DOCSLIB.ORG

Review Mechanisms of the Antinociceptive Action of Gabapentin

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Review Mechanisms of the Antinociceptive Action of Gabapentin J Pharmacol Sci 100, 471 – 486 (2006) Journal of Pharmacological Sciences ©2006 The Japanese Pharmacological Society Review Mechanisms of the Antinociceptive Action of Gabapentin Jen-Kun Cheng1,2,3 and Lih-Chu Chiou1,4,* 1Institute and 4Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan 2Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan 3Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan Received October 12, 2005 Abstract. Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABAB receptors consisting of GABAB1a and GABAB2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K+ channels, activating hyperpolarization-activated cation channels, and modulating Ca2+ current by selectively binding 3 2+ to the specific binding site of [ H]gabapentin, the α2δ subunit of voltage-dependent Ca channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive 2+ action mechanisms of gabapentin and suggest that the α2δ subunit of spinal N-type Ca channels is very likely the analgesic action target of gabapentin. Keywords: gabapentin, GABAB receptor, NMDA receptor, KATP channel, 2+ α2δ subunit of Ca channels 1. Introduction actively studied. Several hypothesis were raised, which have been summarized in the comprehensive review of Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid Taylor et al. in 1998 (1). The cellular action mechanisms (Neurontin)®, was originally developed as a chemical of gabapentin were also recently reveiwed (7 – 9). analogue of γ-aminobutyric acid (GABA) (Fig. 1) to Different mechansims might be involved in the different reduce the spinal reflex for the treatment of spasticity actions of gabapentin (10). The clinical uses of and was found to have anticonvulsant activity in various gabapentin in the management of chronic neuropathic seizure models (1). In addition, it also displays anti- pain have been previoulsy reviewed (11, 12). In this nociceptive activity in various animal pain models. review, we summarized and discussed the recent Clinically, gabapentin is indicated as an add-on medica- progresses in the studies investigating the antinocicep- tion for the treatment of partial seizures (2) and neuro- pathic pain (3). It was also claimed to be beneficial in several other clinical disorders such as anxiety (4), bipolar disorder (5), and hot flashes (6). The possible mechanisms or targets involved in the multiple therapeutic actions of gabapentin have been *Corresponding author. [email protected] Published online in J-STAGE: February 11, 2006 DOI: 10.1254/jphs.CR0050020 Fig. 1. Chemical structures of γ-aminobutyric acid (GABA) and Invited article gabapentin. 471 472 J-K Cheng and L-C Chiou tive action machanisms of gabapentin to elucidate the Table 1. Antinociceptive effects of gabapentin in various animal most likely analgesic action target(s) of gabapentin. pain models Pain model Dose (route) Reference 2. Analgesic effects of gabapentin Gabapentin ineffective 2-1. Animal studies Acute nociception After gabapentin was found to have an analgesic Hot plate test 0.1 – 100 nmol (i.t.) 168 effect in patients with intractable neuropathic pain (13), 10 – 100 mg/kg (i.p.) 168 its antinociceptive effects had been reported in several Tail-flick test 200 µg (i.t.) 15 animal pain models, including the phase 2, but not phase 30 – 300 mg/kg (i.p.) 24 1, of formalin inflammatory (14 – 19), neuropathic Paw pressure test 30 – 300 mg/kg (s.c.) 19 (17, 20 – 26), postoperative (27, 28), lumbar adhesive Plantar thermal test 30 – 300 mg/kg (s.c.) 19 arachnoiditis (29), and cancer-induced bone (30) pain 10 – 300 µg (i.t.) 14 models (Table 1). It seems that gabapentin is effective Warm water tail 100 mg/kg (i.p.) 17 in inflammatory- and tissue-injury induced pain models withdrawal test but not in acute physiological pain models (14, 17, 19) Gabapentin effective (Table 1). Gabapentin is effective when given systemically (10 – Inflammatory pain 300 mg/kg) or intrathecally (10 – 300 µg) (Table 1). Formalin test (phase 2) 100 mg/kg (i.p.) 17 However, it seems that much higher efficacy can be 10 – 300 mg/kg (s.c.) 19 achieved for gabapentin via intrathecal administration. 6–200µg (i.t.) 15 In the postoperative pain model, only 19% of the 10 – 300 µg (i.t.) 14 maximal possible antiallodynic effect was observed at 6–600µg (local) 16 the highest tested dose of gabapentin when it was given Carrageenan-induced 10 – 100 mg/kg (s.c.) 19 intraperitoneally (31). However, intrathecal gabapentin 1–100µg (i.t.) 19 could produce up to 90% – 100% the maximal possible Freund’s complete 30 – 250 mg/kg (s.c.) 21 antiallodynic effect in the same model (28). Similar adjuvant test findings were also reported in certain neuropathic pain Neuropathic pain models such as partial sciatic nerve ligation (21) and Spinal nerve ligation 34 mg/kg (i.p.) a 24 chronic constriction injury (25) models. Takasaki et al. 10 – 100 mg/kg (i.p.) 17 (32) reported that gabapentin was effective when given 10 – 300 µg (i.t.) 26 orally and intrathecally, but not intraventricularlly, intra- Partial sciatic nerve ligation 10 – 250 mg/kg (s.c.) 21 cisternally, or intraplantarlly in relieving the nociceptive 10 – 300 µg (i.t.) 21 behaviors induced by transdermal infection with herpes Chronic constriction injury 103 mg/kg (i.p.)a 24 simplex virus. It seems that the spinal cord is an impor- 30 – 300 mg/kg (i.p.) 25 tant site for the systemic analgesic action of gabapentin. 1–4µmol (i.t.) 25 However, since gabapentin is also effective in the Diabetic neuropathy 10 – 100 mg/kg (p.o.) 22 management of migraine and trigeminal neuralgia (see 1–100µg (i.t.) 22 section 2-2), the contribution of the supraspinal site to Postherpetic neuralgia 30 – 60 mg/kg (i.p.) 23 the systemic analgesic action of gabapentin cannot be 10 – 30 µg (i.t.) 23 ruled out. Trigeminal neuralgia 30 – 50 mg/kg (i.p.) 20 2-2. Clinical studies Postoperative pain 3 – 30 mg/kg (s.c.) 27 Clinically, gabapentin has been reported to be effec- 10 – 100 µg (i.t.) 28 tive in the following pain status, including reflex Cancer-induced bone pain 30 mg/kg (s.c.) 30 sympathetic dystrophy (33), trigeminal neuralgia (34), postherpetic neuralgia (35, 36), diabetic neuropathy (36, Lumbar adhesive 60 nmol (i.t.) 29 arachnoiditis pain 37), migraine (38), acute pain in herpes zoster infection a (39), and other neuropathic pain status (40, 41) : ED50 (Table 2). Gabapentin is also effective in the postopera- tive pain management in different surgeries such as breast (42, 43), hysterectomy (44, 45), cholecystectomy (46), spinal (47), and knee (48) surgeries (Table 2). The Antinociceptive Mechanisms of Gabapentin 473 Table 2. Clinical studies in the analgesic actions of gabapentin Pain status Dosage Patient No. Side effects Reference Neuropathic pain Diabetic neuropathy 900 – 3600 mg/day 165 dizziness 37 somnolence Diabetic neuropathy a 900 – 3200 mg/day 35 sedation 36 dry mouth Lyme borreliosis (late stage) 500 – 1200 mg/day 10 40 Postherpetic neuralgia up to 3600 mg/day 229 somnolence 35 dizziness ataxia Postherpetic neuralgia a 900 – 3200 mg/day 22 sedation 36 dry mouth Trigeminal neuralgia 2 34 Postoperative pain a Radical mastectomy 1200 mg (pre-operative) 70 42 Breast cancer surgery 1200 mg/day 75 43 Hysterectomy 1200 mg (initial) 80 44 600 mg (maitaining) Laparoscopic cholecystectomy 300 mg (pre-operative) 459 sedation 46 nausea vomiting Spinal surgery 1200 mg (pre-operative) 50 47 Knee ligament repair 1200 mg (pre-operative) 40 48 Herpes zoster (acute stage) 900 mg 26 39 Migraine prophylaxis 400 – 1200 mg/day 63 somnolence 38 dizziness tremor fatigue ataxia a: reducing opioids comsumption opioid consumption was found to be reduced in several 4. Mechanisms of actions of gabapentin pain states when gabapentin was co-administered clini- cally (Table 2). On the other hand, gabapentin might 4-1. GABAergic system also be helpful in reducing the dependence and tolerance 4-1-1. GABAA receptors of opioids, as suggested by animal studies (49, 50). It Although being developed as a brain penetrant seems that gabapentin is relatively a pretty safe drug in analogue of GABA, gabapentin showed little affinity at terms of its tolerable effective doses with minor un- GABAA or GABAB receptors in the initial binding wanted or side effects clinically (Table 2). study (57). The antinociceptive effects of intrathecal gabapentin in the formalin test (58) and L5/6 nerve 3. Other clinical implications of gabapentin ligation pain model (26) were unaffected by the GABAA-receptor antagonist bicuculline. Therefore, it is In addition to the management of seizures and pain, generally believed that the GABAA receptor is not several clinical indications for gabapentin have also involved in the actions of gabapentin (1). In the post- been implied, including anxiety (4), bipolar depression operative pain model, where the GABAA-receptor (5), hot flashes (6), social phobia (51), essential tremor agonist isoguvacine is ineffective, bicuculline also failed (52), ataxia in cortical cerebellar atrophy (53), hiccup to reverse the antinociceptive effect of intrathecal (54), post cardiac surgery diaphragmatic spasm (55), and gabapentin (59). antipsychotic-induced akathisia (56). 4-1-2. GABAB receptors GABAB receptors are functional in a heterodimeric 474 J-K Cheng and L-C Chiou form consisting of GABAB1 and GABAB2 subunits (60).
Load more

Recommended publications
  • The CB2 Receptor As a Novel Therapeutic Target for Epilepsy Treatment
    International Journal of Molecular Sciences Review The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment Xiaoyu Ji 1, Yang Zeng 2 and Jie Wu 1,* 1 Brain Function and Disease Laboratory, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China; [email protected] 2 Medical Education Assessment and Research Center, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non- selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB receptors and seizures and emphasize the potential 2 mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia Citation: Ji, X.; Zeng, Y.; Wu, J.
    [Show full text]
  • The Action of a BK Channel Opener
    COMMENTARY The action of a BK channel opener Jianmin Cui Agonists and antagonists of an ion channel are important tools to studies of ischemia and reperfusion in isolated, perfused rat probe the functional role of the channel in specific cells and hearts, Bentzen et al. found that mitochondria BK channel ac- tissues. The effects of the agonist and antagonist on the cellular tivation by NS11021 perfusion reduced tissue damage, decreas- and tissue physiology and pathophysiology can be indications ing infarct size by more than 70% (Bentzen et al., 2009; 2010). A for the ion channel as a drug target for certain diseases. Agonists similar result was observed when studies were performed in and antagonists can also be effective tools for understanding mouse hearts (Soltysinska et al., 2014; Frankenreiter et al., molecular mechanisms for function of the channel. Obviously, to 2018), and NS11021 reduced infarction area in comparison know what a tool does will help a better use of the tool. NS11021 with the BK knockout (Slo1−/−) hearts. NS11021 also increased is a BK channel opener (Bentzen et al., 2007) that has been used survival of isolated ventricular myocytes subjected to metabolic asatooltoprobethefunctionalroleofBKchannelsinvarious inhibition followed by reenergization (Borchert et al., 2013). The tissues and the molecular mechanism of BK channel gating. In cardiac protection effects of NS11021 were suggested to derive this issue of the Journal of General Physiology, Rockman et al. from a beneficial effect on energetics due to enhanced K+ uptake present a comprehensive study of NS11021 modulation of BK via BK channels that resulted in mitochondrial swelling with channels.
    [Show full text]
  • Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy
    International Journal of Molecular Sciences Review Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy Takehiro Kawashiri 1,* , Mizuki Inoue 1, Kohei Mori 1, Daisuke Kobayashi 1, Keisuke Mine 1, Soichiro Ushio 2, Hibiki Kudamatsu 1, Mayako Uchida 3 , Nobuaki Egashira 4 and Takao Shimazoe 1 1 Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; [email protected] (M.I.); [email protected] (K.M.); [email protected] (D.K.); [email protected] (K.M.); [email protected] (H.K.); [email protected] (T.S.) 2 Department of Pharmacy, Okayama University Hospital, Okayama 700-8558, Japan; [email protected] 3 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan; [email protected] 4 Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-92-642-6573 Abstract: Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies.
    [Show full text]
  • Potassium Channel Kcsa
    Potassium Channel KcsA Potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cell functions. Potassium channels function to conduct potassium ions down their electrochemical gradient, doing so both rapidly and selectively. Biologically, these channels act to set or reset the resting potential in many cells. In excitable cells, such asneurons, the delayed counterflow of potassium ions shapes the action potential. By contributing to the regulation of the action potential duration in cardiac muscle, malfunction of potassium channels may cause life-threatening arrhythmias. Potassium channels may also be involved in maintaining vascular tone. www.MedChemExpress.com 1 Potassium Channel Inhibitors, Agonists, Antagonists, Activators & Modulators (+)-KCC2 blocker 1 (3R,5R)-Rosuvastatin Cat. No.: HY-18172A Cat. No.: HY-17504C (+)-KCC2 blocker 1 is a selective K+-Cl- (3R,5R)-Rosuvastatin is the (3R,5R)-enantiomer of cotransporter KCC2 blocker with an IC50 of 0.4 Rosuvastatin. Rosuvastatin is a competitive μM. (+)-KCC2 blocker 1 is a benzyl prolinate and a HMG-CoA reductase inhibitor with an IC50 of 11 enantiomer of KCC2 blocker 1. nM. Rosuvastatin potently blocks human ether-a-go-go related gene (hERG) current with an IC50 of 195 nM. Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 1 mg, 5 mg (3S,5R)-Rosuvastatin (±)-Naringenin Cat. No.: HY-17504D Cat. No.: HY-W011641 (3S,5R)-Rosuvastatin is the (3S,5R)-enantiomer of (±)-Naringenin is a naturally-occurring flavonoid.
    [Show full text]
  • A Correlation Between the in Vitro Drug Toxicity of Drugs to Cell Lines That Express Human P450s and Their Propensity to Cause Liver Injury in Humans
    toxicological sciences 137(1), 189–211 2014 doi:10.1093/toxsci/kft223 Advance Access publication October 1, 2013 A Correlation Between the In Vitro Drug Toxicity of Drugs to Cell Lines That Express Human P450s and Their Propensity to Cause Liver Injury in Humans Frida Gustafsson,*,1 Alison J. Foster,* Sunil Sarda,† Matthew H. Bridgland-Taylor,† and J. Gerry Kenna2 *Global Safety Assessment and †Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom 1To whom correspondence should be addressed at 23S37-69, Molecular Toxicology, Safety Assessment, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Fax: +44(0)1625 513779. E-mail: [email protected]. 2Present address: Safety Science Consultant, Macclesfield, United Kingdom. Received June 25, 2013; accepted September 12, 2013 drugs cause acute or chronic damage to the liver, which results Drug toxicity to T-antigen–immortalized human liver epi- in symptomatic liver injury but not liver failure, and some thelial (THLE) cells stably transfected with plasmid vectors drugs cause asymptomatic abnormalities in serum clinical that encoded human cytochrome P450s 1A2, 2C9, 2C19, 2D6, chemistry (most notably elevated concentrations of the enzyme or 3A4, or an empty plasmid vector (THLE-Null), was investi- gated. An automated screening platform, which included 1% alanine aminotransferase (ALT), which is released from dam- dimethyl sulfoxide (DMSO) vehicle, 2.7% bovine serum in the aged hepatocytes). DILI is an important cause of terminated culture medium, and assessed 3-(4,5-dimethylthiazol-2-yl)-5-(3- development or failed registration of otherwise promising new carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium reduc- therapies, of withdrawal of licensed drugs, and of cautionary tion, was used to evaluate the cytotoxicity of 103 drugs after 24 h.
    [Show full text]
  • Potassium Channels and Their Potential Roles in Substance Use Disorders
    International Journal of Molecular Sciences Review Potassium Channels and Their Potential Roles in Substance Use Disorders Michael T. McCoy † , Subramaniam Jayanthi † and Jean Lud Cadet * Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD 21224, USA; [email protected] (M.T.M.); [email protected] (S.J.) * Correspondence: [email protected]; Tel.: +1-443-740-2656 † Equal contributions (joint first authors). Abstract: Substance use disorders (SUDs) are ubiquitous throughout the world. However, much re- mains to be done to develop pharmacotherapies that are very efficacious because the focus has been mostly on using dopaminergic agents or opioid agonists. Herein we discuss the potential of using potassium channel activators in SUD treatment because evidence has accumulated to support a role of these channels in the effects of rewarding drugs. Potassium channels regulate neuronal action potential via effects on threshold, burst firing, and firing frequency. They are located in brain regions identified as important for the behavioral responses to rewarding drugs. In addition, their ex- pression profiles are influenced by administration of rewarding substances. Genetic studies have also implicated variants in genes that encode potassium channels. Importantly, administration of potassium agonists have been shown to reduce alcohol intake and to augment the behavioral effects of opioid drugs. Potassium channel expression is also increased in animals with reduced intake of methamphetamine. Together, these results support the idea of further investing in studies that focus on elucidating the role of potassium channels as targets for therapeutic interventions against SUDs. Keywords: alcohol; cocaine; methamphetamine; opioids; pharmacotherapy Citation: McCoy, M.T.; Jayanthi, S.; Cadet, J.L.
    [Show full text]
  • FDA Listing of Established Pharmacologic Class Text Phrases January 2021
    FDA Listing of Established Pharmacologic Class Text Phrases January 2021 FDA EPC Text Phrase PLR regulations require that the following statement is included in the Highlights Indications and Usage heading if a drug is a member of an EPC [see 21 CFR 201.57(a)(6)]: “(Drug) is a (FDA EPC Text Phrase) indicated for Active Moiety Name [indication(s)].” For each listed active moiety, the associated FDA EPC text phrase is included in this document. For more information about how FDA determines the EPC Text Phrase, see the 2009 "Determining EPC for Use in the Highlights" guidance and 2013 "Determining EPC for Use in the Highlights" MAPP 7400.13.
    [Show full text]
  • A Way out for Neuropathic Pain?
    REVIEW ARTICLE published: 04 August 2009 MOLECULAR NEUROSCIENCE doi: 10.3389/neuro.02.010.2009 Enhancing M currents: a way out for neuropathic pain? Ivan Rivera-Arconada, Carolina Roza and Jose A. Lopez-Garcia* Departamento de Fisiología, Edifi cio de Medicina, Universidad de Alcala, Madrid, Spain Edited by: Almost three decades ago, the M current was identifi ed and characterized in frog sympathetic Bernard Attali, Tel Aviv University, Israel neurons (Brown and Adams, 1980). The years following this discovery have seen a huge Reviewed by: progress in the understanding of the function and the pharmacology of this current as well as Holger Lerche, Universitätsklinikum Ulm, Germany on the structure of the underlying ion channels. Therapies for a number of syndromes involving Dirk Isbrandt, Zentrum für Molekulare abnormal levels of excitability in neurons are benefi ting from research on M currents. At present, Neurobiologie Hamburg, Germany the potential of M current openers as analgesics for neuropathic pain is under discussion. Here *Correspondence: we offer a critical view of existing data on the involvement of M currents in pain processing. We Jose A. Lopez-Garcia, Departamento believe that enhancement of M currents at the site of injury may become a powerful strategy de Fisiología, Edifi cio de Medicina, Universidad de Alcala, Alcala de to alleviate pain in some peripheral neuropathies. Henares, 28871 Madrid, Spain. Keywords: potassium current, KCNQ, Kv7, pain, analgesia, pain therapy, neuropathy e-mail: [email protected] INTRODUCTION systems and to evaluate their potential as targets for analgesia under Potassium channels constitute a very wide family of ionic channels conditions of neuropathy.
    [Show full text]
  • Pharmacology
    The Ministry of Health of Ukraine Ukrainian Medical Stomatological Academy Viktor M. Bobyrov, Olena M. Vazhnicha, Tetyana O. Devyatkina, Natalia M. Devyatkina PHARMACOLOGY Textbook for English-speaking students of higher education institutions of the Ministry of Health of Ukraine RECTRICRED5th edition, updated Vinnytsia Nova Knyha 2020 UDC 615(075) P56 Recommended by the Ministry of Health of Ukraine as a textbook for students of higher medical educational institutions of the 4th level of accreditation with English as the language of instruction (the letter № 08.01-47/1159 of 02.07.2009 ) Recommended by the Academic Council of the Ukrainian Medical Stomatological Academy as a textbook for foreign students-graduands of Master's degree studying "Medicine" in higher educational institutions of the Ministry of Health of Ukraine (protocol of the meeting of the Academic Council No 11 of 24.06.2020) Reviewers: Kresyun V. I. — Professor of the Department of Pharmacology of Odessa National Medical University, Corresponding member of National Academy of Medical Scienses of Ukraine, Ukraine State Prize lau- reate, Honored Scientist of Ukraine, M.D., Ph.D., Professor. Sheremeta L. M. — Head of the Department of Pharmacology of Ivano-Frankivsk National Medical University, M.D., Ph.D., Professor. Neporada K. S. – Head of the Department of Biological and Bioorganic Chemistry of Ukrainian Medical Stomatological Academy, M.D., Ph.D., Professor. Belyaeva O. M. – Head of the Department of Foreign Languages with Latin Language and medical terminology, Ph.D., Associated professor Authors: Bobyrov V. M. – Professor of the Department of Experimental and Clinical Pharmacology of Ukrainian Medical Stomatological Academy, Ukraine State Prize laureate, Honored Scientist of Ukraine, M.D., Ph.D., Professor.
    [Show full text]
  • KATP Channel Openers Facilitate Glutamate Uptake by Gluts in Rat Primary Cultured Astrocytes
    Neuropsychopharmacology (2008) 33, 1336–1342 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org KATP Channel Openers Facilitate Glutamate Uptake by GluTs in Rat Primary Cultured Astrocytes 1,2 1,2 1 1 1 ,1 Xiu-Lan Sun , Xiao-Ning Zeng , Fang Zhou , Cui-Ping Dai , Jian-Hua Ding and Gang Hu* 1 Laboratory of Neuropharmacology, Department of Anatomy, Histology & Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, P.R. China Increasing evidence, including from our laboratory, has revealed that opening of ATP sensitive potassium channels (KATP channels) plays the neuronal protective roles both in vivo and in vitro. Thus K channel openers (KCOs) have been proposed as potential ATP neuroprotectants. Our previous studies demonstrated that K channels could regulate glutamate uptake activity in PC12 cells as well as ATP in synaptosomes of rats. Since glutamate transporters (GluTs) of astrocytes play crucial roles in glutamate uptake and KATP channels are also expressed in astrocytes, the present study showed whether and how KATP channels regulated the function of GluTs in primary cultured astrocytes. The results showed that nonselective KCO pinacidil, selective mitochondrial KCO diazoxide, novel, and blood–brain barrier permeable KCO iptakalim could enhance glutamate uptake, except for the sarcolemmal KCO P1075. Moreover pinacidil, + diazoxide, and iptakalim reversed the inhibition of glutamate uptake induced by 1-methyl-4-phenylpyridinium (MPP ). These potentiated effects were completely abolished by mitochondrial K blocker 5-hydroxydecanoate. Furthermore, either diazoxide or iptakalim could ATP + inhibit MPP -induced elevation of reactive oxygen species (ROS) and phosphorylation of protein kinases C (PKC). These findings are the first to demonstrate that activation of KATP channel, especially mitochondrial KATP channel, improves the function of GluTs in astrocytes due to reducing ROS production and downregulating PKC phosphorylation.
    [Show full text]
  • Etiology and Pharmacology of Neuropathic Pain
    1521-0081/70/2/315–347$35.00 https://doi.org/10.1124/pr.117.014399 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:315–347, April 2018 Copyright © 2018 by The Author(s) This is an open access article distributed under the CC BY Attribution 4.0 International license. ASSOCIATE EDITOR: LORI L. ISOM Etiology and Pharmacology of Neuropathic Pain Sascha R. A. Alles1 and Peter A. Smith Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada (S.R.A.A.); and Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada (P.A.S.) Abstract. ....................................................................................316 I. Introduction. ..............................................................................317 A. Clinical Presentation and Pharmacotherapy of Neuropathic Pain .........................317 B. Organization of the Spinal Dorsal Horn . ................................................318 1. Lamina I/Marginal Zone. ............................................................319 2. Lamina II/Substantia Gelatinosa .....................................................319 a. Laminar IIo (outer)................................................................319 b. Lamina IIid (inner dorsal) . ......................................................319 c. Lamina IIiv (inner ventral) . ......................................................320 3. Lamina III . ........................................................................320
    [Show full text]
  • Known Bioactive Library: Selleck Bioactive 10Mm, 3.33Mm, 1.11Mm
    Known Bioactive Library: Selleck Bioactive 10mM, 3.33mM, 1.11mM ICCB-L Plate (10mM / 3.33mM / ICCB-L Max Solubility Vendor ID Compound Name Pathway Targets Information CAS Number Form URL 1.11mM) Well in DMSO (mM) Afatinib (BIBW2992) irreversibly inhibits EGFR/HER2 including EGFR(wt), http://www.selleckchem.c Protein Tyrosine EGFR(L858R), EGFR(L858R/T790M) and HER2 with IC50 of 0.5 nM, 0.4 3651 / 3658 / 3665 A03 S1011 Afatinib (BIBW2992) 199 EGFR,HER2 439081-18-2 free base om/products/BIBW2992. Kinase nM, 10 nM and 14 nM, respectively; 100-fold more active against Gefitinib- html resistant L858R-T790M EGFR mutant. Phase 3. http://www.selleckchem.c Deflazacort(Calcort) is a glucocorticoid used as an anti-inflammatory and 3651 / 3658 / 3665 A04 S1888 Deflazacort 199 Others Others 14484-47-0 free base om/products/Deflazacor. immunosuppressant. html http://www.selleckchem.c Irinotecan is a topoisomerase I inhibitor for LoVo cells and HT-29 cells with 3651 / 3658 / 3665 A05 S1198 Irinotecan 17 DNA Damage Topoisomerase 97682-44-5 free base om/products/Irinotecan.ht IC50 of 15.8 μM and 5.17 μM, respectively. ml Enalapril Maleate, the active metabolite of enalapril, competes with http://www.selleckchem.c Endocrinology & 3651 / 3658 / 3665 A06 S1941 Enalapril Maleate 201 RAAS angiotensin I for binding at the angiotensin-converting enzyme, blocking the 76095-16-4 maleate om/products/Enalapril- Hormones conversion of angiotensin I to angiotensin II. maleate(Vasotec).html BX795 is a potent and specific PDK1 inhibitor with IC50 of 6 nM, 140- and 1600-fold more selective for PDK1 than PKA and PKC, respectively.
    [Show full text]