Antiparkinsonian Activity Research Articles

Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Xanthotoxin reverses Parkinson\u2019s disease-like symptoms in zebrafish larvae and mice models: a comparative study

BackgroundThe 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.MethodsXanthotoxin 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.ResultsAcute 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.ConclusionsThe 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.

Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset.

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1mg/kg, P < 0.05; - 38% with 1mg/kg, P < 0.01; - 47% with 10mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.

Impact of rasagiline nanoparticles on brain targeting efficiency via gellan gum based transdermal patch: A nanotheranostic perspective for Parkinsonism

Rasagiline mesylate is used as first line agent for early management of Parkinson's disease but its water soluble nature creates hurdles to cross blood brain barrier also its low oral bioavailability and rapid elimination requires frequent dosing. Thus present study aims to prepare rasagiline mesylate-nanoparticles (RM-NPs) loaded gellan gum transdermal film for non-invasive; self-administration in elderly patients. PLGA coated RM-NPs prepared by solvent evaporation technique were incorporated into film prepared by solvent casting method. Optimized films with 1.127 g gellan gum and 1.962 % linoleic acid showed enhanced ex-vivo diffusion over a period of 72 h. Comparative pharmacokinetic study revealed increased bioavailability of rasagiline on transdermal application compared to oral route. In-vivo anti-Parkinson activity estimated by behavioural and biochemical analysis indicate reserpine to interfere with monoamine storage hence resulting in development of akinesia and PD-like symptoms in rats. Brain targeting monitored by gamma imaging showed effective brain drug uptake from transdermal film which was also supported by increased brain targeting efficiency estimated from biodistribution study. Thus, the data support efficacy of gellan gum film to target drug to brain region compared to oral route and hence can be employed as a convenient approach for long-term treatment of Parkinson's disease in elderly patients.

Dual Target Ligands with 4-tert-Butylphenoxy Scaffold as Histamine H3 Receptor Antagonists and Monoamine Oxidase B Inhibitors.

Dual target ligands are a promising concept for the treatment of Parkinson’s disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.

Synthesis and antiparkinsonian activity of nanocomposite of chitosan-tripolyphosphate-Mucuna pruriens L extract (CS-TPP-MP)

Mucuna pruriens L. (MP) has antiparkinsonian activity because it contains levodopa that acts as a dopamine precursor and plays a role to stimulate dopaminergic receptors in Parkinson's sufferers. The therapeutic efficacy of MP extract can be improved by using a nano drug carrier system, such as chitosan-tripolyphosphate (CS-TPP). This study aims to synthesize, characterize, and evaluate antiparkinsonian activity of chitosan-tripolyphosphate-MP extract (CS-TPP-MP) nanocomposite in mice. MP seed powder was extracted by maceration method using water-ethanol (1:1) by adding citric acid until it reached pH 3. The CS-TPP-MP nanocomposite was synthesized by using ionic gelation method with variations in reactant composition and reaction time. The CS-TPP-MP nanocomposite was characterized by Scanning Electron Microscopy-Energy Dispersive X-ray (SEM-EDX), X-Ray Diffraction (XRD) and Fourier-Transform Infrared (FTIR) Spectroscopy. Catalepsy test was performed to find the antiparkinsonian activity level of CS-TPP-MP nanocomposite at doses of 5, 10, 15, 20, and 25 mg/kg body weight. Based on the results of CS-TPP-MP synthesis, it was found that the reactant composition (CS-TPP:MP) of 1:3 with reaction time of 20 minutes produced the highest yield (14.21%.) SEM-EDX characterization showed that the morphology of CS-TPP-MP nanocomposite was predominantly spherical and the size was approximately 120-170 nm with a composition of C = 55.43%, O = 30.46%, N = 13.46%, P = 0.44%. XRD diffractogram showed that CS-TPP-MP nanocomposite has amorphous structure. FTIR analysis showed the appearance of absorption at wavelength of 1643.35 cm−1 which proved the interaction between the primary amine group of chitosan and the carbonyl group of EMP. Catalepsy test demonstrated that CS-TPP-MP nanocomposite at the doses of 5, 10, 15, 20, and 25 mg/kg body weight could reduce catalepsy symptoms in mice significantly, and the best dosage was 20 mg/kg body weight.

The mGlu2/3 antagonist LY-341,495 reverses the anti-dyskinetic and anti-psychotic effects of the mGlu2 activators LY-487,379 and LY-354,740 in the MPTP-lesioned marmoset.

We have recently shown that activation of metabotropic glutamate 2 (mGlu2) receptors through positive allosteric modulation and orthosteric stimulation is a novel approach to reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and dopaminergic psychosis in Parkinson's disease (PD). We have obtained these benefits with the mGlu2-positive allosteric modulator (PAM) LY-487,379 and the mGlu2/3 orthosteric agonist (OA) LY-354,740 in experiments conducted in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to pharmacologically characterise the anti-dyskinetic and anti-psychotic effects of LY-487,379 and LY-354,740, by assessing whether their benefits would be reversed by the mGlu2/3 orthosteric antagonist LY-341,495. Six MPTP-lesioned marmosets exhibiting stable dyskinesia and psychosis-like behaviours (PLBs) entered the experiments. In the first series of experiments, animals were injected L-DOPA in combination with either vehicle, LY-487,379 (10mg/kg), LY-341,495 (1mg/kg) or LY-487,379/LY-341,495. In the second series of experiments, marmosets were injected L-DOPA in combination with either vehicle, LY-354,740 (1mg/kg), LY-341,495 (1mg/kg) or LY-354,740/LY-341495. As we previously demonstrated, both LY-487,379 and LY-354,740 alleviated dyskinesia (by 44% and 47%, both P < 0.001) and PLBs (by 44% and 39%, P < 0.01 and P < 0.001) when compared to vehicle treatment. When LY-487,379 and LY-354,740 were administered concurrently with LY-341,495, the anti-dyskinetic and anti-psychotic benefits were abolished. When administered with L-DOPA in the absence of LY-487,379 and LY-354,740, LY-341,495 did not worsen dyskinesia or PLBs and did not hamper L-DOPA anti-parkinsonian action. Our results indicate that the anti-dyskinetic and anti-psychotic effects of mGlu2-positive allosteric modulation and mGlu2/3 orthosteric stimulation are reversed by mGlu2/3 orthosteric blockade.

Analysis of Quinone Reductase 2 Implication in Mechanism of Antiparkinsonian Action of Afobazole

Abstract—In an experimental model of Parkinson’s disease, the dopamine content in the striatum, the density of TH+ neurons in the substantia nigra, and the motor activity of mice were studied after the administration of afobazole, which interacts with Sigma-1 and MT1 receptors and regulatory sites of MAO-A and quinone reductase 2 (NQO2, MT3 receptor), and its main metabolite M-11, which selectively interacts only with the regulatory site of NQO2. The drugs were administered intraperitoneally for 14 days with the start of the course 30 minutes after unilateral intrastriatal administration of 5 μg of 6‑hydroxydopamine (6‑OHDA). Afobazole and M‑11 showed neuroprotective properties. In all experiments, the effective dose of afobazole (2.5 mg/kg) was significantly lower than M-11 (7.5 mg/kg). The experimental model used shows the contribution of NQO2 and other drug targets to the antiparkinsonian effect of afobazole.

Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets

Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.

Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson's disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by motor impairment and progressive loss of dopamine (DA) neurons. At present, the acute application of neurotoxic drugs such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are commonly used to simulate the pathology of PD; however, it is difficult to induce the progressive pathogenesis of PD with these models. In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes. The results showed that Dicer cKO mice exhibited progressive loss of DA neurons in the substantia nigra (SN) following tamoxifen administration. Significant DA loss was observed 6 weeks after tamoxifen administration; accordingly, progressive motor function impairment was also observed. We also found that a significant neuroinflammatory response, as evidenced by microglial proliferation, another hallmark of PD pathogenesis, accompanied the loss of DA neurons. The acute application of levo-DOPA (l-DOPA) relieved the PD-like motor impairments in Dicer cKO mice to exert its antiparkinsonian action, indicating that the model can be used to evaluate the antiparkinsonian efficacy of PD drugs. To further elucidate the potential application of this novel PD animal model for PD drug development, we employed the powerful neuroprotective agent dihydromyricetin (DHM) (10 mg/kg) and the selective sigma-1 receptor agonist PRE-084 (1 mg/kg), both of which were previously shown to produce antiparkinsonian effects. The results indicated that the chronic administration of either DHM or PRE-084 attenuated the Dicer cKO-induced loss of DA neurons and motor impairments, although the two drugs acted through different mechanisms. These data indicate that the Dicer cKO mouse model may be a useful model for investigating the pathological development of PD and intervention-mediated changes. In conclusion, this transgenic mouse model appears to simulate the progressive pathogenesis of PD and may be a potentially useful model for PD drug discovery.

Evaluation of Antioxidant and Anti-Parkinson Activity of Portulaca oleracea Seed Methanolic Extract

Aim: Evaluation of Antioxidant and Anti-Parkinson activity of Portulaca oleracea seed methanolic extract.&#x0D; Place: C. U. Shah College of Pharmacy and Research, Wadhwan, Surendranagar, Gujarat, India.&#x0D; Methodology: Collect plant materials were extracted with methanol. Extract was subjected to qualitative and quantitative investigation and antioxidant properties of extract was determine by Nitric oxide free radical scavenging activity and Reducing power by FeCl3 method.&#x0D; Anti-Parkinson activity evaluated by two behavioral models namely, haloperidol induced catalepsy, and orofacial dyskinesia both models various behavioral activity/ parameter (catalepsy, vacuous chewing movement and tongue protrusion) were evaluated.&#x0D; Results: Preliminary qualitative phytochemical screening was to reveal presence of polyphenols, flavanoids, glycoside, alkaloids, carbohydrates and reducing sugar etc. Based preliminary qualitative phytochemical screening; quantitative estimation of methanolic extract showed significant amount of polyphenols. In-vitro antioxidants was performed by two method reducing power by FeCl3 and nitric oxide free radical scavenging, the methanolic extract shows significant antioxidant properties, based on polyphenols and antioxidant properties extracts was used for the Anti-Parkinson activity Haloperidol induced catalepsy in mice Treatment with Portulaca oleracea seed showed a significant (P&lt;0.01) reduction in the duration of cataleptic behavior dose dependently when compared to haloperidol treated group. Haloperidol induced orofacial dyskinesia in rat recovery of orofacial dyskinesia as evidenced by decrease in the frequency of vacuous chewing movement and tongue significant (P&lt;0.05) decrease in the frequency of vacuous chewing &amp; tongue protrusion while Portulaca oleracea seed (200 mg/kg) was found to be insignificant in this respect.&#x0D; Conclusion: After Portulaca oleracea seed (MLPO) treatment, the significant alterations produced in Parkinson’s affected rodents in respect to lipid peroxidation and antioxidant concentration significantly contributing its antioxidant potential. This antiperoxide action observed in Portulaca oleracea seed (MLPO) treated animals might be due to the suppression of the production of reactive oxygen species. This compound may be found to scavenge free radicals, including hydroxyl anions and reduce the level of lipid peroxidation in MLPO animals. Inhibition of oxidative stress may be one of the possible mechanisms for the anti-Parkinson effects of Portulaca oleracea seed (MLPO).

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu2/3 ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti-dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1mg/kg), started concurrently with l-DOPA, once daily for 22days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p<.01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p<.01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

NEUROPROTECTIVE EFFECT OF POLYHERBAL FORMULATION IN PARKINSON’S ANIMAL MODEL

Objective: The study is aimed to evaluate the antiparkinsonian effect of polyherbal formulation containing methanolic extract of Prunus amygdalus, Arachis hypogaea, and Citrullus lanatus (MEPAC) in chlorpromazine (CPZ)-induced Parkinson’s disease in Wistar albino rats.&#x0D; Methods: The antiparkinsonian activity of polyherbal formulation was studied in CPZ (3 mg/kg i.p.) induced Parkinson rat model. Rats were subjected to treatment with MEPAC and standard drug for a period of 21 days. The behavioral assessments, i.e., catalepsy and locomotor activity were assessed during the treatment period. Then animals were sacrificed, brains were isolated and homogenized for the estimation of biochemical parameters such as dopamine (DA), lipid peroxidation (LPO), glutathione (GSH), and superoxide dismutase (SOD). Histopathology of the brains was also done.&#x0D; Results: The cataleptic score of MEPAC (200 mg/kg and 400 mg/kg) treated rats was significantly reduced. On the other hand, there was improved in the locomotor activity. MEPAC (200 mg/kg and 400 mg/kg) treated rats showed increase in the level of DA, reduced GSH, SOD, and decreased LPO significantly.&#x0D; Conclusion: It may be concluded that methanolic extract of polyherbal formulation consisting of P. amygdalus, A. hypogaea, and C. lanatus showed a good antioxidant and neuroprotective effect in CPZ-induced Parkinson rats.

Ondansetron, a highly selective 5-HT3 receptor antagonist, reduces L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease

L-3,4-dihydroxyphenylalanine (L-DOPA) has been the standard treatment for Parkinson's disease (PD), despite that its chronic use leads to motor fluctuations and dyskinesia in as many as 95% of patients. Previous studies have shown that serotonin type 3 (5-HT3) receptor blockade reduces dopamine levels within the striatum, suggesting that it could potentially lead to a reduction of dyskinesia. Here, we assessed the effects of ondansetron on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We performed two series of experiments. First, rats exhibiting stable AIMs were administered ondansetron (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or vehicle in combination with L-DOPA, following which the effect of ondansetron on AIMs was assessed. In the second series of experiments, following 6-OHDA lesion, rats received daily administration of ondansetron (0.0001, 0.001 mg/kg) or vehicle, started concurrently with the first L-DOPA dose, and treatments were continued for 22 days. After a washout period, an acute L-DOPA challenge was administered and AIMs severity was assessed. The effect of ondansetron on L-DOPA anti-parkinsonian action was also determined. We found that the addition of ondansetron 0.0001 mg/kg to L-DOPA resulted in a significant reduction of AIMs severity (by 31%, P < 0.001), when compared to vehicle. Ondansetron 0.0001 mg/kg, when started concurrently with L-DOPA, also attenuated the development of AIMs, with AIMs being 64% less severe (P < 0.05), when compared to L-DOPA/vehicle. Ondansetron did not impair L-DOPA anti-parkinsonian action. Our results suggest that selective 5-HT3 blockade is a promising strategy to reduce the severity of L-DOPA-induced dyskinesia and may also attenuate its development.

Reaction of Carbidopa with cis-[Cr(C2O4)2(H2O)2]− in Aqueous Medium: A Kinetic, Mechanistic and Antiparkinsonian Study of the Product Complex

For the treatment of Parkinson′s disease, the second most common neurodegenerative disorder, requires a combination of levodopa with a peripheral decarboxylase inhibitor, such as carbidopa which provides a symptomatic relief to patients. Reaction of carbidopa with cis-[Cr(C2O4)2(H2O)2]– has been carried out in aqueous medium over the range 35 ≤ t ≤ 50 ºC, 4.0 ≤ pH ≤ 6.0 , 3.75 × 10-3 mol dm-3 ≤ [carbidopa] ≤ 9.38 × 10-3 mol dm-3, I (KNO3) = 0.1 mol dm-3. There is outersphere association between cis-[Cr(C2O4)2(H2O)2]– and conjugate base of carbidopa followed by first chelation. The characterization of the product was performed by using NMR and infrared spectroscopies. The product showed better antiparkinsonian activity than the combination of levodopa and carbidopa

Evaluation of Anti-Parkinson Potential of Ficus carica Fruit Extract

Aim of the study Free radicals are one of the major reasons for the development of Parkinson disease where antioxidant from herbal origin can play beneficial role. Ficus carica reported wide spread of pharmacological activities including its beneficial effects against different CNS disorders majorly due to presence of polyphenols. This present study was designed to investigate the antiparkinsonian potential of acute and chronic treatment of ethanolic extract of Ficus carica fruits EEFCF against haloperidol induced parkinsonism.Materials and methods Rats were divided into five groups and treated with saline combination of levodopa carbidopa and low 100 mgkg p.o. and high dose 200mgkg p.o.. In case of acute model all treatments were given for single dose where as in case of chronic model all treatments were given for 14 days. Apart from normal control all other groups received haloperidol 1mgkg i.p.. In both the models effects of different treatments were evaluated by estimation of motor co-ordination behavioral assessment biochemical estimation and histological studies.Results and conclusions Both the lower and higher dose of ethanolic extract of Ficus carica fruit showed dose dependent significant increase in anti-parkinsonian activity when compared with control. The finding of the present study provides the evidence that the ethanolic extract of Ficus carica fruit reported dose dependent beneficial effect against Parkinsonrsquos disease.

Pharmacological properties and clinical efficacy of rasagiline mesylate (Azilect®)

Parkinson's disease is a neurodegenerative disorder that manifests as motor deficits, tremors, rigidity, and postural instability. The most prominent pathological feature of this disease is reduced striatal dopamine concentration due to the loss of nigrodopaminergic neurons. Symptomatic dopamine replacement therapy is the standard management approach for Parkinson's disease. Treatment with monoamine oxidase B (MAO-B) inhibitors also improves Parkinson's disease symptoms by inhibiting the striatal dopamine metabolism and increasing the intracerebral dopamine concentration. Rasagiline is a potent and specific MAO-B inhibitor and is currently approved as an antiparkinsonian drug in more than 50 countries, including the United States and European countries. Clinical trials conducted in Japan to evaluate the efficacy of rasagiline monotherapy in patients with early-stage Parkinson's disease using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part II (patient motor experience of daily living) and Part III (clinician motor examination) have demonstrated the antiparkinsonian action of rasagiline. Furthermore, in patients with advanced Parkinson's disease receiving levodopa, concomitant rasagiline administration reduced the duration of "wearing-off". Based on these favorable results, rasagiline mesilate (Azilect® tablets) was approved for manufacture and sales in Japan in March 2018. Here, we provide a comprehensive overview of the pharmacological properties and clinical effects of rasagiline based on the results of domestic trials, with the aim of increasing the understanding of rasagiline use in Japan.

8-Propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one: A new coumarin with monoamine oxidase B inhibitory activity and possible anti-parkinsonian effects

Parkinson’s disease is a common neurodegenerative disorder. In this study, the monoamine oxidase inhibitory activity and potential anti-parkinsonian effects of 8-propyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one (FCS303), a new synthetic coumarin, were evaluated. To do this, we used the reserpine model of Parkinson’s disease, an assay of levodopa/carbidopa potentiation, the catalepsy model of haloperidol, and an in vitro assay against monoamine oxidase (MAO) activity. Additionally, lipid peroxidation and protein carbonyl group quantification was performed in mice brain homogenates previously treated with haloperidol. FCS303 inhibited monoamine oxidase B (MAO-B) with an IC50 of 5.46 ± 0.36 µM; however, there was no effect on monoamine oxidase A (MAO-A). The oral administration of FCS303 led to a significant reversal of hypokinesia in the reserpine model (at 24 h, doses of 100 and 200 mg/kg) and in the levodopa/carbidopa potentiation assay (at 2 and 24 h, dose of 200 mg/kg). In addition, FCS303 (100 mg/kg) showed anti-cataleptic activity against haloperidol. FCS303 (50 mg/kg) significantly decreased lipid peroxidation and protein carbonyl quantification. These results suggest that FCS303 could present anti-parkinsonian activity related to MAO-B inhibitory activity.

The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum.

The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum, mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role in pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will also be addressed.

Experimental study of antiparkinsonian action of the harmine hydrochloride original compound.

The effects of chemical products on the nervous system have been studied by various scientists. In this work, the antiparkinsonian action of a water-soluble form of harmine hydrochloride was studied. The present studies aim to research antiparkinsonian action of the harmine hydrochloride original compound. To achieve the objective of the study, the authors used haloperidol-induced catalepsy and a method of Parkinson's syndrome (PS) induced by the MPTP (the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxin. The experiments were performed on rats and mice which were divided into groups of 10 animals. It was established that harmine hydrochloride (HH), at a certain dose, eliminated haloperidol-induced catalepsy in rats and reduced oligokinesia and rigidity in the parkinsonism test in mice. Seven days after the experiment, the authors found the presence of rigidity in animals which had received the neurotoxin. It manifested itself in a shortened stride length compared to this parameter in intact controls. During the study the efficacy of harmine hydrochloride was equivalent to the effects of levodopa at a certain dose, which suggested that harmine hydrochloride compensated dopamine deficiency in the brain.