LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants.

Idiopathic Parkinson's disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

Neuroprotective potential of Mentha piperita extract prevents motor dysfunctions in mouse model of Parkinson's disease through anti-oxidant capacities.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Neurodegeneration of the substantia nigra (SN) and diminished release of dopamine are prominent causes of this progressive disease. The current study aims to evaluate the protective potential of ethanolic extract of Mentha piperita (EthMP) against rotenone-mediated PD features, dopaminergic neuronal degeneration, oxidative stress and neuronal survival in a mouse model. Swiss albino male mice were assigned to five groups: control (2.5% DMSO vehicle), PD (rotenone 2.5 mg/kg), EthMP and rotenone (200mg/kg and 2.5mg/kg, respectively), EthMP (200 mg/kg), and Sinemet, reference treatment containing levodopa and carbidopa (20 mg/kg and rotenone 2.5mg/kg). Behavioral tests for motor functional deficit analysis were performed. Anti-oxidant capacity was estimated using standard antioxidant markers. Histopathology of the mid-brain for neurodegeneration estimation was performed. HPLC based dopamine level analysis and modulation of gene expression using quantitative real-time polymerase chain reaction was performed for the selected genes. EthMP administration significantly prevented the rotenone-mediated motor dysfunctions compared to PD group as assessed through open field, beam walk, pole climb down, stepping, tail suspension, and stride length tests. EthMP administration modulated the lipid peroxidation (LPO), reduced glutathione (GSH), and superoxide dismutase (SOD) levels, as well as glutathione-s-transferase (GST) and catalase (CAT) activities in mouse brain. EthMP extract prevented neurodegeneration in the SN of mice and partially maintained dopamine levels. The expression of genes related to dopamine, anti-oxidant potential and synapses were modulated in M. piperita (MP) extract treated mice brains. Current data suggest therapeutic capacities of MP extract and neuroprotective capacities, possibly through antioxidant capacities. Therefore, it may have potential clinical applications for PD management.

U.S. Tax Credits to Promote Practical Proactive Preventative Care for Parkinson's Disease.

Persons with Parkinson's disease (PD) and society at large can profit from a strategic investment into a forward leaning, practical, preventative, and proactive multidisciplinary care policy. The American healthcare system is not easily bent to accommodate this type of care, and thus a tax benefit is an attractive option. An individual federal income tax benefit of $6200 each year for every person residing in the US with a diagnosis of PD, could among other offerings provide monthly access to a licensed clinical social worker and access to mental health services. The implementation of more coordinated care has the potential reduce the burden of depression, anxiety, and demoralization. Personal training would also be covered and directed by physical and occupational therapists. The combination of home-based and telemedicine services would have the added benefit of improving access. The tax benefit would also provide access to a dietician. This type of care strategy could be designed to proactively identify early signs of aspiration and urinary tract infections to 'head off' significant morbidity. A $6200/year individual tax benefit for those diagnosed with PD will thus translate into more fall prevention, more care in the home setting, less hospitalizations, less depression, less anxiety, less demoralization, better diets, and less persons placed in nursing facilities. Additionally, this tax benefit will provide the potential for billions of dollars in savings to the healthcare system. A tax benefit for PD is a practical preventative and proactive strategy which can serve to advantage both this generation and the next.

Perspectives of People At-Risk on Parkinson's Prevention Research.

 The movement toward prevention trials in people at-risk for Parkinson's disease (PD) is rapidly becoming a reality. The authors of this article include a genetically at-risk advocate with the LRRK2 G2019 S variant and two patients with rapid eye movement sleep behavior disorder (RBD), one of whom has now been diagnosed with PD. These authors participated as speakers, panelists, and moderators in the "Planning for Prevention of Parkinson's: A Trial Design Forum" hosted by Massachusetts General Hospital in 2021 and 2022. Other authors include a young onset person with Parkinson's (PwP) and retired family physician, an expert in patient engagement in Parkinson's, and early career and veteran movement disorders clinician researchers. Several themes emerged from the at-risk participant voice concerning the importance of early intervention, the legitimacy of their input in decision-making, and the desire for transparent communication and feedback throughout the entire research study process. Challenges and opportunities in the current environment include lack of awareness among primary care physicians and general neurologists about PD risk, legal and psychological implications of risk disclosure, limited return of individual research study results, and undefined engagement and integration of individuals at-risk into the broader Parkinson's community. Incorporating the perspectives of individuals at-risk as well as those living with PD at this early stage of prevention trial development is crucial to success.

Protective effect of sterubin against neurochemical and behavioral impairments in rotenone-induced Parkinson's disease.

This study was conducted to evaluate how sterubin affects rotenone-induced Parkinson's disease (PD) in rats. A total of 24 rats were distributed into 4 equal groups: normal saline control and rotenone control were administered saline or rotenone (ROT), respectively, orally; sterubin 10 received ROT + sterubin 10 mg/kg po; and sterubin alone was administered to the test group (10 mg/kg). Rats of the normal saline and sterubin alone groups received sunflower oil injection (sc) daily, 1 h after receiving the treatments cited above, while rats of the other groups received rotenone injection (0.5 mg/kg, sc). The treatment was continued over the course of 28 days daily. On the 29th day, catalepsy and akinesia were assessed. The rats were then euthanized, and the brain was extracted for estimation of endogenous antioxidants (MDA: malondialdehyde, GSH: reduced glutathione, CAT: catalase, SOD: superoxide dismutase), nitrative (nitrite) stress markers, neuroinflammatory cytokines, and neurotransmitter levels and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)). Akinesia and catatonia caused by ROT reduced the levels of endogenous antioxidants (GSH, CAT, and SOD), elevated the MDA level, and altered the levels of nitrites, neurotransmitters, and their metabolites. Sterubin restored the neurobehavioral deficits, oxidative stress, and metabolites of altered neurotransmitters caused by ROT. Results demonstrated the anti-Parkinson's activities of sterubin in ROT-treated rats.

Flavonoid intake and risk of Parkinson's disease.

BACKGROUND: Flavonoids have been proposed to reduce the risk of Parkinson's disease (PD). However, results from epidemiological studies have been inconclusive. OBJECTIVE: To prospectively examine the association between the intake of flavonoids and their subclasses and the risk of PD and how pesticides may confound or modify that association. METHODS: The study population comprised 80 701 women (1984-2016) and 48 782 men (1986-2016) from two large US cohorts. Flavonoid intake was ascertained at baseline and every 4 years thereafter using a semiquantitative Food Frequency Questionnaire. We conducted multivariable-adjusted Cox regression models to estimate HRs and 95% CIs of PD according to quintiles of baseline and cumulative average intakes of flavonoids and subclasses. We repeated the analyses, adjusting for intakes of high-pesticide-residue fruits and vegetables (FVs) and stratifying by servings/day of high-pesticide-residue FV intake. RESULTS: We identified 676 incident PD cases in women and 714 in men after 30-32 years of follow-up. Higher total flavonoid intake at baseline was not associated with a lower PD risk, neither in men (HR comparing highest to lowest quintile: 0.89, 95% CI: 0.69 to 1.14) nor in women (HR comparing highest to lowest quintile: 1.27, 95% CI: 0.98 to 1.64). Similar results were observed for cumulative average intakes and flavonoid subclasses. Results remained similar after adjustment for and stratification by high-pesticide-residue FV and when analyses were restricted to younger PD cases. CONCLUSION: These results do not support a protective effect of flavonoid intake on PD risk. Pesticide residues do not confound or modify the association.

Cost-effectiveness analysis of insecticide ban aimed at preventing Parkinson's disease in Central California.

BACKGROUND: Our study assessed whether banning specific insecticides to reduce the PD burden in three Central California (CA) counties is cost-effective. METHOD: We applied a cost-effectiveness analysis using a cohort-based Markov model to estimate the impact and costs of banning seven insecticides that were previously associated with PD in these counties as well as mixture exposures to some of these pesticides. We relied for our estimations on the cohort of 65- and 66-year-olds living in these counties who were unaffected by PD at baseline in 2020 and projected their incidence, costs, and reduction in quality-adjusted-life-years (QALY) loss due to developing PD over a 20-year period. We included a shiny app for modeling different scenarios (https://sherlockli.shinyapps.io/pesticide_pd_economics_part_2/). RESULTS: According to our scenarios, banning insecticides to reduce the occurrence of PD in three Central CA counties was cost-effective relative to not banning insecticides. In the worst-case scenario of exposure to a single pesticide, methomyl, versus none would result in an estimated 205 (95 % CI: 75, 348) additional PD cases or 12 % (95 % CI: 4 %, 20 %) increase in PD cases over a 20-year period based on residential proximity to pesticide applications. The increase in PD cases due to methomyl would increase health-related costs by $72.0 million (95 % CI: $5.5 million, $187.4 million). Each additional PD patient due to methomyl exposure would incur $109,327 (95 % CI, $5554, $347,757) in costs per QALY loss due to PD. Exposure to methomyl based on workplace proximity to pesticide applications generated similar estimates. The highest PD burden and associated costs would be incurred from exposure to multiple pesticides simultaneously. CONCLUSION: Our study provides an assessment of the cost-effectiveness of banning specific insecticides to reduce PD burden in terms of health-related QALYs and related costs. This information may help policymakers and stakeholders to make decisions concerning the regulation of pesticides.

Vitamin C, vitamin E, ß-carotene and risk of Parkinson's disease: a systematic review and dose-response meta-analysis of observational studies.

OBJECTIVE: This study aimed to explore the relationship between the intake of vitamin C, vitamin E and ß-carotene, and the risk of Parkinson's disease (PD). METHODS: Web of Science, Embase, PubMed, Cochrane library, CNKI, and WanFang databases were searched from inception to 29 August 2022 for observational studies reporting the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by Vitamin C/Vitamin E/ß-carotene intake. Random-effects models, publication bias assessment, subgroup, sensitivity and dose-response analyses were performed, using.Stata version 12.0. RESULTS: A total of 13 studies were included. There was no significant association between high-dose vitamin C intake and the risk of PD compared with low-dose vitamin C intake (RR = 0.98, 95%CI:0.89,1.08). Compared with low-dose intake, high-dose intake of vitamin E can prevent the risk of PD (RR = 0.87, 95%CI:0.77,0.99). Compared with lower ß-carotene intake, there was a borderline non-significant correlation between higher intake and PD risk (RR = 0.91, 95%CI:0.82,1.01), and high dose ß-carotene intake was found to be associated with a lower risk of PD in women (RR = 0.78, 95%CI:0.64,0.96). CONCLUSION: This study shows that vitamin E intake can reduce the risk of PD and play a preventive role.

The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers.

The aggregation of α-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining α-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlorophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to α-Syn residues, demonstrating promising inhibitory activity against α-Syn aggregation in vitro, with low IC50 values (1.35 and 1.08 µM, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing α-Syn's conformation and preventing the formation of ß-sheet aggregates. They also effectively disassembled preformed α-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric α-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting α-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.

Neuroprotective effect of dexpanthenol on rotenone-induced Parkinson's disease model in rats.

Parkinson's disease (PD) is the second most common and progressive neurodegenerative disease. This experimental study was designed to investigate the neuroprotective effects of dexpanthenol on antioxidant and anti-inflammatory processes in a rotenone-induced Parkinson's disease model in rats. Twenty-one male rats were randomly divided into 2 groups. The rotenone group (n = 14) was administered rotenone by intrastriatal injection, and the vehicle group (n = 7) was administered DMSO with the same application route. All animals underwent rotational movement testing with apomorphine injection 10 days later. Those with Parkinson's disease model were randomly divided into 2 groups. While 1 ml/kg of saline was applied to the saline group (n = 7), 500 mg/kg was administered to the dexpanthenol group intraperitoneally for 28 days. After 28 days, all rats were euthanized and brain tissue was removed. While striatal areas were evaluated immunohistochemically, brain MDA, TNF-α, and HVA levels were measured to evaluate their anti-oxidative and anti-inflammatory effects. In the dexpanthenol group, the total count (p < 0.001) and intensity (p < 0.001) of dopaminergic neurons in the striatal areas increased compared to the saline group. It was revealed that MDA (nmol/g) (p < 0.001) and TNF-α (pg/g) (p < 0.001) levels decreased in the dexpanthenol group, while HVA (ng/mg) levels increased (p < 0.01). This study suggests that dexpanthenol may have a neuroprotective effect by reducing neuronal loss, oxidative damage, and neuroinflammation in the striatum in rats.

[Risk factors for Parkinson's disease: possibilities for prevention and intervention]. / Risicofactoren voor de ziekte van Parkinson.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.

Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

Low and high doses of oral maslinic acid protect against Parkinson's disease via distinct gut microbiota-related mechanisms.

The use of oral agents that can modify the gut microbiota (GM) could be a novel preventative or therapeutic option for Parkinson's disease (PD). Maslinic acid (MA), a pentacyclic triterpene acid with GM-dependent biological activities when it is taken orally, has not yet been reported to be effective against PD. The present study found both low and high dose MA treatment significantly prevented dopaminergic neuronal loss in a classical chronic PD mouse model by ameliorating motor functions and improving tyrosine hydroxylase expressions in the substantia nigra pars compacta (SNpc) and increasing dopamine and its metabolite homovanillic acid levels in the striatum. However, the effects of MA in PD mice were not dose-responsive, since similar beneficial effects for low and high doses of MA were observed. Further mechanism studies indicated that low dose MA administration favored probiotic bacterial growth in PD mice, which helped to increase striatal serotonin, 5-hydroxyindole acetic acid, and γ-aminobutyric acid levels. High dose MA treatment did not influence GM composition in PD mice but significantly inhibited neuroinflammation as indicated by reduced levels of tumor necrosis factor alpha and interleukin 1ß in the SNpc; moreover, these effects were mainly mediated by microbially-derived acetic acid in the colon. In conclusion, oral MA at different doses protected against PD via distinct mechanisms related to GM. Nevertheless, our study lacked in-depth investigations of the underlying mechanisms involved; future studies will be designed to further delineate the signaling pathways involved in the interactive actions between different doses of MA and GM.

Lactobacillus plantarum CCFM405 against Rotenone-Induced Parkinson's Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis.

Recent studies have demonstrated that disturbances in the gut microbiota and microbiota -derived metabolites contribute to the pathogenesis of Parkinson's disease (PD), suggesting that probiotic treatments that restore them may delay disease progression. This study aimed to examine the attenuating efficacy of L. plantarum CCFM405 and the potential mechanisms in mice with rotenone-induced PD. Our results indicate that L. plantarum CCFM405 ameliorated rotenone-induced motor deficits and constipation, decreased dopaminergic neuronal death, reduced intestinal inflammation and neuroinflammation, and raised dopamine levels, 5-HT, and associated metabolites in the striatal region of the brain in mice with PD. Sequencing of 16S rRNA from fecal microbiota revealed that L. plantarum CCFM405 normalized the gut bacterial composition in mice with PD, as evidenced by the increased relative abundance of the following genus, Bifidobacterium, Turicibacter, and Faecalibaculum, and decreased relative abundance of Alistipes, Bilophila, Akkermansia, and Escherichia-Shigella. The PICRUSt-predicted gut microbiota function revealed that L. plantarum CCFM405 enhanced the biosynthesis of amino acid pathways, particularly valine, leucine, and isoleucine (branched-chain amino acids, BCAAs). A non-metabolomic analysis of the serum and feces showed that L. plantarum CCFM405 markedly increased the levels of BCAAs. Pathway enrichment analysis based on the KEGG database further suggested that L. plantarum CCFM405 supplementation can promote BCAAs biosynthesis. Collectively, L. plantarum CCFM405 can help to prevent rotenone-induced PD by modulating the gut microbiota-metabolite axis. BCAAs may play a dominant role in L. plantarum CCFM405-associated neuroprotection in PD mice. This probiotic could be utilized as a potential food supplement in the management of PD.

ß-carotene-loaded nanoparticles protect against neuromotor damage, oxidative stress, and dopamine deficits in a model of Parkinson's disease in Drosophila melanogaster.

ß-carotene-loaded nanoparticles improves absorption by increasing bioavailability. The Drosophila melanogaster model of Parkinson's disease must be helpful in investigating potential neuroprotective effects. Four groups of four-day-old flies were exposed to: (1) control; (2) diet containing rotenone (500 µM); (3) ß-carotene-loaded nanoparticles (20 µM); (4) ß-carotene-loaded nanoparticles and rotenone for 7 days. Then, the percentage of survival, geotaxis tests, open field, aversive phototaxis and food consumption were evaluated. At the end of the behaviors, the analyses of the levels of reactive species (ROS), thiobarbituric acid reactive substances (TBARS), catalase (CAT) and superoxide dismutase (SOD) activity was carried out, as well as an evaluation of the levels of dopamine and acetylcholinesterase (AChE) activity, in the head of flies. Nanoparticles loaded with ß-carotene were able to improve motor function, memory, survival and also restored the oxidative stress indicators (CAT, SOD, ROS and TBARS), dopamine levels, AChE activity after exposure to rotenone. Overall, nanoparticles loaded with ß-carotene showed significant neuroprotective effect against damage induced by the Parkinson-like disease model, emerging as a possible treatment. Overall, ß-carotene-loaded nanoparticles presented significant neuroprotective effect against damage induced by model of Parkinson-like disease, emerging as a possible treatment.

Vinpocetine prevents rotenone-induced Parkinson disease motor and non-motor symptoms through attenuation of oxidative stress, neuroinflammation and α-synuclein expressions in rats.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Epidemiological reports showed a significant association between environmental toxicants-induced gut dysbiosis and PD. Neuroinflammation, mitochondrial dysfunction and decreased cerebral blood flow are hallmarks of PD. This study sought to evaluate the protective ability of vinpocetine (VIN), a neuroprotectant, on rotenone (ROT) (mitochondrial complex I inhibitor) induced PD in rats. Sixty male Sprague Dawley rats were randomly divided into six groups (n = 10) and treated orally as follows; group 1: vehicle (10 ml/kg); group 2: rotenone (10 mg/kg) + vehicle; group 3-5: vinpocetine (5, 10 or 20 mg/kg) + rotenone (10 mg/kg), respectively, or group 6: vinpocetine 20 mg/kg before behavioural assay for motor symptoms (fore-limb hanging test and open field test) and non-motor symptoms (working memory and learning capabilities in Y-maze/Morris water maze tasks, anxiety in hole board test and gut motility with intestinal transit time). Following treatment for 28 days, biochemical assays and immunostaining was performed. We examined the effect of vinpocetine on rotenone-induced oxidative stress and inflammatory markers. The pretreatment of rats with vinpocetine reversed rotenone-induced locomotor deficit, motor incoordination, cognition deficits and gut dysfunction. In addition, rotenone-induced a significant increase in the level of interleukin-6 and tumor necrotic factor-α, oxidative stress markers, cholinergic signalling, gut dysfunction and haematologic dysfunctions which were attenuated by vinpocetine administration. Immunostainings showed that rotenone-induced dopamine neuron loss, microglia reactivity, astrocytes activation, toll-like receptor 4 (TLR4) and α-synuclein (SNCA) expressions which were attenuated by vinpocetine administration. Findings from this study revealed a neuroprotective effect of vinpocetine on rotenone-induced PD through anti-neuroinflammatory and antioxidant mechanisms.

HR LC-MS/MS metabolomic profiling of Yucca aloifolia fruit and the potential neuroprotective effect on rotenone-induced Parkinson's disease in rats.

Yucca aloifolia L. fruit (Yucca or Spanish bayonet, family Asparagaceae) is recognized for its purplish red color reflecting its anthocyanin content, which has a powerful antioxidant activity. This study aimed to investigate yucca (YA) fruit extract's protective effect on Parkinson's disease (PD). In vitro study, the anti-inflammatory activity of yucca fruit extracts was explored by measuring tumor necrosis factor receptor 2 (TNF-R2) and nuclear factor kappa B (NF-KB) to choose the most effective extract. Afterward, a detailed in vivo investigation of the protective effect of the most active extract on rotenone-induced PD was performed on male albino Wister rats. First, the safety of the extract in two different doses (50 and 100 mg/kg in 0.9% saline orally) was confirmed by a toxicological study. The rats were divided into four groups: 1) normal control (NC); 2) rotenone group; and third and fourth groups received 50 and 100 mg/kg yucca extract, respectively. The neurobehavioral and locomotor activities of the rats were tested by rotarod, open field, and forced swim tests. Striatal dopamine, renal and liver functions, and oxidative stress markers were assessed. Western blot analysis of brain tissue samples was performed for p-AMPK, Wnt3a, and ß-catenin. Histopathological examination of striatal tissue samples was performed by light and electron microscopy (EM). The metabolites of the active extract were characterized using high-resolution LC-MS/MS, and the results showed the prevalence of anthocyanins, saponins, phenolics, and choline. Biochemical and histopathological tests revealed a dose-dependent improvement with oral Yucca extract. The current study suggests a possible neuroprotective effect of the acidified 50% ethanol extract (YA-C) of the edible Yucca fruit, making it a promising therapeutic target for PD.