Lycium barbarum polysaccharide improves dopamine metabolism and symptoms in an MPTP-induced model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly populations, whereas there is no cure for PD so far. Novel animal models and medications await development to elucidate the aetiology of PD and attenuate the symptoms, respectively. METHODS: A neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was used in the current study to establish a PD pathologic model in silkworms. The time required to complete specific behaviours was recorded. Dopamine content was detected by ultra-performance liquid chromatography (UPLC). The activity of insect tyrosine hydroxylase (TH) was determined using a double-antibody sandwich method. Oxidative stress was assessed by changes in antioxidant enzyme activity and the content of oxidative products. RESULTS: MPTP-treated silkworms were characterized by impaired motor ability, reduced dopamine content, and elevated oxidative stress level. The expression of TH, a dopamine biosynthetic enzyme within dopaminergic neurons in the brain, was significantly reduced, indicating that dopaminergic neurons were damaged. Moreover, MPTP-induced motility impairment and reduced dopamine level in the silkworm PD model could be rescued after feeding a combination of levodopa (L-dopa [LD]) and carbidopa (CD). MPTP-induced oxidative damage was also alleviated, in ways consistent with other PD animal models. Interestingly, administration of Lycium barbarum polysaccharide (LBP) improved the motor ability, dopamine level, and TH activity, and the oxidative damage was concomitantly reduced in the silkworm PD model. CONCLUSIONS: This study provides a promising animal model for elucidating the pathogenesis of PD, as well as a relevant preliminary drug screening (e.g., LBP) and evaluation.

Wuzi Yanzong pill attenuates MPTP-induced Parkinson's Disease via PI3K/Akt signaling pathway.

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

Protective effect of plastrum testudinis extract on dopaminergic neurons in a Parkinson's disease model through DNMT1 nuclear translocation and SNCA's methylation.

The pathological characteristics of Parkinson's disease (PD) include dopaminergic neuron damage, specifically disorders caused by dopamine synthesis, in vivo. Plastrum testudinis extract (PTE) and its bioactive ingredient ethyl stearate (PubChem CID: 8122) were reported to be correlated with tyrosine hydroxylase (TH), which is a biomarker of dopaminergic neurons. This suggests that PTE and its small-molecule active ingredient ethyl stearate have potential for development as a therapeutic drug for PD. In this study, we treated 6-hydroxydopamine (6-OHDA)-induced model rats and PC12 cells with PTE. The mechanism of action of PTE and ethyl stearate was investigated by western blotting, bisulfite sequencing PCR (BSP), real-time PCR, immunofluorescence and siRNA transfection. PTE effectively upregulated the TH expression and downregulated the alpha-synuclein expression in both the substantia nigra and the striatum of the midbrain in a PD model rat. The PC12 cell model showed that both PTE and its active monomer ethyl stearate significantly promoted TH expression and blocked alpha-synuclein, agreeing with the in vivo results. BSP showed that PTE and ethyl stearate increased the methylation level of the Snca intron 1 region. These findings suggest that some of the protective effects of PTE on dopaminergic neurons are mediated by ethyl stearate. The mechanism of ethyl stearate may involve disrupting the abnormal aggregation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) with alpha-synuclein by releasing DNMT1, upregulating Snca intron 1 CpG island methylation, and ultimately, reducing the expression of alpha-synuclein.

Gamma-decanolactone: Preliminary evaluation as potential antiparkinsonian drug.

Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A1, A2A A2B and A3 adenosine receptors were performed. A docking study of gamma-decanolactone has been carried out with the molecular targets of MAO-A and MAO-B isoforms. The physicochemical properties and ability to cross physiological barriers, as the blood brain barrier (BBB), was elucidated by computational studies. The in vivo assays, the rota-rod test, body temperature assessment and open field test were performed in reserpinized mice (1.5 mg/kg, i.p.; 18:00 before) to evaluate the effect of gamma-decanolactone (300 mg/kg), alone or associated with Levodopa plus Benserazide (LD + BZ, 100:25 mg/kg, i.p.). Gamma-decanolactone inhibited preferentially the MAO-B in a reversible manner, with an inhibitory concentration of 50% (IC50) 55.95 ± 9.06 µM. It was shown to be a safe drug since only at the highest concentration decreased the viability of HepG2 cells. It also does not bind to adenosine receptors investigated in this study. The molecular docking study show that the gamma-decanolactone ligand adopts a relatively compact conformation in the active site of hMAO-B, while we note an extended conformation of gamma-decanolactone ligand in the hMAO-A isoform. The physicochemical properties obtained, and the theoretical models utilized for the evaluation of ability to cross the BBB, predict a good gamma-decanolactone bioavailability and access to the central nervous system (CNS). In the in vivo studies, gamma-decanolactone partially reversed the ataxia of the reserpinized mice at 01:00 h and 01:30 h post-administration. Concomitant treatment of gamma-decanolactone with LD + BZ, at 01:30 h showed a potentiation of the reversibility of ataxia and facilitated the reversal of hypothermia caused by reserpine for all measured times (P <0.01 vs vehicle), except at 24:00 h, but not reversed the hypokinesia in the open field test. In summary, the results herein obtained and in conjunction with previous studies, suggest that gamma-decanolactone could be a drug with potential utility as antiparkinsonian drug.

Pesticides and Parkinson's disease: Current and future perspective.

Inappropriate use of pesticides has globally exposed mankind to a number of health hazards. Still their production is rising at the rate of 11 % annually and, has already exceeded more than 5 million tons in 2000 (FAO 2017). Plenty of available data reveals that pesticides exposures through agricultural use and food-preservative residue consumption may lead to neurodegenerative disorders like Parkinson's and Alzheimer's diseases. Parkinson's disease (PD) is a progressive motor impairment and a neurodegenerative disorder, considered as the leading source of motor disability. Pesticides strongly inhibit mitochondrial Complex-I, causing mitochondrial dysfunction and death of dopaminergic neurons in the substantia nigra (SN), thus leading to pathophysiologic implications of PD. Current medical treatment strategies, including pharmacotherapeutics and supportive therapies can only provide symptomatic relief. While complementary and alternative medicines including traditional medicine or acupuncture are considered as beneficial ways of treatment with significant clinical effect. Medically non-responding cases can be treated by surgical means, 'Deep Brain Stimulation'. Cell therapy is also an emerging and promising technology for disease modeling and drug development in PD. Their main aim is to replace and/or support the lost and dying dopaminergic neurons in the SN. Recently I/II clinical phase trial (Japan) have used dopaminergic progenitors generated from induced pluripotent stem (iPS) cells which can unveil a successful cell therapy to treat PD symptoms efficiently. This review focuses on PD caused by pesticides use, current treatment modalities, and ongoing research updates. Since PD is not a cell-autonomous disease rather caused by multiple factors, a combinatorial therapeutic approach may address not only the motor-related symptoms but also non-motor cognitive-behavioral issues.

Neuroprotective effects of garlic extract on dopaminergic neurons of substantia nigra in a rat model of Parkinson's disease: motor and non-motor outcomes.

Parkinson's disease (PD) is a common and severe neurodegenerative disorder associated with a selective loss of dopaminergic neurons in substantia nigra pars compacta. The crucial role of oxidative stress and inflammation in PD onset and progression is evident. It has been proven that garlic extract (GE) protects the cells from oxidative stress, inflammation, mitochondrial dysfunction and apoptosis. That is, we aimed to investigate if GE reveals protective features on the preclinical model of PD. The study has been designed to evaluate both preventive (GE administered before 6-OHDA injection) and therapeutic (GE administered after 6-OHDA injection) effects of GE on the animal model. Forty male Wistar rats were divided into 4 groups including control, lesion, treatment I (received GE before 6-OHDA injection) and treatment II (received GE both before and after 6-OHDA injection). At the end of treatment, hanging, rotarod, open field and passive avoidance tests as well as immunohistochemistry were performed to evaluate the neuroprotective effects of garlic against PD. Our immunohistochemistry analysis revealed that the tyrosine hydroxylase positive cells (TH+) in GE treated groups were significantly higher (p˂0.001) than the lesion group. The motor deficiency significantly improved in hanging, rotarod, open-field and apomorphine-induced rotational tests. We observed an attenuation in memory impairment induced by PD on GE treated group. Therefore, we found that GE protects dopaminergic neurons in 6-OHDA-induced neurotoxicity and ameliorates movement disorders and behavioral deficits.

Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with obscure etiology and no disease-modifying therapy to date. Hence, novel, safe, and low cost-effective approaches employing medicinal plants are currently receiving increased attention. A growing body of evidence has revealed that cinnamon, being widely used as a spice of unique flavor and aroma, may exert neuroprotective effects in several neurodegenerative diseases, including PD. In vitro evidence has indicated that the essential oils of Cinnamomum species, mainly cinnamaldehyde and sodium benzoate may protect against oxidative stress-induced cell death, reactive oxygen species generation, and autophagy dysregulation, thus acting in a potentially neuroprotective manner. In vivo evidence has demonstrated that oral administration of cinnamon powder and sodium benzoate may protect against dopaminergic cell death, striatal neurotransmitter dysregulation, and motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse models of PD. The underlying mechanisms of its action include autophagy regulation, antioxidant effects, upregulation of Parkin, DJ-1, glial cell line-derived neurotrophic factor, as well as modulation of the TLR/NF-κB pathway and inhibition of the excessive proinflammatory responses. In addition, in vitro and in vivo studies have shown that cinnamon extracts may affect the oligomerization process and aggregation of α-synuclein. Herein, we discuss recent evidence on the novel therapeutic opportunities of this phytochemical against PD, indicating additional mechanistic aspects that should be explored, and potential obstacles/limitations that need to be overcome, for its inclusion in experimental PD therapeutics.

Xanthotoxin reverses Parkinson's disease-like symptoms in zebrafish larvae and mice models: a comparative study.

BACKGROUND: The aim of this study is to preliminary evaluate the antiparkinsonian activity of furanocoumarin-xanthotoxin, in two behavioral animal models, zebrafish larvae treated with 6-hydroxydopamine and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in order to compare both models. METHODS: Xanthotoxin was isolated from Pastinaca sativa L. (Apiaceae) fruits. Then, the compound was administered by immersion to zebrafish 5 days after fertilization (dpf) larvae or intraperitoneally to male Swiss mice, as a potential therapeutic agent against locomotor impairments. RESULTS: Acute xanthotoxin administration at the concentration of 7.5 µM reversed locomotor activity impairments in 5-dpf zebrafish larvae. In mice model, acute xanthotoxin administration alleviated movement impairments at the concentration of 25 mg/kg. CONCLUSIONS: The similar activity of the same substance in two different animal models indicates their compatibility and proves the potential of in vivo bioassays based on zebrafish models. Results of our study indicate that xanthotoxin may be considered as a potential lead compound in the discovery of antiparkinsonian drugs.

Hexane extract from SpoSndias mombin L. (Anacardiaceae) prevents behavioral and oxidative status changes on model of Parkinson's disease in zebrafish.

The search for new therapies, derived from natural compounds in order to prevent and treat Parkinson's disease (PD) has aroused the interest of many researchers. Spondias mombin (L) has active constituents with known antioxidant and anti-inflammatory activities. The aim of this study was to evaluate the neuroprotective potential of the hexane extract of S. mombin (EHSm) in an experimental model of DP induced by rotenone in zebrafish. The analysis of GC/MS demonstrated cyclogallipharaol (13.88%) and dl-α-tocopherol (8.08%) mostly, while HPLC-DAD indicated the presence of quercetin (<5), quercetrin (6.54 mg/g) and rutin (8.83 mg/g). The zebrafish exposed for 4 weeks to rotenone (ROT, 3 µg/L) and EHSm (5, 15, 25 mg/L). EHSm (25 mg/L) was able to reverse the behavioral damage induced by ROT in the entries and time spent in the top area of the tank. The parameters biochemicals indicated of EHSm prevented oxidative stress (TBARS e total thiols), inflammation and dopamine uptake triggered by ROT, evidenced of increased on the CAT, SOD and GSH and decreased of GST, O2- production and NADPH oxidase activities. We conclude that EHSm demonstrate a neuroprotector effect mediated through anxiolytic and antioxidant activities. However, more studies are necessary to elucidate the exact mechanism underlying the effects of EHSm on DP induced by rotenone in zebrafish.

Contribution of DHA diols (19,20-DHDP) produced by cytochrome P450s and soluble epoxide hydrolase to the beneficial effects of DHA supplementation in the brains of rotenone-induced rat models of Parkinson's disease.

Docosahexaenoic acid (DHA) has been shown to have neuroprotective effects in Parkinson's disease, but the underlying mechanism has not been fully elucidated. DHA is metabolized to DHA epoxides (EDPs) and hydroxides by cytochrome P450s (P450s), and EDPs are further hydroxylated to the corresponding diols, dihydroxydocosapentaenoic acids (DHDPs) by soluble epoxide hydrolase (sEH). In the present study, we investigated the roles of these DHA metabolites in the beneficial effects of DHA supplementation on a rotenone-induced rat model of Parkinson's disease. Metabolite analysis by LC-MS revealed that CYP2A1, 2C11, 2C13, 2C23, and 2E1 contributed to the formation of EDPs, and these P450s and sEH were expressed in the rat brain. We found that DHA supplementation in rats improved the motor dysfunction induced by rotenone. In addition, DHA reversed the decrease in tyrosine hydroxylase and the increase in lipid peroxidation generated by rotenone in the striatum. DHA supplementation also induced mRNA expression of antioxidant genes, such as sod1 and catalase, and Nrf2 protein expression in the striatum. However, these effects of DHA supplementation were eliminated by cosupplementation with the sEH inhibitor TPPU. Supplementation with DHA increased the amount of 19,20-DHDP in the rat brain, while the amount of EDPs was not significantly increased. In addition, TPPU suppressed the increase in DHDPs and increased EDPs in the brain. In PC12 cells, 19,20-DHDP increased the mRNA levels of sod1 and catalase along with Nrf2 induction. This study suggests that DHA metabolites-DHDPs generated by P450s and sEH-have an important role in improving rotenone-induced Parkinson's disease.

Neuroprotective Effects of Safflower Flavonoid Extract in 6-Hydroxydopamine-Induced Model of Parkinson's Disease May Be Related to its Anti-Inflammatory Action.

Safflower (Carthamus tinctorius. L.), a Chinese materia medica, is widely used for the treatment of cardiovascular and cerebrovascular diseases, with flavonoids being the major active components. Multiple flavonoids in safflower bind to Parkinson's disease (PD)-related protein DJ-1. Safflower flavonoid extract (SAFE) improved behavioral indicators in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD; however, the underlying mechanisms remain unclear. We used a 6-OHDA-induced mouse model of PD and a primary neuron-astrocyte coculture system to determine the neuroprotective effects and mechanisms of SAFE. After three weeks of SAFE administration, behavioral indicators of PD mice were improved. SAFE regulated the levels of tyrosine hydroxylase (TH) and dopamine metabolism. It significantly inhibited the activation of astrocytes surrounding the substantia nigra and reduced Iba-1 protein level in the striatum of PD mice. SAFE reduced the plasma content of inflammatory factors and suppressed the activation of nod-like receptor protein 3 (NLRP3) inflammasome. In the coculture system, kaempferol 3-O-rutinoside and anhydrosafflor yellow B significantly improved neuronal survival, suppressed neuronal apoptosis, and reduced IL-1ß and IL-10 levels in the medium. Thus, SAFE showed a significant anti-PD effect, which is mainly associated with flavonoid anti-inflammatory activities.

α-Bisabolol, a Dietary Bioactive Phytochemical Attenuates Dopaminergic Neurodegeneration through Modulation of Oxidative Stress, Neuroinflammation and Apoptosis in Rotenone-Induced Rat Model of Parkinson's disease.

Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson's disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.

Amelioration of motor and non-motor deficits and increased striatal APoE levels highlight the beneficial role of pistachio supplementation in rotenone-induced rat model of PD.

Pistachio contains polyphenolic compounds including flavonoids and anthocyanins which have antioxidant and antiinflammatory activity. Present study was aimed to evaluate the protective effects of pistachio on neurobehavioral and neurochemical changes in rats with Parkinson's disease (PD). Animal model of PD was induced by the injection of rotenone (1.5 mg/kg/day, s.c.) for 8 days. Pistachio (800 mg/kg/day, p.o.) was given for two weeks in both pre- and post-treatment. At the end of treatment brain was dissected out and striatum was isolated for biochemical and neurochemical analysis. Memory was assessed by Morris water maze (MWM) and novel object recognition (NOR) test while open field test (OFT), Kondziela inverted screen test (KIST), pole test (PT), beam walking test (BWT), inclined plane test (IPT) and footprint (FP) test were used to observe motor behavior. Rotenone administration significantly (p < 0.01) impaired the memory but pistachio in both pre- and post-treatment groups significantly (p < 0.01) improved memory performance. Rotenone-induced motor deficits were significantly attenuated in both pre- and post-pistachio treatment. Increased oxidative stress and decreased DA and 5-HT levels induced by rotenone were also significantly attenuated by pistachio supplementation. Furthermore, raised apolipoprotein E (APoE) levels in rotenone injected rats were also normalized following treatment with pistachio. Present findings show that pistachio possesses neuroprotective effects and improves memory and motor deficits via increasing DA levels and improving oxidative status in brain.

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson's Disease Associated α-Synuclein Levels.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

An Evaluation of the Effects of Pyridoxal Phosphate in Chlorpromazineinduced Parkinsonism using Mice.

BACKGROUND: Parkinsonism is a neurodegenerative disorder with a heavy disease burden, despite the discovery and application of drugs. Current research is beginning to suggest the possible crucial roles of micronutrients such as pyridoxal phosphate in the prevention or management of neurodegenerative disorders. OBJECTIVE: We investigated the possible protective effects of supplemental pyridoxal phosphate in Chlorpromazine (CPZ)-induced Parkinsonism-like changes in mice. METHODS: Mice were assigned to eight groups of 30 mice each. Groups included Vehicle control (fed standard diet (SD), and administered intraperitoneal {ip} injection of saline and saline per orem), levodopa-carbidopa (LD) group (SD, saline ip and LD per orem), two groups fed pyridoxal phosphate-supplemented diet (at 100 and 200 mg/kg of feed), and administered saline both ip and orally, CPZ group (SD, CPZ ip and saline per orem), CPZ/LD group (SD, CPZ ip and LD per orem) and finally two groups fed pyridoxal phosphate -supplemented diet (at 100 and 200 mg/kg of feed) and administered CPZ ip plus saline per orem. Treatments were administered daily for a period of 21 days to allow for the induction of Parkinsonism features. Body weight and food intake were measured weekly while neurobehavioural and biochemical tests were assessed at the end of the experimental period. RESULTS: Pyridoxal phosphate supplementation was associated with a reduction in CPZ-induced suppression of open-field horizontal locomotion and rearing; and a significant increase in grooming activity. Administration of pyridoxal phosphate-supplemented diet was also associated with improvements in working-memory in CPZ-treated mice; and there was reduction in the index of anxiety and catalepsy score. CONCLUSION: Pyridoxal phosphate supplementation was associated with significant benefits in CPZ-induced Parkinsonism-like changes in mice.

Neuroprotective effects of Bacopa monnieri in Parkinson's disease model.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra region and the presence of α-synuclein aggregates in the striatum and surrounding areas of brain. Evidences suggest that neuroinflammation plays a role in the progression of PD. We examined the neuro-protective effects of Bacopa monnieri (BM) in regulating neuroinflammation. Administration of BM suppressed the level of pro-inflammatory cytokines, decreased the levels of α-synuclein, and reduced reactive oxygen species (ROS) generation in PD animal model. Pre-treatment of BM showed more prominent results as compare to co- and post-treatment. Results suggest that Bacopa can limit inflammation in the different areas of brain, thus, offers a promising source of novel therapeutics for the treatment of many CNS disorders.

Systems pharmacology based approach to investigate the in-vivo therapeutic efficacy of Albizia lebbeck (L.) in experimental model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons in substantia nigra pars compacta and clinically manifested mainly with motor dysfunctions. Plants are rich source of medicinally important bioactive compounds and inhabitants of underdeveloped countries used plants for treatment of various ailments. Albizia lebbeck has been reported to possess antioxidant and neuroprotective properties that suggest the evaluation of its traditional therapeutic potential in neurodegenerative diseases. The aim of present study was to validate the traditional use of Albizia lebbeck (L.) and delineate its mechanism of action in PD. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. METHODS: The haloperidol-induced catalepsy was adopted as experimental model of PD for in-vivo studies in wistar albino rats. The systems pharmacology approach was employed to explain the Albizia lebbeck (L.) mechanism of action in PD. RESULTS: In-vivo studies revealed that Albizia lebbeck improved the motor functions and endurance as demonstrated in behavioral studies which were further supported by the rescue of endogenous antioxidant defense and reversal of ultrastructural damages in histological studies. System pharmacology approach identified 25 drug like compounds interacting with 132 targets in a bipartite graph that revealed the synergistic mechanism of action at system level. Kaemferol, phytosterol and okanin were found to be the important compounds nodes with prominent target nodes of TDP1 and MAPT. CONCLUSION: The therapeutic efficiency of Albizia lebbeck in PD was effectively delineated in our experimental and systems pharmacology approach. Moreover, this approach further facilitates the drug discovery from Albizia lebbeck for PD.

Coumarin analogue 3-methyl-7H-furo[3,2-g] chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. OBJECTIVE: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. MATERIALS AND METHODS: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. RESULTS: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. CONCLUSION: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model.

BACKGROUND: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. AIMS: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson's Disease (PD) rat model and to delineate the possible associated molecular mechanisms. METHODS: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. RESULTS: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. CONCLUSION: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.