Hindawi BioMed Research International Volume 2018, Article ID 4067597, 12 pages https://doi.org/10.1155/2018/4067597

Review Article Natural Compounds for the Management of Parkinson’s Disease and Attention-Deficit/Hyperactivity Disorder

Juan Carlos Corona

Laboratory of Neurosciences, Hospital Infantil de Mexico´ Federico Gomez,´ Mexico

Correspondence should be addressed to Juan Carlos Corona; [email protected]

Received 28 June 2018; Revised 31 October 2018; Accepted 11 November 2018; Published 22 November 2018

Guest Editor: Francesco Facchiano

Copyright © 2018 Juan Carlos Corona. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder with an unknown aetiology. Te pathogenic mechanisms include oxidative stress, mitochondrial dysfunction, protein dysfunction, infammation, autophagy, apoptosis, and abnormal deposition of �-synuclein. Currently, the existing pharmacological treatments for PD cannot improve fundamentally the degenerative process of dopaminergic neurons and have numerous side efects. On the other hand, attention-defcit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and is characterised by hyperactivity, impulsiv- ity, and inattention. Te aetiology of ADHD remains unknown, although it has been suggested that its pathophysiology involves abnormalities in several brain regions, disturbances of the catecholaminergic pathway, and oxidative stress. Psychostimulants and nonpsychostimulants are the drugs prescribed for the treatment of ADHD; however, they have been associated with increased risk of substance use and have several side efects. Today, there are very few tools available to prevent or to counteract the progression of such neurological disorders. Tus, therapeutic approaches with high efciency and fewer side efects are needed. Tis review presents a brief overview of the two neurological disorders and their current treatments, followed by a discussion of the natural compounds which have been studied as therapeutic agents and the mechanisms underlying the benefcial efects, in particular, the decrease in oxidative stress.

1. Introduction characterised by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and their projections to For many years, natural compounds have provided an ef- the striatum. Tus, the function of the nigrostriatal pathway cient resource for the discovery of potential therapeutic becomes reduced and causes the development of movement agents. Among them, many natural products possess antiox- disorder [1]. Te basic characteristics of PD include tremor, idative, antiapoptotic and anti-infammatory activities. In this rigidity, bradykinesia, and impaired balance; depression is review,wesummarizetheroleofnaturalcompoundsand also present in patients, afecting the quality of life. One their therapeutic use for the management of dopamine- of the pathological features of PD is the presence of Lewy related diseases, divided into part 1 for Parkinson’sdisease and bodies, which are intraneuronal proteinaceous cytoplasmic part 2 for attention-defcit/hyperactivity disorder. In addi- inclusions and include �-synuclein, ubiquitin, and neuro- tion, the current knowledge of the mechanisms underlying flaments found in all afected brain regions [2]. Te the potential benefcial efects of diverse natural compounds pathogenic mechanisms of PD include oxidative stress, capable of counteracting the progression of this type of dis- mitochondrial dysfunction, protein dysfunction, infam- eases is reviewed, as demonstrated by their antioxidative mation, autophagy, and apoptosis [3]. PD occurs 95 % as efects. a sporadic form, while familial forms involve mutations in proteins that include PINK1, DJ-1, PARKIN, FBXO7, and 2. Parkinson’s Disease LRRK2 [4], even though pesticides, chemicals, and metals may increase the risk of developing PD. Currently, the Parkinson’s disease (PD) is the second most common treatment of PD includes drugs such as L-DOPA, which is progressive and chronic neurodegenerative disorder, catalysed primarily by dopa decarboxylase in the brain and is 2 BioMed Research International converted into dopamine, producing its therapeutic efects. iron homeostasis [16]. In low-dose whole-body �-irradiation Another treatment includes anticholinergic drugs that can in the reserpine model of PD, EGb761 was protective by block striatal cholinergic receptors inhibiting the excitability ameliorating the reserpine-induced state of oxidative stress, of cholinergic nerves; it has also been demonstrated that mitochondrial dysfunction, and apoptosis in the brain [15]. they can inhibit dopamine reuptake to enhance the function Te pretreatment with ginkgolide B or bilobalide protected of dopaminergic neurons [5]. At present, there are also SH-SY5Y cells against �-synuclein-induced cell injury and other drugs in Phase III clinical trials. Nevertheless, the apoptosis [17]. Ultimately, the G. biloba extract treatment current drugs used for the PD treatment have some side improved locomotor activity, decreased oxidative damage, efects, limiting their clinical applications [6]. Drugs used maintained the dopamine homeostasis, and inhibited the for the PD treatment and their side efects are shown in development of PD in A53T �-synuclein transgenic mice [18]. Table 1. Tus, the growing interest in alternative therapies for neurodegenerative disorders, including PD, has focused 2.2. Ginseng. Ginseng is a traditional Chinese herb con- on the neuroprotective and antioxidant efects of natural taining more than 30 ginsenosides, the active ingredients products that may provide alternatives, since they can have of ginseng. Ginsenosides Rb1 and Rg1 are regarded as the high efciency and fewer side efects. Natural compounds main compounds responsible for the therapeutic actions used as alternative therapies for the management of PD are of ginseng. Previous studies have shown that, in SN-K-SH shown in Table 2. cells, both ginsenosides Rb1 and Rg1 reversed MPTP-induced cell death [19]. Te protective efect of Rg1 against MPTP- 2.1. Ginkgo biloba. Ginkgo biloba is an ancient tree native to induced apoptosis was attributed to enhancing Bcl-2 and China and has been extensively used in traditional Chinese Bcl-xl expression, reducing Bax and iNOS expression, and medicine to manage symptoms associated with dysfunctions inhibiting activation of caspase-3 [20]. Te ginseng extract oftheheartandlungs.G.bilobausuallycontainsthreeingre- G115 signifcantly blocked tyrosine hydroxylase- (TH-) dients, which include favonoids, terpenoids, and ginkgolic positive cell loss in the SN and reduced the appearance of acid [81]. Ginkgolides well-known plant extracts obtained locomotor dysfunction in two rodent models of PD [21]. from leaves from G. biloba, especially in the preparation Pretreatments of Rg1 or N-acetylcysteine were found to EGb761, which contains ginkgolide B and bilobalide, have protect against MPTP-induced SN neuron loss by preventing emerged as natural therapeutic compounds, in part due to glutathione (GSH) reduction, attenuate the phosphorylations their antioxidant activity. Tese efects have been observed in of JNK and c-Jun, and activate superoxide dismutase (SOD) + the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) [22]. MPP -induced cytotoxicity in SH-SY5Y was inhibited treated mouse model of PD, where chronic ingestion of by water extract of ginseng, as demonstrated by the inhibitory EGb761 prevented MPTP-induced reduction in the dopamin- efect on cell death, overproduction of ROS, elevated Bax/Bcl- ergic nerve endings [9]. In addition, EGb761 administered 2 ratio, release of cytochrome c, and activation of caspase- before or afer MPTP treatment protected against MPTP- 3 expression [23]. It was demonstrated that ginsenosides induced dopaminergic neurotoxicity [10]. Moreover, EGb761 protect by reducing intracellular ROS levels, enhancing attenuated the neurotoxic efect of levodopa in the 6- antioxidant activity, preserving the activity of complex I, sta- hydroxydopamine (6-OHDA) model of PD, indicated that bilising the û Ψm, and increasing intracellular ATP levels. Rg1 levodopa is neurotoxic and that EGb761 may decrease this treatment restored motor functions in MPTP-treated mice toxicity [11]. Te neuroprotective efects of EGb761 were and these behavioural ameliorations were accompanied by demonstrated in the 6-OHDA rat model, as indicated by the restoration of dopaminergic neurons in the SN and striatum reduction in the behavioural defcit in the rat [12]. Paraquat is [24]. Additionally, the ginsenoside Rb1 exhibited a strong a pesticide that has been linked to PD, and it has been demon- ability to disaggregate fbrils and to inhibit the polymerisation strated that EGb761 protects against paraquat-induced apop- of �-synuclein [25]. Rg1 treatment inhibited the activation of tosis of PC12 cells by increasing bcl-2 activation, maintaining microglia and reduced the infltration of CD3+ and T cells of mitochondrial membrane potential (û Ψm)anddecreasing and also protected TH-positive cells in the SN and reduced caspase-3 activation through the mitochondria-dependent the serum concentrations of proinfammatory cytokines pathway [13]. Te neuroprotective efect of EGb761 against TNF�,IFN�,IL-1�,andIL-6inMPTPmousemodels[26]. MPTP neurotoxicity is associated with the blockade of lipid Also, using in vivo and in vitro models of PD, it was demon- peroxidation, reduction of oxidative stress, and attenuation of strated that ginsenoside Rg1 may exert therapeutic efects on MPTP-induced neurodegeneration of the nigrostriatal path- PD via the Wnt/�-catenin signalling pathway [27]. In the way [14]. Also, it was demonstrated in an extensive review that MPTP-probenecid mouse model, the oral treatment with Rg1 EGb761 may exert therapeutic actions in an animal model signifcantly attenuated MPTP-induced mortality, behaviour of PD via the antioxidant efects [82]. Ginkgetin, a natural defects, and loss of dopaminergic neurons. Te protective bifavonoid isolated from leaves of G. biloba, protected efect of Rg1 may be mediated by reducing aberrant �- + against 1-methyl-4-phenylpyridinium ion- (MPP -) induced synuclein-mediated neuroinfammation [28]. Te neurotoxin cell damage in vitro by decreasing the levels of intracellular rotenone is an inhibitor of complex I and has been widely reactive oxygen species (ROS) and by maintaining û Ψm used in vivo and in vitro to model PD. Tus, cotreatment with and also improved the sensorimotor coordination in a mouse ginsenosides Rd and Re inhibited the increased intracellular PD model induced by MPTP, suggesting that the neuro- ROS production and lipid peroxidation accumulation caused protective mechanism of ginkgetin occurs via regulating by rotenone. Besides, the major ginsenosides Rd and Re BioMed Research International 3 suicidality Side efects toxicity, vomiting, dizziness agitation, nervousness, depression arrhythmia, somnolence, nightmares Oedema, hallucinations, insomnia, confusion persistent diarrhoea, constipation, weight loss hypertension, headache, stomach pain, numbness ankle oedema, orthostatic hypotension, constipation unusually fast or irregular heartbeat, increased suicidality Dry mouth, fatigue, dizziness, profound withdrawal efects Abnormal movements, dizziness, nausea, vomiting, dry mouth, Dry mouth, sedation, fatigue, increased sweating, hypertension, Decrease appetite, weight loss, irritability, hypertension, anxiety, Dyskinesia, nausea, sleep disturbances, arterial hypotension, liver Dry mouth, urine retention, hallucinations, dry eyes, constipation, Dry mouth, sweating abnormalities, drowsiness/sedation, increased Nausea, vomiting, insomnia, psychosis, hallucinations, hypotension, blurred vision, loss of memory, and confusion, somnolence, dizziness Anxiety, agitation, insomnia, decrease appetite, weight loss, irritability, decrease appetite, dizziness, drowsiness, insomnia, itching, impotence, Nausea, dyskinesia, hallucinations, sleepiness, sleep attacks, confusion, cortex Table 1: Drugs used in PD and ADHD and their side efects. receptors Mechanism Mechanism Side efects norepinephrine -2A adrenergic receptors in the prefrontal � stimulates dopamine release -2 and aromatic amino acid decarboxylase � Selective norepinephrine reuptake inhibitor Inhibit reuptake of dopamine and norepinephrine Inhibits reuptake of dopamine and norepinephrine Anticholinergics; block acetylcholine in the striatum Tricyclic antidepressants; Inhibit reuptake of dopamine and Is an antagonist of the NMDA type glutamate receptor and also Catechol-O-methyltransferase inhibitors (COMT); Increase CNS Monoamine oxidase B inhibitors (MAO-B); increase the synaptic A precursor to dopamine, combined with carbidopa, which blocks availability of dopamine; safnamide also inhibits glutamate release Agonists of the Dopamine agonists; stimulate the action of dopamine at postsynaptic L-DOPA bioavailability by decreasing peripheral L-DOPA metabolism Selegiline, Rasagiline, Safnamide Entacapone and Tolcapone Drugs for PD [7] L-DOPA and Carbidopa Drugs For ADHD [8] Methylphenidate Pramipexole, Ropinirole, Rotigotine, Apomorphine Trihexyphenidyl and Benztropine Amantadine Amphetamines Atomoxetine Imipramine, Nortriptyline, Amitriptyline, Desipramine Clonidine and Guanfacine 4 BioMed Research International [17] [18] [16] [57] [52] [58] [54] [59] [60] Refs [9–15] [50, 51] [61, 62] [43, 53] [55, 56] [19–28] [41–43] [31–40] [29, 30] [48, 49] [44–47] , m PKD1, ↑ ΔΨ -synuclein catalase ↓� ↑ oxidative stress , maintain ↓ behavioural defcit, � ↓ GHS, -synuclein aggregation, ↑ DNA fragmentation ↓ ↓� complex I activity, GSK-3 ↑ ↑ SOD, ↑ autophagy ↑ lipid peroxidation, JNK ↓ catalase, m ↓ -catenin, ↑ lipid peroxidation, ↓ ROS ΔΨ caspase-3, ↓ BDNF oxidative stress ↓ ↑� oxidative stress, DNA fragmentation malondialdehyde, ↑ ↓ ↓ lipid peroxidation ↓ ERK, ↓ ↓ ↓ ATPase, malondialdehyde B, ↑ iNOS, ↓ � ROS, Wnt-1, ROS, ↓ ↓ CREB, ↑ ↓ caspase-3, ↑ ↓ Antioxidant Antioxidant Antioxidant NF- oxidative stress, catalase, oxidative stress lipid peroxidation, ↓ ↓ ↑ GHS, ↓ Bax, ↓ IL-6, ROS, maintain ↑ ↓ Infammation, cytochrome c release Action mechanism Akt, ↓ ↓ ↓ ↓ ↑ -synuclein, anti-apoptotic bcl-2, , ↑ Infammation, DJ-1, � GPx, GHS, , dopamine levels, ↓ ↑ ↑ GHS, ↓� ↑ ↓ SOD, m bcl-2, ↑ ↑ ↑ IL-1 oxidative stress, ↓ ΔΨ Infammation, ↓ Normalised SOD and catalase mRNAs , ↓ ROS, SOD, � ↓ ↑ SOD, ↑ lipid peroxidation, ↓ GPx, IFN- ↑ serotonin, ↓ ↑ , � Antioxidant, anti-apoptotic, improved mitochondrial function SOD, ↑ TNF- ↓ oxidative stress, ↓ fbrils, anti-apoptotic, maintain Antioxidant, anti-apoptotic, Antioxidant, inhibited toxic efect of levodopa, inhibited MAO activity, Antioxidant, lipid peroxidation, ↓ Table2:EfectsofnaturalcompoundsusedasanalternativetherapyforPD. Rutin EGb761 Luteolin Apigenin Baicalein Quercetin Ginkgetin Bilobalide Troxerutin Hesperidin Kaempferol Compound Isoquercitrin Ginkgolide B and Extract of valerian Valeriana wallichii Ginkgo biloba extract Ginsenosides Rd and Re Ginsenosides Rb1 and Rg1 ifora incarnata Extract of passion fower s Pas Valeriana ofcinalis Valeriana wallichii Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Ginkgo biloba Ginseng Ginkgo biloba Flavonoid Ginseng Source Ginkgo biloba Ginkgo biloba Passifora cincinnataHypericum perforatum Extract of Passifora cincinnata St. John’s wort Antioxidant, anti-apoptotic, BioMed Research International 5 upregulate SOD and aconitase activities, and GSH also of NF-�B, ERK, and JNK and attenuates astrocyte activation 2+ attenuates the depolarisation of û Ψm and restores Ca in MPTP mice [37]. Baicalein inhibits the upregulation levels and moreover prevents apoptosis by modulating Bax of proinfammatory cytokines in the SN and striatum in and Bcl-2 and inhibiting cytochrome c release and caspase- PD mice models [38]. Luteolin also reduces cytotoxicity 3 activation [29]. Additionally, ginsenoside Rd reversed the induced by 6-OHDA and ROS production in neuronal PC12 loss of TH-positive cells in SN in vivo and in vitro PD models, cells by modulating changes in the stress response pathway which may involve its antioxidant efects and mitochondrial [42]. In MPTP-treated mice, luteolin and apigenin protect function preservation [30]. dopaminergic neurons by reducing oxidative damage, neu- roinfammation, and microglial activation and also improve 2.3. Flavonoids. Flavonoids are part of a large group of muscular and locomotor activity [43]. Te favonoids and natural polyphenol phytochemicals with a long history of their metabolites can interact with neuronal receptors and use as therapeutic agents. Baicalin, a favonoid isolated from modulate kinase signalling pathways, transcription factors, Scutellaria baicalensis, is the main metabolite of baicalein. Te and gene and/or protein expression, which control memory neuroprotective efcacy of baicalein has been shown in an in and learning processes in the hippocampus [83]. Naringin vivo model of PD using the neurotoxin 6-OHDA, where the is a favonoid glycoside that is contained abundantly in the protective efects on dopaminergic dysfunction and lipid per- skin of grapefruit and orange and is the origin of their oxidation were seen [31]. Other reports showed that baicalein bitterness. It protects dopaminergic neurons by induction of prevented abnormal behaviour by increasing dopaminergic the activation of mammalian target of rapamycin complex 1 neurons and dopamine and serotonin levels in the striatum (mTORC1) and inhibited microglial activation in the SN of and also inhibited oxidative stress and astroglial response the mouse treated with 6-OHDA [84]. In a rotenone mouse [32]. Luteolin and apigenin are favones with similar struc- model, baicalein prevented the progression of �-synuclein ture;luteolinisfoundincelery,broccoli,parsley,thyme,and accumulation and protected dopaminergic neurons and also olive oil, and apigenin is present in vegetables, several fruits, inhibited the formation of �-synuclein oligomers [39]. It has and herbs. Luteolin protects dopaminergic neurons against been shown that baicalein inhibits �-synuclein aggregates + infammation-induced neurotoxicity by inhibiting microglial and autophagy in rats treated with MPP [40]. Besides, in the activation [41]. Moreover, baicalein exerts protective efects in same model, apigenin ameliorated dopaminergic neuronal vivo and in vitro against 6-OHDA [33]. In addition, baicalein loss and improved behavioural, biochemical, and mitochon- protects cells against the toxicity of a point mutation in �- drial enzyme activities; such efects were associated with synuclein [34]. Baicalein also inhibited the formation of �- the suppression of oxidative stress and neuroinfammation synuclein oligomers and consequently prevents its oligomeri- [53]. Recently, it was demonstrated that quercetin improved sation [35]. Quercetin is the aglycone form of a number mitochondrial biogenesis and induced the activation of of other favonoid glycosides, such as rutin and quercitrin, two major cell survival kinases, PKD1, and Akt and also and is found in citrus fruit, onions, and grains. In the 6- enhanced CREB and BDNF (a CREB target gene) in MN9D OHDA rat model, treatment of quercetin increased levels of cells against 6-OHDA-induced neurotoxicity, and in the antioxidant and striatal dopamine and reduced dopaminergic MitoPark transgenic mouse model of PD, quercetin improved neuronal loss [44]. Kaempferol is a natural favonoid which behavioural defcits and reduced TH cell loss [47]. Troxerutin has been found in grapefruit, and other plant sources. It (also known as vitamin P4) is a natural derivative of the improves motor coordination, raises striatal dopamine and biofavonoid rutin that is present in cofee, cereal grains, tea, its metabolite levels, increases SOD and GSH activity, and and vegetables. Te neuroprotective efects of troxerutin were reduces the content of lipid peroxidation, also preventing the reported in a 6-OHDA rat model to reduce striatal lipid per- loss of TH-positive neurons induced by MPTP [48]. Tere is oxidation, ROS, GFAP, and DNA fragmentation. Meanwhile, also evidence of neuroprotection by kaempferol by autophagy troxerutin was capable of preventing loss of TH-positive in SH-SY5Y cells and primary neurons against rotenone neurons in the SN [54]. Te biofavonoid hesperidin is a toxicity [49]. It has been demonstrated that rutin pro- specifc favonoid glycoside frequently found in oranges and tects dopaminergic neurons against oxidative stress induced lemons. Hesperidin protects against iron-induced oxidative by 6-OHDA [50]. Furthermore, it has been shown that damage and dopamine depletion in Drosophila melanogaster quercetin protects against oxidative stress and increases activ- model of PD [55]. In addition, in 6-OHDA-treated mice, ities of glutathione peroxidase (GPx), SOD, ATPase, AchE, hesperidin protects by reducing oxidative damage, increasing and dopamine depletion in MPTP-treated mice [45]. Te the dopamine levels and also improving the behavioural biofavonoid rutin inhibits 6-OHDA-induced neurotoxicity parameters [56]. in PC12 cells by activation of SOD, catalase, GPx, and total GSH and by inhibition of lipid peroxidation [51]. Moreover, 2.4. Valeriana ofcinalis. Valeriana ofcinalis (Valerian) is in a rotenone model, quercetin has been shown to upregulate a plant with sedative and antispasmodic efect, traditionally mitochondrial complex I activity and increase catalase and used in the treatment of insomnia, anxiety, and restlessness. SOD activity [46]. Mitochondrial dysfunction in SH-SY5Y Te efects of valerian on rotenone-induced cell death in SH- cells and upregulation of DJ-1 protein expression induced SY5Y cells have been demonstrated [85]. Moreover, extract by 6-OHDA is prevented by baicalein [36]. Te favonol of valerian was efective in reducing the toxicity induced by isoquercitrin protects PC12 cells against 6-OHDA-induced rotenone in Drosophila melanogaster, as confrmed by the oxidative stress [52]. Baicalein downregulates the activation normalisation in the expression of SOD and catalase mRNAs, 6 BioMed Research International suggesting that the efects of valerian are, at least in part, is characterised by inattention, impulsivity, and hyperactiv- associated with the antioxidant properties of the plant due ity.TeworldwideprevalenceofADHDinchildrenand to its phenolic and favonoid constituents [57]. Valeriana adolescents is 5.3% [88]; across cultures the prevalence is wallichii, also known as Indian valerian or Tagar-Ganthoda, estimated to range from 5% to 7% [88, 89]. ADHD has belongs to the family Valerianaceae and is considered as an high impact on school performance and causes impairments important Asian counterpart of the European valerian. Tus, in personal, social, or occupational function, leading to valeriana wallichii treatment signifcantly recuperated the isolation, poorer grades, and in adolescence there is increased altered behaviour, striatal dopamine levels, increased GFAP risk of depression, delinquent and antisocial behaviour, expression, and the histopathological changes observed incurring comorbid conditions, and later substance abuse in mice treated with MPTP. Likewise, it ameliorated the [90]. ADHD has been associated with deregulation of the increased levels of ROS, infammatory cytokines and lipid catecholaminergic pathway in the brain [91], although exten- peroxidation and also ameliorated the diminished levels of sive data point to oxidative stress as potential contributor antioxidants [58]. to the pathophysiology in ADHD [92]. Currently, ADHD treatment is pharmacologic and improves the attention, 2.5. Passion Flower. Passion fower, commonly known as reducing distractibility and impulsive behaviour. Pharma- Passifora incarnata (Passiforaceae), contains favonoids, gly- cologic agents used for the treatment of ADHD increase cosides, alkaloids, and phenolic compounds. Also, it has levels of catecholamines in the brain, alleviating ADHD been used for the treatment of anxiety, insomnia, epilepsy, symptoms, and can be divided into two: psychostimulants muscular spasms, and other diseases [86]. Terefore, the and nonpsychostimulants [93]. Methylphenidate (MPH) is a biological efects of passion fower have been investigated in psychostimulant that increases extracellular dopamine and PD. Te extract of passion fower reduced the number of jaw norepinephrine levels, thereby correcting the underlying movements induced by tacrine, which is a widely used animal abnormalities in catecholaminergic functions and restoring model of PD tremors. In addition, the model showed cog- neurotransmitter imbalance [94]. Atomoxetine (ATX) is nitive improvement, with signifcantly reduced duration of a nonpsychostimulant, a norepinephrine specifc reuptake haloperidol-induced catalepsy. Te passion fower possesses inhibitor that increases catecholamine levels in the brain antioxidant activity, as shown by its signifcant scavenging resulting in behavioural improvement [94, 95]. ADHD is a ability [59]. Passifora cincinnata is a Brazilian native species heterogeneous disorder and is categorized into three sub- of passion fower and its possible biological efects have been types: hyperactive/impulsive, inattentive, and the combined investigated. Tus, in a model of PD induced by reserpine, subtype[89,90].Teremaybealsodiferencesintermsof Passifora cincinnata extract prevented the decrease in TH treatment responses, for example, the hyperactive/impulsive in the SN induced by reserpine, delayed the onset of motor subtype responds well to MPH, the inattentive subtype impairments, and prevented the occurrence of increased responds better to ATX, and the combined type responds catalepsy behaviour. However, the extract did not modify well to ATX and MPH, although controversy still persists reserpine-induced cognitive impairments [60]. about which is the best treatment for each subtype. However, it has been demonstrated that the pharmacological treat- ments to improve ADHD symptoms have some side efects, 2.6. St. John’s Wort. Te use of St. John’s wort, known as which include nausea, headache, insomnia, abdominal pain, Hypericum perforatum, dates back to the time of the ancient decreased appetite, and motor tics [96]. Drugs used for the Greeks. Active compounds of St. John’s wort have been ADHD treatment and their side efects are shown in Table 1. identifed and include naphthodianthrones, phloroglucinols, Moreover, the use of psychostimulant medications in ADHD and favonoids (such as phenylpropanes, favonol glycosides, has been also associated with increased risk of substance and bifavones), as well as essential oils. Terefore, the use disorder [97]. Tus, there has been growing interest in active compounds provide antioxidant and neuroprotective alternative treatments for ADHD, including natural com- efects [87]. Two standardised extracts of St. John’s wort have pounds because of their antioxidant properties [98]. Natural been tested on the neurodegeneration induced by chronic compounds used as alternative therapies for the management administration of rotenone in rats. Accordingly, St. John’s of ADHD are shown in Table 3. wort reduced neuronal damage and inhibited the apoptotic cascade by decreasing Bax levels [61]. Besides, intrastriatal 3.1. Ginkgo biloba. Te extract from G. biloba leaves has been 6-OHDA-lesioned rats were treated with an the extract of used as a herbal medicine for dementia [81, 99]. Terefore, St. John’s wort and showed lowered striatal level of malondi- several reports indicate that G. biloba may have therapeutic aldehyde, enhanced catalase activity, reduced GSH content, benefts in ADHD, given that the cotreatment with G. biloba � normalised expression of GFAP and TNF , lowered DNA and ginseng were found to alleviate ADHD symptoms in fragmentation and prevention of damage to dopaminergic children, with minor side efects observed [63]. Moreover, neurons [62]. in a double-blind, randomised trial the administration of G. biloba was less efective than MPH in the treatment of ADHD 3. Attention-Deficit/Hyperactivity Disorder [64].G.bilobaextracttreatmentatamaximaldosageof240 mg improved the behavioural ratings of ADHD symptoms Attention-defcit/hyperactivity disorder (ADHD) is the most and the electrical brain activity in children, suggesting that common neurodevelopmental disorder in childhood and G. biloba extract seems to be well tolerated in the short term BioMed Research International 7 [71] [78] [73] [72] [77] [79] [70] [63] [80] [65] [68] [67] [69] [64] [66] Refs [74–76] oxidative stress ↓ oxidative damage to DNA and ↓ norepinephrine transporter ↑ inattention and hyperactivity scores in children with ADHD Outcome ↓ dopamine transporter, ↑ in children with ADHD BDNF, hyperactivity, normalised catecholamine concentrations and ↑ ↓ improved attention in children with ADHD p-TrkB, ↑ hyperactivity, inattention and impulsivity in the SHR model ↓ Alleviates ADHD symptoms in children and has minor side efects A preliminary study; improved some symptoms in ADHD patients Randomised, placebo-controlled trial; the response rate was higher double-blind, placebo-controlled pilot study; improved ADHD symptoms Randomised study, alleviated ADHD symptoms and has tolerable side efect BDNF levels, Observational clinical study, improved inattentiveness in children with ADHD ↑ Randomised controlled trial; did not improve symptoms in children with ADHD Double blind, randomised trial; was less efective than MPH in children with ADHD Table3:EfectsofnaturalcompoundsusedasanalternativetherapyforADHD. ROS, ↓ Open trial, improved the inattention and hyperactive/impulsive score in children with ADHD Improved behavioural ratings of ADHD symptoms and the electrical brain activity in children hyperactivity, improved attention and visual-motor coordination and concentration of children with ADHD ↓ dopaminergic neurotransmission, improved synaptosomal ATPase, regulated motor ability, learning and memory, Double-blind randomised placebo-controlled trial; ↑ Randomised, double-blind controlled design; Randomised, double-blind and placebo controlled study; normalised total antioxidant status, Flavonoid Valeriana ofcinalis Hypericum perforatum Passifora incarnata Hypericum perforatum Flavonoid Flavonoid Flavonoid Ginsenoside Rg3 and Ginkgo biloba Ginkgo biloba Ginseng Ginseng Ginkgo biloba Ginkgo biloba Compound Ginkgo biloba Ginseng 8 BioMed Research International and may be a useful treatment [65]. Lately, in a randomised, impulsivity in the SHR [75]. Baicalin regulated the motor placebo-controlled trial the response rate was higher with G. ability and learning and memory abilities in the SHR and thus bilobatreatmentcomparedtoplacebo.Tus,G.bilobacould controlled the core symptoms of ADHD [76]. Also, baicalin be an efective complementary treatment for ADHD [66]. improved synaptosomal ATPase and LDH activities in the SHR, suggesting that baicalin exerts its therapeutic efect by 3.2. Ginseng. Ginseng contains a class of phytochemicals upregulating the AC/cAMP/PKA signalling pathway [101]. A called ginsenosides, which are known as potent antioxidants randomised, double-blind trial to investigate the therapeutic and for their neuroprotective properties. Ginseng has been beneft of pycnogenol in ADHD patients is in progress [102]. shown to alleviate efectively symptoms of ADHD. In an open trial, ginseng medication improved the inattention and 3.4. Valeriana ofcinalis. Te efcacy of valerian has been hyperactive/impulsive score in children with ADHD [67]. evaluated in a double-blind, placebo-controlled pilot study, Indeed, an observational clinical study showed that ginseng, where valerian showed improvement in ADHD symptoms, given at 1000 mg for 8 weeks, improved inattentiveness in particular, sustained inattention, anxiety and impulsivity, in children with ADHD [68]. A double-blind randomised, and/or hyperactivity [77]. Te GABA- A receptors are the placebo-controlled trial reported that ginseng decreased substrate for the anxiolytic action of valerenic acid, a major inattention and hyperactivity scores in children with ADHD constituent of valerian root extracts [103]. GABA is the main [69]. Hence, ginseng has the potential to be used as an inhibitory neurotransmitter in the CNS, and its defciency alternative therapy for ADHD. On the ADHD-like condition causes anxiety, restlessness, and obsessive behaviour, symp- induced by Aroclor1254, YY162, which consists of terpenoid- toms ofen seen in ADHD. Te European Medicine Agency strengthened G. biloba and ginsenoside Rg3, attenuated deemed that root extracts of valerian could be used for the the increase in ROS and decrease in BDNF levels in SH- relief of mild nervous tension and sleep disorders. However, SY5Y cells. Moreover, YY162 attenuated reductions in p- more research is required to support the efcacy of valerian TrkB, BDNF, dopamine transporter, and norepinephrine in the treatment ADHD. transporter expression [70].

3.3. Flavonoids. Pycnogenol is a herbal dietary supplement 3.5. Passion Flower. Te efect of passion fower in alleviating extracted from French maritime pine bark whose main ADHD symptoms was tested in a randomised study. In ingredient is procyanidin. Procyanidins are members of the addition, a tolerable side efect profle may be considered proanthocyanidin a class of favonoids and are powerful as one of the advantages of passion fower as compared antioxidants also found in food such as grapes, berries, with MPH [78]. It seems that the mechanism of action of pomegranates, red wine, and nuts. Te treatment of 1-month passion fower is mediated via modulation of the GABA-A pycnogenol administration resulted in a signifcant reduc- and GABA-B receptors and its efects on GABA uptake [104]. tion in hyperactivity, improved attention, and visual-motor Although the passion fower has shown pharmacological coordination and concentration in children with ADHD [71]. activity in preclinical experiments, including sedative, anxi- Moreover, pycnogenol reduced oxidative damage to DNA, olytic, antitussive, antiasthmatic, and antidiabetic activities, normalised total antioxidant status, and improved attention, its supposed efcacy does not appear to be adequately cor- as demonstrated in a randomised, double-blind, placebo- roborated in the literature, since clinical studies ofen present controlled study [72]. Also, the administration of pycnogenol methodologies and procedures with weaknesses [105]. in children with ADHD, normalised catecholamine concen- trations, leading to less hyperactivity, and reduced oxidative 3.6. St. John’s Wort. St. John’s wort produces its therapeutic stress, in a randomised, double-blind, controlled design [73]. efects by involving inhibition of the reuptake of dopamine, St. John’s wort and pycnogenol have been tested as therapeutic serotonin, and norepinephrine [106]. In a randomised con- alternatives to treat ADHD. A signifcant increase of SH- trolled trial, the use of St. John’s wort for the treatment SY5Y cell survival was induced by pycnogenol, which did of ADHD over the course of eight weeks did not improve not cause any cytotoxic efect when used in therapeutically symptoms [79]. However, a preliminary study reported that relevant concentrations; also, treatment with St. John’s wort treatment with St. John’s wort improved some symptoms in signifcantly increased ATP levels [100]. Oroxylin A is a ADHD patients [80]. Because of fndings that St. John’s wort favonoid isolated from the root of Scutellaria baicalensis has no adverse efects, more studies are required to determine Georgi, a herb found in East Asia. It has been observed efcacy in the treatment of ADHD. that oroxylin A is an antagonist of the GABA-A receptor and its neuroprotective actions include antioxidant, anti- 4. Conclusions infammatory, and memory-enhancing efects. On the other hand, spontaneously hypertensive rats (SHRs) display some Te natural compounds discussed in this review appear to symptoms of ADHD, which makes them a model of the be promising for the treatment of PD and ADHD. Tere- disorder. It was demonstrated that oroxylin A improved fore, these compounds can lay the foundation for a new ADHD-like behaviours via enhancement of dopaminergic therapeutic approach for the treatment of these disorders. neurotransmission and not the modulation of the GABA Natural compounds are more easily accepted by patients, pathway in the SHR [74]. Furthermore, an oroxylin A since they are considered healthier than synthetic drugs. analogue reduced hyperactivity, sustained inattention, and Although the use of natural compounds for the neurological BioMed Research International 9

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