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.

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.

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.

In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET.

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.

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.

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.

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.

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.

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.

Mercury sulfide-containing Hua-Feng-Dan and 70W (Rannasangpei) protect against LPS plus MPTP-induced neurotoxicity and disturbance of gut microbiota in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Mercury sulfides (HgS) are frequently included in Ayurveda, Tibetan and Chinese medicines to assist the presumed therapeutic effects, but the ethnopharmacology remains elusive. The present study examined the protective effects of α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) against Parkinson's disease mice induced by lipopolysaccharide (LPS) plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHOD: A single injection of LPS (5 mg/kg ip) was given to adult male C57BL/6 mice, and 150 days later, the low dose of MPTP (15 mg/kg, ip, for 4 days) was given to produce the "two-hit" Parkinson's disease model. Together with MPTP treatment, mice were fed with clinically-relevant doses of Hua-Feng-Dan (0.6 g/kg) and 70W (0.2 g/kg) for 35 days. Rotarod test was performed to examine muscle coordination capability. At the end of the experiment, brain was transcardially perfused with paraformaldehyde, the substantia nigra was sectioned for microglia (Iba1 staining) and dopaminergic neuron (THir staining) determination. Colon bacterial DNA was extracted and subjected to qPCR analysis with 16S rRNA probes. RESULTS: The low-grade, chronic neuroinflammation produced by LPS aggravated MPTP neurotoxicity, as evidenced by decreased motor activity, intensified microglia activation and loss of dopaminergic neurons. Both Hua-Feng-Dan and 70W increased rotarod activity and ameliorated the pathological lesions in the brain. In gut microbiomes examined, LPS plus MPTP increased Verrucomicrobiaceae, Methanobacteriaceae, Pronicromonosporaceae, and Clostridaceae species were attenuated by Hua-Feng-Dan and 70W. CONCLUSIONS: α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70W at clinical doses protected against chronic LPS plus MPTP-induced toxicity to the brain and gut, suggesting HgS-containing traditional medicines could target gut microbiota as a mechanism of their therapeutic effects.

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.

Effects of Electroacupuncture on Metabolic Changes in Motor Cortex and Striatum of 6-Hydroxydopamine-Induced Parkinsonian Rats.

OBJECTIVE: To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. METHODS: Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. RESULTS: Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). CONCLUSIONS: EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Alzheimer's Disease and Parkinson's Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals.

Introduction: Alzheimer's disease is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while Parkinson's disease is primarily a movement disorder illness having movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. While aging is the main risk factor, epidemiological evidence suggests that the exposure to environmental toxicants, mainly pesticides, metals and solvents could increase the risk of developing neurodegenerative conditions.Oxidative stress in neurodegenerative diseases: Mitochondria function impacts cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis. In neurodegenerative diseases, mitochondrial dysfunction is associated with a compromised energy production, impaired calcium buffering, activation of proteases and phospholipases, and increased oxidative stress. Oxidative stress induced microglial cells activation, protein aggregation, neuroinflammation and mitochondrial dysfunction lead to neuronal deaths in these disorders.Role of nutrition: Neurodegenerative disease is not curable, but treatment is available to manage the symptoms and slow down the disease progression. The drugs for treating these diseases only reduce the cognitive impairment and behavioral problems, but do not stop the progression of neurodegeneration. Healthy diet, lifestyle improvement and nutraceuticals targeting of oxidative stress, inflammation, abnormal mitochondrial dynamics and the mitochondrial interaction with abnormal disease-related proteins and assessment of impact of environmental contaminants including occupational exposures to pesticides, can be a promising approach in the treatment of neurodegenerative diseases.Conclusion: These innovations can be benchmarked on firm understanding of nutrigenomics and the personalized management of individuals at risk.

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.

Potential therapeutic effects of antagonizing adenosine A2A receptor, curcumin and niacin in rotenone-induced Parkinson's disease mice model.

Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.

Neuroprotective Effect of Quercetin in Combination with Piperine Against Rotenone- and Iron Supplement-Induced Parkinson's Disease in Experimental Rats.

Parkinson's disease (PD) is a neurodegenerative disorder caused by selective dopaminergic neuronal loss. Rotenone is a neurotoxin that selectively destroys dopaminergic neurons, leading to PD-like symptoms. Quercetin possesses antioxidant, anti-inflammatory, and neuroprotective properties but a major drawback is its low bioavailability. Therefore, the present study was designed to evaluate the neuroprotective effect of quercetin in combination with piperine against rotenone- and iron supplement-induced model of PD. Rotenone was administered at a dose of 1.5 mg/kg through an intraperitoneal route with iron supplement at a dose of 120 µg/g in diet from day 1 to day 28. Pre-treatment with quercetin (25 and 50 mg/kg, p.o.), piperine (2.5 mg/kg, p.o.) alone, quercetin (25 mg/kg, p.o.) in combination with piperine (2.5 mg/kg), and ropinirole (0.5 mg/kg, i.p.) was administered for 28 days 1 h prior to rotenone and iron supplement administration. All behavioral parameters were assessed on weekly basis. On the 29th day, all animals were sacrificed and striatum was isolated for biochemical (LPO, nitrite, GSH, mitochondrial complexes I and IV), neuroinflammatory (TNF-α, IL-1ß, and IL-6), and neurotransmitter (dopamine, norepinephrine, serotonin, GABA, glutamate) estimation. Quercetin treatment attenuated rotenone- and iron supplement-induced motor deficits and biochemical and neurotransmitter alterations in experimental rats. However, combination of quercetin (25 mg/kg) with piperine (2.5 mg/kg) significantly enhanced its neuroprotective effect as compared with treatment with quercetin alone. The study concluded that combination of quercetin with piperine contributed to superior antioxidant, anti-inflammatory, and neuroprotective effect against rotenone- and iron supplement-induced PD in experimental rats.

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.