Antiparkinsonian Activity Research Articles

The anti-dyskinetic effect of the clinic-ready mGluR2positive allosteric modulator AZD8529 in the 6-OHDA-lesioned rat.

L-3,4-dihydroxyphenylalanine (L-DOPA) remains the main treatment for motor symptoms of Parkinson's disease (PD). However, chronic use is associated with the development of complications such as L-DOPA-induced dyskinesia. We previously demonstrated that LY-487,379, a highly selective metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulator (PAM), reduces the severity of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, without interfering with the anti-parkinsonian action of L-DOPA. Here, we seek to determine the effect of AZD8529, another highly selective mGluR2 PAM, on L-DOPA-induced AIMs in the 6-OHDA-lesioned rat. Unlike LY-487,379, AZD8529 has previously undergone clinical trials and could therefore be repurposed if proven efficacious in pre-clinical studies. We first determined the pharmacokinetic (PK) profile of AZD8529 to administer doses leading to clinically relevant plasma levels in the behavioural studies. Then, dyskinetic 6-OHDAlesioned rats were administered AZD8529 (0.1, 0.3, and 1 mg/kg) or vehicle in combination with L-DOPA followed by assessment of AIMs severity. The cylinder test was then used to evaluate the effect of AZD8529 on the anti-parkinsonian action of L-DOPA. We found that AZD8529 (0.1, 0.3 and 1 mg/kg) in combination with L-DOPA significantly reduced the severity of AIMs duration (P < 0.05), but not amplitude, when compared to L-DOPA/vehicle. AZD8529 administration did not interfere with L-DOPA anti-parkinsonian action. Our results provide evidence that mGluR2 positive allosteric modulation with AZD8529 may be a viable, yet relatively modest, treatment strategy to alleviate L-DOPA-induced.

Inhibitory Activity of N- and S-Functionalized Monoterpene Diols Towards Monoamine Oxidases A and B

Monoamine oxidase B (MAO-B) inhibitors are widely used as part of combination drug therapy for Parkinson’s disease. As demonstrated in both in vitro and in vivo experiments, the monoterpenoid Prottremine and some of its derivatives exhibit high antiparkinsonian activity. In this study, the inhibitory activity of Prottremine and its derivatives (including 14 new 9-N- and S-derivatives) against MAO-A and MAO-B enzymes has been investigated for the first time. Compounds containing fragments of substituted anilines have demonstrated the highest activity against MAO-A; for example, compound 28 had an IC50 of 178 ± 44 μM. A significant proportion of the compounds tested, including Prottremine, exhibited moderate inhibitory activity towards MAO-B, with the most active being the o-aminoacetophenone derivative, which had an IC50 of 95 ± 5 μM. A molecular docking method for studying murine MAO-A and -B enzymes was developed using AlphaFold2 (v2.3.2), with further improvements. For the MAO-B enzyme, a strong correlation was observed between the molecular docking data and the measured activity of the compounds, with the maximum binding affinity registered for the most active compound. It is conceivable that the antiparkinsonian activity of Prottremine and some of its derivatives may be partially mediated, among other mechanisms, by MAO-B enzyme inhibition.

The Role of Ocimene in Decreasing α-Synuclein Aggregation using Rotenone-induced Rat Model.

Parkinson's disease is defined by the loss of dopaminergic neurons in the midbrain of substantia nigra associated with Lewy bodies. The precise mechanism is not yet entirely understood. The study aims to determine whether ocimene has antiparkinsonian activity by reducing α-Synuclein aggregation levels in the brains of rotenone-induced rat models. 36 male rats were used for six groups, with six animals in each group. Vehicle, control (rotenone, 2.5 mg/kg, i.p), standard (L-Dopa, 10 mg/kg, i.p), Test drug of low dose (66.66 mg/kg, i.p), medium dose (100 mg/kg, i.p), and high dose (200 mg/kg, i.p) were administered to the rats. The open field, actophotometer, hanging wire, and catalepsy tests were used to assess the rat's motor performance. The expressions of biomarkers such as AchE, D2 Receptor, and α- Synuclein were evaluated, and their level of expression in the brain samples was checked using ELISA. Histopathological analysis was also carried out to determine the degree of neuron degeneration in the brain samples. The open field test showed significant anxiety levels, whereas test groups showed fewer anxiety levels but increased motor activity. The biochemical tests revealed that rotenonetreated rats had higher levels of AchE, but ocimene-treated rats had a significant decrease in AchE levels. The test drug-treated rats also expressed high levels of D2 receptors. In ocimenetreated rats, α-Synuclein aggregation was reduced, however, in rotenone-treated rats' brain samples, higher clumps of α-Synuclein were observed. Ocimene has neuroprotective properties. As a result, this essential oil might be helpful as a therapeutic treatment for Parkinson's disease.

BBPT attenuated 6-OHDA-induced toxicity by modulating oxidative stress, apoptotic, and inflammatory proteins in primary neurons and rat models of Parkinson's Disease

Parkinson’s disease (PD) results from the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Adenosine A2AR acting through the striato-pallidal pathway has emerged as a non-dopaminergic target in the therapy of PD. In the present work, the anti-parkinsonian potential of (4E)-4-(4-bromobenzylideneamino)-3-phenyl-2,3-dihydro-2-thioxo- thiazole-5-carbonitrile (BBPT) was explored. BBPT exhibited significant antioxidant activity in situ. In the MTT assay, the BBPT treatment showed insignificant toxicity to the primary midbrain neuronal (PMDN) cells. 6-OHDA induced PMDN cells, 3h post-treated with BBPT showed 80-85% survival of the cells and restoration of dopamine and TNF-α levels. The acute and sub-acute toxicity test for BBPT was performed with Sprague Dawley (SD) rats. In toxicity assay, any significant physical, hematological, or biochemical changes in the rats were not observed. To evaluate the effect of BBPT in vivo, a 6-OHDA-induced unilaterally lesioned SD rat model of PD was established. We observed that the BBPT treatment improved the behavioral symptoms in 6-OHDA-induced unilaterally lesioned rats. The proteins of 6-OHDA-induced BBPT-treated rats were isolated from the brain tissue to assess the antioxidant effect (GSH, catalase, SOD, lipid-peroxidation, nitrite), dopamine levels, and the restoration in the apoptosis and inflammation. Our results demonstrated that BBPT increased the anti-oxidant enzyme levels, restored the caspase-3/Bcl-2 levels to arrest apoptosis, and attenuated the TNF-α/IL-6 levels, thus restoring the neuronal damage in unilaterally lesioned 6-OHDA-induced SD rats. Precisely, the findings suggested that BBPT possessed significant anti-parkinsonian activity and has the potential to prevent dopaminergic neurodegeneration.

Effect of mGluR2 and mGluR2/3 activators on parkinsonism in the MPTP-lesioned non-human primate.

We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR2) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR2/3) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR2 positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR2 positive allosteric modulation and combined mGluR2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.

Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model

Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.

Positive allosteric mGluR2 modulation with BINA alleviates dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset.

There is mounting evidence that positive allosteric modulation of metabotropic glutamate type 2 receptors (mGluR2) is an efficacious approach to reduce the severity of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, psychosis-like behaviours (PLBs), while conferring additional anti-parkinsonian benefit. However, the mGluR2 positive allosteric modulators (PAMs) tested so far, LY-487,379 and CBiPES, share a similar chemical scaffold. Here, we sought to assess whether similar benefits would be conferred by a structurally-distinct mGluR2 PAM, biphenylindanone A (BINA). Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and PLBs were administered L-DOPA with either vehicle or BINA (0.1, 1, and 10mg/kg) in a randomised within-subject design and recorded. Behaviour was analysed by a blinded rater who scored the severity of each of parkinsonism, dyskinesia and PLBs. When added to L-DOPA, BINA 0.1mg/kg, 1mg/kg, and 10mg/kg all significantly reduced the severity of global dyskinesia, by 40%, 52% and 53%, (all P < 0.001) respectively. BINA similarly attenuated the severity of global PLBs by 35%, 48%, and 50%, (all P < 0.001) respectively. Meanwhile, BINA did not alter the effect of L-DOPA on parkinsonism exhibited by the marmosets. The results of this study provide incremental evidence of positive allosteric modulation of mGluR2 as an effective therapeutic strategy for alleviating dyskinesia and PLBs, without hindering the anti-parkinsonian action of L-DOPA. Furthermore, this therapeutic benefit does not appear to be confined to a particular chemical scaffold.

Brain-targeted nasal chrysin microemulsion for reducing oxidative stress in Parkinson's disease: Pharmacodynamic, biochemical evaluation and brain distribution studies

Chrysin, a flavone reported to treat Parkinson's, has limited oral bioavailability due to poor solubility and extensive pre-systemic metabolism. Therefore, a chrysin microemulsion (Chy-ME) was developed to improve bioavailability and brain targeting for treating Parkinson's disease via the nasal route. Chy-ME was prepared using the phase titration method and characterized for physicochemical parameters, nasociliotoxicity, and anti-Parkinson activities in a rotenone-induced experimental rat model. Chy-ME showed spherical globules with a size of 365.03 nm ± 6.8, a PDI of 0.107 ± 0.0316 and a zeta potential of −24.86 mV ± 2.286. It was non-irritant to the nasal mucosa and had in vitro and ex vivo drug release of 90.52 % and 68.67 %, respectively at 24 h. The in vivo study showed significantly improved locomotor activity and catalepsy score in the Chy-ME treated group than in oral or nasal chrysin suspension groups in rats. Chy-ME treatment showed elevated dopamine levels than the other two groups. Also, enhanced oxidative stress markers, i.e., SOD, GSH, and catalase levels, indicated the antioxidant potential of Chy-ME linked with preventing neuronal damage in Parkinson's. The maximum chrysin amount was estimated in the Chy-ME group (8.3212 ± 1.8125 μg/mL) than in oral (4.1364 ± 1.1095 μg/mL) or nasal (5.0879 ± 0.0058 μg/mL) suspension groups in the brain distribution study. In vivo studies revealed the brain-targeting potential of Chy-ME, evidenced by a substantial alleviation of Parkinson's symptoms, increased dopamine levels, improved oxidative stress markers and higher chrysin content in the brain. Therefore, nasal delivery of chrysin could overcome poor oral bioavailability and be explored for treating Parkinson-related symptoms as a brain-targeted approach.

Anti-Parkinsonian Activity of Mushrooms Against Orofacial Dyskinesia Induced by Reserpine in Wistar Rats

A neurological ailment called Parkinson’s disease (PD) which distresses roughly 1.5% of people above age 65 in the world. Dopamine nerve cell death (DA) in the Substantia nigra parc compacta (SNc) with the development of a striatal DA deficiency are two features of PD.As of now, the focalization of PD is uncertain. The goal was to assess the neuroprotective efficacy of ethanolic extracts from different mushroom species viz. P. ostreatus, A. bisporus and C. cibarius are against orofacial dyskinesia (OD) by reserpine and their in vivo antioxidant status. In this study, reserpine (1-mg/kg) was repeatedly administered on alternate days over a five-day interval to produce vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. Evaluation of reserpine-induced catalepsy was done. Catalase (CAT), glutathione reductase (GSH), superoxide dismutase (SOD) and lipid peroxidation (LPO) concentrations were examined in prosencephalon in response to an ethanolic extract of mushrooms. The histological evaluation of attenuating oxidative stress also shows the effectiveness of all these mushroom extracts. In animal models of Parkinson’s disease produced by reserpine, P. ostreatus, A. bisporus and C. cibarius were found to have a therapeutic impact against the disease.

Biochemical properties and biological potential of Syzygium heyneanum with antiparkinson's activity in paraquat induced rodent model.

Syzygium heyneanum is a valuable source of flavonoids and phenols, known for their antioxidant and neuroprotective properties. This research aimed to explore the potential of Syzygium heyneanum ethanol extract (SHE) in countering Parkinson's disease. The presence of phenols and flavonoids results in SHE displaying an IC50 value of 42.13 when assessed in the DPPH scavenging assay. Rats' vital organs (lungs, heart, spleen, liver, and kidney) histopathology reveals little or almost no harmful effect. The study hypothesized that SHE possesses antioxidants that could mitigate Parkinson's symptoms by influencing α-synuclein, acetylcholinesterase (AChE), TNF-α, and IL-1β. Both in silico and in vivo investigations were conducted. The Parkinson's rat model was established using paraquat (1 mg/kg, i.p.), with rats divided into control, disease control, standard, and SHE-treated groups (150, 300, and 600 mg/kg) for 21 days. According to the ELISA statistics, the SHE treated group had lowers levels of IL-6 and TNF-α than the disease control group, which is a sign of neuroprotection. Behavioral and biochemical assessments were performed, alongside mRNA expression analyses using RT-PCR to assess SHE's impact on α-synuclein, AChE, TNF-α, and interleukins in brain homogenates. Behavioral observations demonstrated dose-dependent improvements in rats treated with SHE (600 > 300 > 150 mg/kg). Antioxidant enzyme levels (catalase, superoxide dismutase, glutathione) were significantly restored, particularly at a high dose, with notable reduction in malondialdehyde. The high dose of SHE notably lowered acetylcholinesterase levels. qRT-PCR results indicated reduced mRNA expression of IL-1β, α-synuclein, TNF-α, and AChE in SHE-treated groups compared to disease controls, suggesting neuroprotection. In conclusion, this study highlights Syzygium heyneanum potential to alleviate Parkinson's disease symptoms through its antioxidant and modulatory effects on relevant biomarkers.

Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.

L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.

Anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities of poly-fused ring pyrimidine derivatives

Purpose: To investigate the anti-inflammatory, anti-cancer, anti-parkinsonian, anti-microbial, analgesic, and anti-hyperglycemic properties of a variety of poly-fused pyrimidine derivatives.&#x0D; Methods: A novel series of fused pyrimidine derivatives 1-6 were synthesized by reacting amino pyrazole derivatives with active methylene derivatives to give the corresponding compounds 1-6. Anti-parkinsonian activity was investigated with benzotropene as a reference drug, anti-inflammatory effect in mice was evaluated using carrageenan in paw edema with indomethacin as reference drug, anti-microbial activity was assessed using nutritional agar with ciprofloxacin and ketoconazole as reference drugs, analgesic activity was evaluated using valdecoxib as reference drug, anti-hyperglycemic activity was investigated using alloxan and sucrose models (SLM) with pioglitazone as reference drug and anticancer activity was investigated using the MTT micro-cultured tetrazolium assay method with doxorubicin as reference drug.&#x0D; Results: Pyrimidine derivatives 1-6 possess significant active anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities in comparison to the reference drugs used for each model. Compared to Benzotropene®, compounds 1 and 3 showed a significantly stronger anti-parkinsonian activity (p &lt; 0.03). Compound 3 showed a significantly stronger anti-inflammatory effect than Indomethacin® (p &lt; 0.05). Compounds 5 and 6 exhibited significant anti- microbial activity compared to ciprofloxacin® (p &lt; 0.05). Compounds 4 and 6 exhibited significantly improved analgesic activity as compared to Valdecoxib® (p &lt; 0.01). Compounds 1 and 3 exhibited significantly higher anti-hyperglycemic effects in SLM model when compared to pioglitazone® (p &lt; 0.02). Compound 5 demonstrated the highest activity against human colon cancer cell line (HT-29) and human prostate cancer cell line (DU145), and also, significantly improved level of efficacy against human lung cancer cell line (A549) compared to Doxorubicin® (p &lt; 0.02). &#x0D; Conclusion: Using the six pyrimidine derivatives 1 - 6 as a lead molecule, a novel class of clinically beneficial anti-cancer, anti-inflammatory, anti-microbial, analgesic, and anti-hyperglycemic drugs may be produced.

Potential Anti-Parkinsonian Activity of Gastrodia Elata: The Principle of Antioxidant Qualities in a Rat Model

Potential Anti-Parkinsonian Activity of Gastrodia Elata: The Principle of Antioxidant Qualities in a Rat Model

Phytochemical screening, antioxidant and anti-Parkinson activities of Berula erecta: A novel medicinal plant.

Berula erecta L. is traditionally used for the treatment of various human ailments. The present project was arranged to study the antioxidant and anti-Parkinson efficacy of B. erecta extracts against rotenone-induced Parkinson diseases in rats. Fine powder of the plant was extracted with methanol and then fractionated through various solvents with increasing order of polarity. Phytochemical screenings were done using standard protocols and High-performance liquid chromatography (HPLC) while in-vitro antioxidant activities of plant fractions were evaluated using different free radicals. In-vivo anti-Parkinson and oxidative dysfunction experiments were conducted in rats. Results revealed that various fractions possessed flavonoids, alkaloids, terpenoids saponins, tannin, anthraquinon, and phlobatanine, while terpeniods and alkaloids were absent in aqueous fraction. Chromatographic analysis of methanol fraction showed the presence of various bioactive compounds viz., vitexin, orientin, rutin, catechin and myricetin. In-vitro antioxidant activities of various fractions of Berula erecta (B.erecta) showed that methanol fraction has remarkable scavenging efficacy of 2,2-Diphenyl-1-picrylhydrazyl (DPPH), beta carotene, and superoxide free radicals followed by chloroform fraction. Free radicals produced by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), Hydrogen peroxide (H2O2), and hydroxyl free radicals were considerably scavenged by methanol fraction followed by ethyl acetate fractions. In-vivo study of animal model showed that methanol fraction has significant recovery effects at behavioural, physiological and biochemical level against rotenone induced Parkinson disease. B.erecta has significantly improved rotenone-induced motor and nonmotor deficits (depression and cognitive impairments), increased antioxidant enzyme activity, and reduced neurotransmitter changes. It has been concluded from the present data that B.erecta enhances neurotransmitter levels by alleviating oxidative stress and antioxidant enzyme activity, hence improving motor activity, cognitive functioning, and decreasing depressed behavior. These data suggest that B. erecta may be a promising medicinal agent for reducing the risk and progression of Parkinson's disease.

Antiparkinsonian Activity of Hydroalcoholic Extract of Operculina turpethum Roots in Reserpine Induced Parkinsonism in Wistar Rats

Antiparkinsonian Activity of Hydroalcoholic Extract of Operculina turpethum Roots in Reserpine Induced Parkinsonism in Wistar Rats

Screening of anti-Parkinson activity of tannic acid via antioxidant and neuroprotection in Wistar rats

BackgroundInflammation in the brain is a severe pathological state to facilitate neurodegenerative disorders. Various inflammatory mediators, such as tumor necrosis factor-α (TNF-α), nitric oxide (NO), interleukin-1 (IL-1), and prostaglandins, promote inflammation. The expression of these major inflammatory mediators is induced by the activation of microglia and astrocytes. Diseases likewise Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis are caused by uncontrolled release of pro-inflammatory cytokines. MethodsAcute (5, 50, and 300 mg kg−1), subacute study (30, 100, and 300 mg kg−1) toxicity in rats. In addition, consequence of tannic acid (TA) on haloperidol stimulated catalepsy model of PD in Wistar rats (6–8 weeks) was analysed. Toxicity study of TA has been done to identify the safer dose for experimental animals. ResultsIn vivo antioxidant assays demonstrate the suppressed amount of oxidative stress caused due to lipid peroxidation (LPO) and elevated amount of reduced glutathione (GSH),superoxide dismutase (SOD) and catalase (CAT) after assessment with TA as compared to those in only haloperidol treated rats. TNF-α and NO amount were too found to be reduced in rat model of PD when pretreated with TA. haematological analyses also demonstrated the normal level of haemoglobin (Hb), Red blood cell (RBC) count, White blood cell(WBC) count, lymphocyte count, granulocyte count, mean corpuscular volume (MCV) and platelet count in rats pretreated with TA. Histopathological analysis of rat brain tissue showed neuroprotection in groups pretreated with TA. In addition, ADMET results based on structure to activity calculation related to pharmacokinetics and toxicity assessment revealed that TA had reasonably acceptable qualities. These attributes add to our understanding of structural aspects that may boost the bioavailability of TA before going on to the early stages of medication development. ConclusionResults obtained from the present study suggest that TA have potential to be extended as effective curative candidate for PD and various neurodegenerative diseases.

Tetramic acid-motif natural products from a marine fungus Tolypocladium cylindrosporum FB06 and their anti-Parkinson activities.

The online version contains supplementary material available at 10.1007/s42995-023-00198-7.

A New Stereoselective Approach to the Substitution of Allyl Hydroxy Group in para-Mentha-1,2-diol in the Search for New Antiparkinsonian Agents.

Two approaches to the synthesis of para-menthene epoxide ((1S,5S,6R)-4) are developed. The first approach includes a reaction between chlorohydrin 7 and NaH in THF. The second involves the formation of epoxide in the reaction of corresponding diacetate 6 with sodium tert-butoxide. One possible mechanism of this reaction is proposed to explain unexpected outcomes in the regio- and stereospecificity of epoxide (1S,5S,6R)-4 formation. The epoxide ring in (1S,5S,6R)-4 is then opened by various S- and O-nucleophiles. This series of reactions allows for the stereoselective synthesis of diverse derivatives of the monoterpenoid Prottremine 1, a compound known for its antiparkinsonian activity, including promising antiparkinsonian properties.

Evaluation of the Neurobehavioural Toxicity Potential of Aqueous Ethanol Extracts of Leaf/Seed of Datura metel, Mucuna pruriens, and Tapinanthus globiferus Growing on Azadirachta indica Host Tree in Mice

Aqueous ethanol extracts of Mucuna pruriens seed (AEMPS), Datura metel leaf (AEDML) and seed (AEDMS), and Tapinanthus globiferus (AETGL) Growing on Azadirachta indica host tree are being evaluated for their anxiolytic, antidepressant, anti-parkinsonian, and addictive activities in other studies. The aim of this study was to investigate the liability or otherwise of extracts of the selected medicinal plants for some benzodiazepines-related neurobehavioural toxicities in mice. Actophotometry was used for the evaluation of the locomotory activity related to central nervous system depressant (cns) effect, diazepam-induced sleep potentiation for hypnotic liability, rodent beam (rod)-walking assay for balance and motor co-ordination, and novel object recognition test (NORT) for cognitive deficit evaluation. The results indicate, compared to negative control (distilled water) treatment mean values of 4.69±0.95 % locomotory activity reduction, 430.71±16.80 sec. sleep onset and 168.43±10.56 min. duration, 5.00±0.00 balance/motor co-ordination performance, and 54.41±1.99 novel object recognition, treatments with high oral doses of AETGL and AEMPS (1500 mg/kg each) did not significantly negatively impact these behavioural indices but even enhanced novel object recognition. High oral doses of AEDML and AEDMS (750 mg/kg each), and tramadol (133 mg/kg) caused significant (p&lt;0.05) 42.24±2.64, 27.73±2.17, and 36.74±4.44, mean % locomotory activity reductions, 196.86±10.12, 193.88±15.39, and 189.14±18.31 second mean sleep onsets and 319.71±18.85, 309.57±20.27, and 356.00±26.01 minute mean sleep durations, 1.67±0.42, 1.30±0.40, 1.833±0.48 mean balance/motor co-ordination performances, and 40.49±5.45, 31.33±5.23, 19.37±3.96 mean novel object recognitions, respectively. Diazepam (2 mg/kg) treatment caused 33.71±2.19 mean % locomotory activity reduction, 1.33±0.49 mean balance/motor co-ordination performance, and 29.91±2.81 mean novel object recognitions. Additionally, most mouse groups exposed to tramadol, AEDML, and AEDMS extracts displayed unusual (hallucination-like, predator-like) fearful trepidations when in proximity with the novel objects. These findings indicate AETGL and AEMPS extracts may be devoid of neurobehavioural toxicities but tramadol, diazepam, AEDML and AEDMS extracts may be liable to significant sedative, hypnotic, myo-relaxant, and anti-cognitive effects. These findings justify the traditional uses of Tapinanthus species and Mucuna pruriens extracts for the treatment of memory deficits and related neurological disorders. They also justify the morbid and fatal toxicity risks associated with the use of Datura metel extracts, tramadol, and the benzodiazepines.