dependent 100 show research substantia Epilepsy mice rat damage. out the neuronal knock in receptor cells 1 stamine GABAergic 320 letters Gr excites Neuroscience TK, Histamine vitro. Kukko-Lukjanov (2002). in area RE tegmental Brown ventral & and nigra HL, Haas methodologies TM, 18 complementary Korotkova Neuroscience with optogenetics reviews of Nature Integration neuroscience. (2017). K systems Deisseroth in & A, Adhikari M CK, 69 & Kim Neuroscience BE, vitro. Jones in histamine A, by 305 Pegna excited letters P, Neuroscience Fort mouse. M A, the Sawada Khateb of T, Morimoto-Ishizuka cells T, microglial 28 Kawamura cultured E&B epilepsy: Y, by : of Yamamoto in production behavior M, Efficacy BF2.649) & Niimi (2013). tiprolisant; Epilepsy Y, as E model. Katoh known photosensitivity Hirsch human (formerly & the pitolisant JC, in antagonist Schwartz effects (H3R) P, dose-dependent receptor Masnou 3 P, Cerebral histamine of Genton the Society D, International Parain the Trenit´e of D, journal Kasteleijn-Nolst official 19 endothelial : Metabolism cerebral metabolism in and and dexamethasone Flow flow by Blood blood levels Jo´o F mRNA cerebral PO, receptor of H2 Journal Couraud and cells. M, H1 of Lintunen down-regulation KS, and synthesis Eriksson Sallm´en T, amygdaloid-kindled K, in mechanisms Karlstedt 30 Histaminergic research (1998). Epilepsy M 33 Fukunaga rats. (Print) & in nurse H, seizures school Kakinoki K, NASN Ishizawa Modalities. C, Treatment Kamei and Disorders 73 Epilepsy research (2018). Epilepsy J rats. Kaeberle in JH protection Luo S, seizure Wang postictal YY, attenuates Zhu DC, E2-region Wu ZB, Zhuge CL, Jin L ˙ esaD aeaM aeo ,Mglk ,Ltc ,KrzT Karcz G, Latacz S, Mogilski S, Hagenow M, Kaleta D, La˙zewska shrW ltar ,Tya E cmd 21) e vne o nieietcdu discovery drug anti-epileptic for avenues New discovery (2013). D the Schmidt in & used RE, epilepsy Twyman and H, seizures Klitgaard of W, ¨ models oscher animal current of review Critical (2011). W ¨ oscher : 8-15. na ,Lnue ,Lu´nH,McesnK,Pnl P Panula KA, Michelsen Laur´en HB, M, Lintunen M, ¨ onman : 2573-2585. : 321-330. : : 187-194. 64-69. : 80-92. hehlrM(95.Coiegcncesbslsnuosare neurons basalis nucleus Cholinergic (1995). 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(2003). and lobe L Tuomisto epilepticus temporal & status of IS, Biases Midzyanovskaya during models Function neurotransmitters rat acid two Receptor L amino in & H(3) and epileptogenesis J, acetylcholine subsequent Histamine Klein hippocampal W, of levels Theilmann (2020). cellular C, BA Brandt psychiatry. Grueter S, Biological Meller & Accumbens. of Nucleus CA, Journal the The Grueter in 30 Gain neurons. JC, Neuroscience Excitatory preoptic body Becker for of influences Society KM, populations Histamine the distinct Manz of (2010). on journal receptors IV official Tabarean H3 the and & : H1 J, neuroscience at Klaus acting Y, by Ghochani 55 temperature M, A pharmacology Sanchez-Alavez inhibits Huvar Molecular EG, J, directly receptor. Lundius Pyati H3 mepyramine X, histamine Antihistamine human Jiang the SJ, 54 of Wilson Neuropharmacology (2008). expression BL, H Roland neurons. TW, Zhang ganglion Lovenberg & cervical G, superior histaminergic Zhang rat limbic depolarizes C, the 639. in and Wang changes channel X, Transient 20 KCNQ/M Zhang disease (2005). of B, Neurobiology P Liu Panula seizures. on acid-induced & seizures kainic K, kindled Zhejiang systemic Karlstedt of transauricular after Journal T, chronic system = of Sallmen ban xue [Effect M, Yi Lintunen bao (2006). xue Z xue 35 Chen da sciences Zhejiang & Medical WX, rats]. rats. University in Zhou in retention YY, memory kindling Zhu test passive-avoidance LY, transauricular Liu chronic Q, by Li induced deficits 26 memory LY Sinica spatial Liu pharmacologica LX, improves Acta Yang and ZB, Zhu-Ge 53 seizures LS, Ca(2+)-dependent science against Xu on visual CL, histamine Jin & of Q, ophthalmology Li Effect Investigative (2012). cells. 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No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. cnie H efr 21) h itmn 4rcpo n h eta n eihrlnrossystem: nervous 106 peripheral Neuropharmacology and central literature. the the and of H4-receptor histamine analysis The critical lessons (2016). A R 42 system: Seifert histaminergic reviews & the biobehavioral EH, by Schneider and behavior Neuroscience of 87 Modulation mice. Neurosurgery H(2)R-deficient (2014). R Control? H(1)R-and Seifert from Seizure & in D, Tract Neumann EH, Mammillothalamic Schneider the N of Blom Modulation P, injury. for Boon Role nerve 602-610. GL, noradrener- Wagner A after AJ, in Epilepsy: mice Colon pathway in knockout BR, ERK/CREB Plantinga receptor of F, Activation H4 Schaper in (2018). phenotype N hypernociceptive Galeotti 128 to & Neuropharmacology contributes E, neurons Masini 114 Neuropharmacology T, gic functions. Mello histamine neuronal MD, of central phenotype Sanna Behavioural on Focus (2017). N mice: Galeotti knockout & E, receptor Masini H(4) pathway. RL, locus Thurmond the inhibitory C, Ghelardini in noradrenergic MD, stimulation Sanna coeruleospinal receptor 868 H(4) the pharmacology Histamine promoting of (2020). by journal N pain European Galeotti neuropathic & attenuates E, (2012). Masini coeruleus Wistar V, L Borgonetti and Tuomisto WAG/Rij MD, & in Sanna increase AS, histamine 101 Bazyan regional research brain GD, Epilepsy and Kuznetsova rats. modifications IS, behavioral Midzyanovskaya induced LM, Metoprine Birioukova imidazopropanol. IS, of Samotaeva carbamates 23 N-substituted letters to chemistry belonging medicinal ligands & receptor Kie´c-KononowiczBioorganic H3 M, K histamine Shafiullah of D, properties Subramanian M, sant Wiecek 77 S, chemistry Shehab medicinal B, Sadek of journal European moieties. A antiepileptic 279. Adem incorporating M, Walter ligands L, receptor Weizel rats. D, H3 adult Subramanian JS, male Schwed in B, DL77 Sadek antagonist isomeric receptor of H3 effects histamine non-imidazole Anticonvulsant 106 Anticonvulsant the Neuropharmacology for of (2016). Kie´c-Kononowiczc (2016). target & properties K M, La˙zewska H D, 10 potential procognitive Shafiullah Stark therapy D, and a Subramanian and & A, as development Saad M, design, receptor B, Walter Sadek Drug H3 L, antagonists. Histamine Weizel receptor JS, H(3) (2016). Schwed histamine H A, nonimidazole 312 Stark Saad research B, & brain Sadek F, Behavioural Jalal diseases. neuropsychiatric A, in Sadeq symptoms A, cognitive design, Saad Drug B, rats. Sadek adult male in T 10 models Karcz seizure therapy A, different and Olejarz in development K, activity anticonvulsant Kuder with G, antagonists Latacz D 25 receptor La˙zewska A, pharmacology H, Saad Behavioural Stark B, antagonists. 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Data may be preliminary. ntomuesris rlmnr nig.Iflmainrsac ffiiljunlo h uoenHistamine behaviour European 1 the seizure Suppl of and 52 journal turnover official al] histamine : and [et research Brain barriers, Society Inflammation (2003). findings. management Research J preliminary burden, Tarhanen strains: & Disease mouse two P, Asia: in Freeman in G, Sturman Epilepsy L, (2019). Tuomisto A pig 1 Dash guinea Suppl & The 60 B, Epilepsia (1995). Lee challenges. P, M Kwan Ruat E, & Trinka counterpart. 211 human JC, communications its of Schwartz research localization biophysical chromosomal E, and and expression Souil Biochemical tissue cloning, J, gene Tardivel-Lacombe receptor: H2 ML, histamine Vizuete 62 E, K pharmacology Ngo Traiffort H2 Molecular C, via receptors. Weber cells H(3) AD, Purkinje histamine Laposky cerebellar lacking M, rat mice Koehl excites C, Histamine Dugovic (2000). H, Toyota JJ 36 Wang research & Neuroscience CC, vitro. Zuo in HZ, structures. receptors Li brain YQ, in Wen concentrations L, acid Tian amino and 58 J test Walkowiak PR maze P, : Morris of water reports Maciejak in Group Sk´orzewskaPharmacological A, behavior the K, rat on in Blecharz-Klin seizures Ligands A, kindled Receptor Piechal H3 J, Histamine the Szyndler 25 on (2018). chemistry medicinal cimetidine K Current Kiec-Kononowicz of Derivatives. mice. & Influence (Homo)piperazine K, in Kuder (2006). seizures K, SJ pentetrazole-induced Szczepanska Czuczwar 58 against PR & drugs : M, antiepileptic reports Wielosz conventional Pharmacological K, of Swiader 14 activity Neuropsychopharmacology J, anticonvulsant anticonvulsant of Porebiak the College MJ, on European ketotifen Swiader neuropsychopharma- the and European of antazoline journal mice. the of the in of Influence electroshock : maximal duration cology (2004). against the SJ 42 antiepileptics conventional development Czuczwar on of & & antihistamine activity Brain M, of Wielosz meta-analysis. effects M, and European The review Swiader the systematic (2020). a of A with journal study Matsui center official & 103-112. single H, A : Nariai seizure: research Y, febrile Okubo Inflammation 2 R, Suppl Sugitate epilepsy. 50 al] (epilepsy- lobe EL [et the temporal Society in Research seizures of potentiate Histamine H1-antagonists model Histamine mouse histamine (2001). L in like) Quinn firing & spontaneous P, Freeman of G, mechanism Sturman The 124 (2001). research HL brain Haas effects Behavioural & anticonvulsant RE, neurons. and Brown synthesis, KS, Eriksson Design, 35 DR, chemistry moiety. (2020). Stevens medicinal triazole X containing and Deng agonists inhibition & antagonists/inverse enzyme N, toxicology receptor of Zhou H(3) & Journal D, histamine pharmacology Guo nonimidazole clinical Y, of Zhang evaluation & R, of Basic Yan model M, mechanisms. kindled Song lamotrigine-resistant resistance a drug of of Characterization evaluation (2014). 115 M mice: Mehndiratta in and & epilepsy histamine KK, by Pillai excitability E, hippocampal of Singh increase Long-term 36 al] (1997). Neuropharmacology [et HL AMP. Society Haas cyclic & Research RE, Histamine Brown European O, the Selbach chemical-induced of mouse journal two in official 2 H2-agonist, histamine Suppl : a research 50 amthamine, Inflammation of Effect models. (2001). seizure G Sturman & N, Seeley : 373-378. : S82-83. : : : 7-21. 75-82. 131-134. : : S27-28. 1539-1548. : 105-112. : 61-66. : S80-81. 17 : : 1310-1321. 570-577. : tal. et , 1609-1626. : 389-397. 20) eairlcaatrzto of characterization Behavioral (2002). : 307-318. tal. et , 20) ffc of Effect (2006). : Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ad ,Dotoamd ,PuhsenMjrhnF eehiS(00.Bthsie prevents Betahistine, pentylenetetrazole. (2020). by S induced 105 Beheshti neurodegeneration E&B & and : F, behavior comorbidities & behavioral Majarshin Epilepsy 132 the Pourhossein research ameliorates brain M, histaminergic Molecular kindling, of research Doostmohammadi Role Brain A, (2004). mice. H1 K EL Yazdi Nakano histamine in & seizures a epileptic YL, with of Murashima development associated Y, in Watanabe spasms neurons Y, Infantile Nakagawa K, Tanaka (1998). I, Yawata Y Kobayashi & 29 Y, Neuropediatrics Harada antagonist. A, Ochi X 5 A, Zhang Commun arterial Yasuhara W, Nat in Hou mechanisms. involved J, histamine-independent nucleus Ma by W, injury tract Hu ischaemic solitary X, histamin- the Zhang a H, for to Yan Evidence nucleus 5. (2017). reports tuberomammillary H Physiological Waki ventral & regulation. the M, pressure 32 Maeda from Neuroscience A, input for Kohsaka Society M, ergic Takagishi the SS, The of H Gouraud activation. journal K, Kawasaki Yamanaka MAPK official C, PKC-dependent the mediating Seo : by neuroscience B, depression of synaptic Lee Journal official long-term Y, cerebellar : Kim for research D, required 49 Inflammation al] Lee [et cells. Y, Society endothelial Yamamoto Research microvascular Histamine T brain European Watanabe rat the K, of in Yanai rats. journal activity E, infant induced Sakurai and in A, seizures protein Kuramasu on seizures boxylase E, antihistamines the Sakurai of promotes J, effect Yamakami olopatadine, The 35 not bulletin (2012). but pharmaceutical T & ketotifen, Kanda Biological & electroshocks: T, increasing-current Tamura by 107 F, Takizawa Neuron F Tracers. K, Zhao Anterograde Yamada GD, Trans-synaptic Horwitz in KT, Advances Beier Recent MH, and Luo Mapping TC, CL Holmes Jin X, Xu S, rats. Wang Sprague-Dawley 32 in Q, disease acquisition Fang amygdaloid-kindling of electrical Neurobiology CY, facilitates Yu nucleus tuberomammillary ZB, the 33 Zhu-Ge bulletin J Neuroscience DC, Wang Epilepsy. Toward ZJ, Wu of Lin development: Mechanism N, drug and He Potential, antiepileptic T, Pathogenic and Su Alteration, L- research LM, epilepsy precursor Yan F, for 201 histamine Wei therapeutics update the & An of Pharmacology action therapy. (2019). 204 circuit Z Biphasic letters precise Chen Neuroscience (1996). & epilepsy. Y, Y of Wang model Koshino kindling & rat M, the Nakamura in epileptic J, histidine H(2)-histamine and Shiraishi (2002). mania Y, N secondary Wada Bergemann long-standing & with C, 35 reactions Mundt Pharmacopsychiatry CNS K, seizures. adverse Sartor induced K, induced Diebold (famotidine) acoustically D, antagonist Roesch-Ely of RW, modulation Einsiedel 1148 Histaminergic von research Brain (2007). rats. histamine L in Tuomisto the behavior 38 & of running research AB, long-term effects experimental Shatskova and and Differential LV, clinical plasticity Vinogradova Alcoholism, paired-pulse excitability, (2014). rats. cell DD alcohol-exposed granule prenatal Savage dentate in on & potentiation methimepip DA, agonist Hamilton receptor MJ, H(3) Rosenberg RK, Varaschin M 39 J, Pitsch Subunit CK, Channel Rummel KMJ, Loo van : 3175-3187. α 2 δ sRgltdb al rwhRsos n aiiae plpoeei.JNeurosci J Epileptogenesis. Facilitates and 1 Response Growth Early by Regulated Is 4 : 151-156. : 320-321. : : 106956. 152-154. : le A ibe F atnzCae E Martinez-Chavez AF, Bikbaev JA, uller ¨ 693-697. : tal. et , 198-204. tal. et , 18 21) o hne ee n plpy Functional Epilepsy: and Genes Channel Ion (2017). 21) itmn 3rcposagaaecerebral aggravate receptors H3 Histamine (2014). : tal. et , tal. et , 77-93. tal. et , : 231-235. 21) a iaeihbtr rti is protein inhibitory kinase Raf (2012). 22) ia etr o erlCircuit Neural for Vectors Viral (2020). 20) o-rqec tmlto of stimulation Low-frequency (2008). : : 205-208. tal. et , 3334-3334. : 14254-14264. 20) -itdn decar- L-Histidine (2000). : tal. et , 1029-1047. : 455-477. 21) Calcium (2019). : 1902-1911. : 13-17. Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. n eaiu nartmdl ri,bhvo,adimnt 76 immunity and pathology behavior, Parkinson-like Brain, X of model. Meng progression rat W, the a Li prevents of in and J, behaviour Journal Wang and microglia Q, pro-inflammatory regulation. Fang inhibits JR, JNJ7777120 estrogenic Homberg and P, mechanisms Zhou H2 responses ionic and excitatory Histamine-induced H1 neurons: (2007). histamine DW 98 hypothalamic of Pfaff neurophysiology & for 96 functions ventromedial LM, neurophysiology Target Kow Opposite mouse Q, of Therapeutic Zhang Journal (2006). in N, Potential Devidze FM reticulata. AW, A pars Lee Zhou J, nigra & Receptors: Zhou substantia MS, 5-HT3 in LeDoux receptor Y, H3 (2018). Zhao and H receptors JJ, Huo Xu & FW, X, Zhou Li 16 S, neuropharmacology Chen Current Y, pharmacology Epilepsy. of Lin journal = H, British Zhao ban rats. brain the in xue of underlying neurons mechanisms nucleus Yi effect Postsynaptic vestibular the (2013). bao medial JJ Wang 170 on of xue & histamine [Mechanisms JN, of xue Zhu action SY, Peng (2004). da excitatory QX, Zhuang Z Zhejiang L, Yu Chen XY, 33 & Zhang pentylenetetrazole]. sciences MH, Zhejiang Medical by University Zhao of induced Zhejiang WW, Journal of epilepsy by Hu = Journal chronic induced CL, ban impairment on Jin xue memory HQ, histamine Yi on Shen bao histamine LS, xue endogenous Zhang xue of da [Effects on 35 Zhejiang sciences histamine (2006). Medical endogenous rats]. Q University of Li in Effects & epilepsy (2003). YY, pentylenetetrazole-kindled K 69 Ma Yanai Pharmacology & LS, rats. EQ, Zhang Wei in WW, kindling pentylenetetrazole-induced Hu of YW, development Huang journal development seizure Z, seizure medical Chen on Chinese LS, thioperamide of rats. Zhang Effects in (2013). epilepsy W MP pentylenetetrazole-kindling Ding Zhang by & 126 induced J, XY, impairment Hu Chen memory GF, Chen and R, 482 JF, pharmacology Chen Leurs LS, of Zhang journal K, of European Ren Journal rats. = in Z, ban seizures xue pentylenetetrazole-kindled Chen Yi L, bao xue Zhang impairment xue memory da ameliorating 46 histamine Zhejiang sciences of [Mechanisms Medical rats]. for University (2017). in pathway Zhejiang X epilepsy Hu therapeutic & pentylenetetrazole-kindling potential X, by He a induced J, Chen channels: G, Chen K+ L, Neuronal Zhang of 83 SUMOylation Neuron SUDEP? (2014). 58 and LL Headache epilepsy Isom Migraine. & and Y, Histamine Yuan (2018). thioperamide seizures. SD H(3)-antagonist Silberstein kindled the & amygdaloid of H, on Yuan effect substantial betahistine of H(3)-antagonist/H(1)-agonist Lack 40 mixed research non-selective (2000). Epilepsy antag- N the H1 217 Tsuru of histamine letters & acting Neuroscience and E, Centrally rats. Noguchi (1996). in M, T kindling Yoshida Watanabe amygdala & of development K, of the Onodera promote K, effect 15 onists Iinuma Proconvulsant pharmacology M, electroen- clinical (1993). Sato monitoring and H, K with Yokoyama experimental d-chlorpheniramine Onodera in of & use findings the E, and by Sakurai Methods : confirmed cephalography. in T, antagonist, international H1 Watanabe overdose Pediatrics histamine K, Ketotifen a Yanai ketotifen, retardation. K, (2012). Iinuma mental S 54 H, Society mild Kimura Yokoyama Pediatric & and Japan K, epilepsy the Iinuma of of journal K, development official Haginoya with M, associated Uematsu infancy M, Hirose H, Yokoyama : : 156-169. 95-100. : : 3143-3152. 141-145. : 630-634. : 996-998. : : 1-6. 29-36. : 963. : 201-204. 19 tal. et , tal. et , : 61-73. 21) itmn- eetrantagonist receptor Histamine-4 (2019). 20) ffcso lbnrpton clobenpropit of Effects (2003). : 184-193. : : 169-175. : 183-188. 27-32. : 194-196. : 1581-1591. Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. 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International Figure seizures. febrile of characteristics legend clinical Figure and 5 antagonists medicine general H1 neurobiology of Histamine Molecular journal Receptors. (2012). H2 MA and Zolaly H1 Postsynaptic JJ via Wang Neurons WH, Yung 55 Receptor-Expressing B, D2 nuclear Li 21 and vestibular XJ, Neuro-Signals superior Lu D1 rat HT, vitro. excites Xu in Histamine QX, receptors Zhuang (2013). H2 JJ and Wang H1 & postsynaptic JN, Zhu via GY, neurons Wu YH, Wu QX, Zhuang : 8059-8070. : 277-281. 20 tal. et , 21) itmn xie titlDopamine Striatal Excites Histamine (2018). : 174-183. Posted on Authorea 30 Dec 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160937136.67710116/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. histaminergic-signaling-neural-excitability-and-epilepsy table3.pdf file Hosted histaminergic-signaling-neural-excitability-and-epilepsy table2.pdf file Hosted histaminergic-signaling-neural-excitability-and-epilepsy table1.pdf file Hosted vial at available at available at available https://authorea.com/users/386393/articles/501803-central- https://authorea.com/users/386393/articles/501803-central- https://authorea.com/users/386393/articles/501803-central- 21