Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, but whether its etiology is cell autonomous remains unclear. Increasing evidence implicates the blood-central nervous system (CNS) barriers in disease development, highlighting the importance of identifying genetic risk factors linked to cells forming the cerebrovasculature to advance this emerging area of research. The objective of this study is to identify PD genetic risk factors associated with blood-brain (BBB) and blood-cerebrospinal fluid (BCSFB) barriers, and to validate protein localization in human tissue and experimental models. To do so, we integrated genome-wide association studies and single nuclei RNA-sequencing datasets from the human postmortem substantia nigra (SN), midbrain, or cortical samples from control and PD donors. An in-depth bioinformatics analysis identified genes enriched in cell types that form the multicellular architecture of brain barriers, including CAVIN2, ANXA1, ANO2, and LRP1B. We further validated whether corresponding proteins were present in cell types associated with the blood-CNS barriers in human and mouse post-mortem tissues, as well as in iPSC-differentiated cells and choroid plexus organoids. Results showed that quantifying the proportion of endothelial cells expressing PD-related genes was under-evaluated at the transcript level compared to immunofluorescence analyses. In addition, we observed that CAVIN2 and ANXA1 proteins were more abundant at the vasculature of the substantia nigra vs. cortex, and CAVIN2 protein levels were reduced in PD vs. control human postmortem tissues. In contrast, the investigation of mouse postmortem samples demonstrated that the CAVIN2 protein is only present in a subset of mouse blood vessels, compared to nearly all vessels in human tissue. Similarly, mouse ANXA1 protein localizes to dopaminergic neurons of the substantia nigra and not at the vasculature, as seen in human tissue. The primary outcome of this study is the identification of PD-relevant risk genes specifically expressed at brain barriers and enriched in PD-relevant brain regions. The secondary outcome is the demonstration of poor transcript-protein correlation in – at least – a subset of PD risk factors, and a low interspecies conservation of protein localization for the selected candidates. In conclusion, the BBB and BCSFB may represent understudied contributors to PD, endothelial-specific proteins appear differentially regulated compared to transcripts, and experimental models require comprehensive validation to ensure relevance to the human condition.

The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.

Medical research that meaningfully serves global populations must reflect the complexity of human diversity. However, historically, much of biomedical and public health research has failed to incorporate key dimensions such as sex/gender, ethnicity, culture, and socioeconomic status (Braveman and Gottlieb, 2014; George et al., 2014; Oh et al., 2015; Subramaniapillai et al., 2024). Health outcomes—particularly those related to brain and neurological function—are shaped not only by biological factors but also by environmental factors and structural inequities that influence access to care, exposure to risk, and inclusion in scientific research (National Academies of Sciences, 2023; Legaz et al., 2025; Williams and Collins, 2013). This Research Topic brings together five timely contributions that illuminate how social, economic, and demographic disparities intersect to shape major neurological and public health challenges—from stroke and concussion to gender-based violence and premature mortality. Together, these contributions underscore the urgent need for equity-driven approaches in both research and policy, offering insight into the systemic reforms needed to close persistent gaps in health outcomes.

Parkinson's disease (PD) is a neurodegenerative illness characterized by motor and non-motor features. Hallmarks of the disease include an extensive loss of dopaminergic neurons in the substantia nigra pars compacta, evidence of neuroinflammation, and the accumulation of misfolded proteins leading to the formation of Lewy bodies. While PD etiology is complex and identifying a single disease trigger has been a challenge, accumulating evidence indicates that non-neuronal and peripheral factors may likely contribute to disease onset and progression. The brain is shielded from peripheral factors by the blood-brain barrier (BBB), which tightly controls the entry of systemic molecules and cells from the blood to the brain. The BBB integrates molecular signals originating from the luminal (blood) and abluminal (brain) sides of the endothelial wall, regulating these exchanges. Of particular interest are erythrocytes, which are not only the most abundant cell type in the blood, but they also secrete extracellular vesicles (EVs) that display disease-specific signatures over the course of PD. Erythrocyte-derived EVs (EEVs) could provide a route by which pathological molecular signals travel from the periphery to the central nervous system. The primary objective of this study was to evaluate, in a human-based platform, mechanisms of EEV transport from the blood to the brain under physiological conditions. The secondary objective was to determine the ability of EEVs, generated by erythrocytes of healthy donors or patients, to induce PD-like features. We leveraged two in vitro models of the BBB, the transwell chambers and a microfluidic BBB chip generated using human induced pluripotent stem cells. Our findings suggest that EEVs transcytose from the vascular to the brain compartment of the human BBB model via a caveolin-dependant mechanism. Furthermore, EEVs derived from individuals with PD altered BBB integrity compared to healthy EEV controls, and clinical severity aggravated the loss of barrier integrity and increased EEV extravasation into the brain compartment. PD-derived EEVs reduced ZO-1 and Claudin 5 tight junction levels in BMEC-like cells and induced the selective atrophy of dopaminergic neurons. In contrast, non-dopaminergic neurons were not affected by treatment with PD EEVs. In summary, our data suggest that EEV interactions at the human BBB can be studied using a highly translational human-based brain chip model, and EEV toxicity at the neurovascular unit is exacerbated by disease severity.

Parkinson’s disease is a neurodegenerative disorder with limited treatment options, and current medications often cause side effects. This has led to growing interest in non-pharmacological interventions, including natural health products such as cannabis, coffee, and velvet bean. However, little is known about how many people with Parkinson’s disease use or wish to use these products and their awareness of potential interactions with prescribed medication.

A survey of 367 individuals with Parkinson’s disease found that 36% had used natural health products for symptom relief, with coffee (16%), cannabis (13%), and turmeric (10%) being the most popular. Additionally, 71% of participants expressed interest in learning more about these products, but only 39% of users were aware of possible interactions with prescribed medication. Furthermore, just 39% had discussed their use with healthcare providers.

These findings highlight the need for further research on the benefits and safety of natural health products. Open discussions with healthcare professionals are encouraged to ensure their safe integration into treatment plans for Parkinson’s disease.

Our limited understanding of complex neurodegenerative disorders has held us back on the development of efficient therapies. While several approaches are currently being considered, it is still unclear what will be most successful. Among the latest and more novel ideas, the concept of blood or plasma transfusion from young healthy donors to diseased patients is gaining momentum and attracting attention beyond the scientific arena. While young or healthy blood is enriched with protective and restorative components, blood from older subjects may accumulate neurotoxic agents or be impoverished of beneficial factors. In this commentary, we present an overview of the compelling evidence collected in various animal models of brain diseases (e.g., Alzheimer, Parkinson, Huntington) to the actual clinical trials that have been conducted to test the validity of blood-related treatments in neurodegenerative diseases and argue in favor of such approach.

Understanding how natural products promote brain health is key to designing diverse strategies to improve the lives of people with, or at risk of developing neurodegenerative disorders. The mechanisms of action involved and recent technological progress are discussed.

Astrocyte dysfunction has previously been linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Among their many roles, astrocytes are mediators of the brain immune response, and astrocyte reactivity is a pathological feature of PD. They are also involved in the formation and maintenance of the blood-brain barrier (BBB), but barrier integrity is compromised in people with PD. This study focuses on an unexplored area of PD pathogenesis by characterizing the interplay between astrocytes, inflammation and BBB integrity, and by combining patient-derived induced pluripotent stem cells with microfluidic technologies to generate a 3D human BBB chip. Here we report that astrocytes derived from female donors harboring the PD-related LRRK2 G2019S mutation are pro-inflammatory and fail to support the formation of a functional capillary in vitro. We show that inhibition of MEK1/2 signaling attenuates the inflammatory profile of mutant astrocytes and rescues BBB formation, providing insights into mechanisms regulating barrier integrity in PD. Lastly, we confirm that vascular changes are also observed in the human postmortem substantia nigra of both males and females with PD.

Parkinson’s disease (PD) is a neurodegenerative disorder involving motor symptoms caused by a loss of dopaminergic neurons in the substantia nigra region of the brain. Epidemiological evidence suggests that anthocyanin (ANC) intake is associated with a low risk of PD. Previously, we reported that extracts enriched with ANC and proanthocyanidins (PAC) suppressed dopaminergic neuron death elicited by the PD-related toxin rotenone in a primary midbrain culture model. Here, we characterized botanical extracts enriched with a mixed profile of polyphenols, as well as a set of purified polyphenolic standards, in terms of their ability to mitigate dopaminergic cell death in midbrain cultures exposed to another PD-related toxicant, paraquat (PQ), and we examined underlying neuroprotective mechanisms. Extracts prepared from blueberries, black currants, grape seeds, grape skin, mulberries, and plums, as well as several ANC, were found to rescue dopaminergic neuron loss in PQ-treated cultures. Comparison of a subset of ANC-rich extracts for the ability to mitigate neurotoxicity elicited by PQ versus rotenone revealed that a hibiscus or plum extract was only neuroprotective in cultures exposed to rotenone or PQ, respectively. Several extracts or compounds with the ability to protect against PQ neurotoxicity increased the activity of the antioxidant transcription factor Nrf2 in cultured astrocytes, and PQ-induced dopaminergic cell death was attenuated in Nrf2-expressing midbrain cultures. In other studies, we found that extracts prepared from hibiscus, grape skin, or purple basil (but not plums) rescued defects in O2 consumption in neuronal cells treated with rotenone. Collectively, these findings suggest that extracts enriched with certain combinations of ANC, PAC, stilbenes, and other polyphenols could potentially slow neurodegeneration in the brains of individuals exposed to PQ or rotenone by activating cellular antioxidant mechanisms and/or alleviating mitochondrial dysfunction.

The use of human derived induced pluripotent stem cells (hiPSCs) differentiated to dopaminergic (DA) neurons offers a valuable experimental model to decorticate the cellular and molecular mechanisms of Parkinson's disease (PD) pathogenesis. However, the existing approaches present with several limitations, notably the lengthy time course of the protocols and the high variability in the yield of DA neurons. Here we report on the development of an improved approach that combines neurogenin-2 programming with the use of commercially available midbrain differentiation kits for a rapid, efficient, and reproducible directed differentiation of hiPSCs to mature and functional induced DA (iDA) neurons, with minimum contamination by other brain cell types. Gene expression analysis, associated with functional characterization examining neurotransmitter release and electrical recordings, support the functional identity of the iDA neurons to A9 midbrain neurons. iDA neurons showed selective vulnerability when exposed to 6-hydroxydopamine, thus providing a viable in vitro approach for modeling PD and for the screening of small molecules with neuroprotective proprieties.

Drug-refractory forms of neurological diseases could find their next breakthrough therapy in non-pharmacological approaches to brain repair. Lentini et al. present the potential of in situ brain regeneration to address neurodegeneration in the epileptic brain

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Huntington's disease is classically described as a neurodegenerative disorder of monogenic aetiology. The disease is characterized by an abnormal polyglutamine expansion in the huntingtin gene, which drives the toxicity of the mutated form of the protein. However, accumulation of the microtubule-associated protein tau, which is involved in a number of neurological disorders, has also been observed in patients with Huntington's disease. In order to unravel the contribution of tau hyperphosphorylation to hallmark features of Huntington's disease, we administered weekly intraperitoneal injections of the anti-tau pS202 CP13 monoclonal antibody to zQ175 mice and characterized the resulting behavioral and biochemical changes. After 12 weeks of treatment, motor impairments, cognitive performance and general health were improved in zQ175 mice along with a significant reduction in hippocampal pS202 tau levels. Despite the lack of effect of CP13 on neuronal markers associated with Huntington's disease pathology, tau-targeting enzymes and gliosis, CP13 was shown to directly impact mutant huntingtin aggregation such that brain levels of amyloid fibrils and huntingtin oligomers were decreased, while larger huntingtin protein aggregates were increased. Investigation of CP13 treatment of Huntington's disease patient-derived induced pluripotent stem cells (iPSCs) revealed a reduction in pS202 levels in differentiated cortical neurons and a rescue of neurite length. Collectively, these findings suggest that attenuating tau pathology could mitigate behavioral and molecular hallmarks associated with Huntington's disease.

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Background: The COVID-19 pandemic has necessitated the social isolation of the population and the rapid implementation of remote care for patients with neurodegenerative diseases. The objective of this study was to explore the perceived impact of confinement in patients with Parkinson's disease and document the effects of gender and living environment.

Methods: We recruited two cohorts from the Canadian provinces of Québec and Alberta, which differed in the dynamics of COVID-19 spreading at the time of the study, and administered a questionnaire on the perceived effects of confinement on daily living and disease management.

Results: The data reveals that approximately half of the patients experienced a change in one or more clinical symptoms, with differences observed between gender (e.g. day-to-day changes in slowness in men, aggravated headaches in women) and geographic location (e.g. increased depression in Alberta but reduced sleep quality in Québec). Furthermore, participants identifying as women or living in Alberta implemented more frequently home or online exercise. Lastly, high levels of satisfaction with phone or video consultations did not translate into a sustained interest to pursue this mode of healthcare.

Conclusions: This study suggests that COVID-19-related confinement affected Parkinson's disease manifestation and management. Patients also reported varying levels of interest to continue remote care. A number of differences reported in our study were seemingly related to gender and living environment.

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Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remain largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes and identify the abnormal accumulation of key PD-related proteins within multivesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs and that LRRK2 G2019S EVs are abnormally enriched in neurites and fail to provide full neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein α-synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the disease's motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. In this study, we characterized the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

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Neurodegenerative disorders emerge from the failure of intricate cellular mechanisms, which ultimately lead to the loss of vulnerable neuronal populations. Research conducted across several laboratories has now provided compelling evidence that pathogenic proteins can also contribute to non-cell autonomous toxicity in several neurodegenerative contexts, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic Lateral Sclerosis. Given the nearly ubiquitous nature of abnormal protein accumulation in such disorders, elucidating the mechanisms and routes underlying these processes is essential to the development of effective treatments. To this end, physiologically relevant human in vitro models are critical to understand the processes surrounding uptake, release and nucleation under physiological or pathological conditions. This review explores the use of human-induced pluripotent stem cells (iPSCs) to study prion-like protein propagation in neurodegenerative diseases, discusses advantages and limitations of this model, and presents emerging technologies that, combined with the use of iPSC-based models, will provide powerful model systems to propel fundamental research forward.

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Neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis are characterized by the loss of specific subpopulations of neurons in different regions of the brain, as well as by pathological alterations characteristic of dysfunctional glia. Disease-related alterations in glial biology result in cellular dysfunction including neuroinflammation, increased oxidative stress, and metabolic alterations that affect the homeostasis of the brain microenvironment and impair glia-to-neuron communication. In particular, disruption of astrocyte-mediated neurotrophic support, or activation of astrocyte neurotoxic signaling are two possible mechanisms of non-cell autonomous neurodegeneration, and suggest that restoring astrocyte function is an attractive therapeutic strategy. This chapter will explore the use of induced pluripotent stem cells to model astrocyte-mediated neuron loss in neurodegenerative diseases, and the potential of dietary and medicinal natural products to restore healthy astrocytic functions. Furthermore, regenerative medicine approaches leveraging in vivo genetic manipulations to convert astrocytes into neurons and replenish lost neuronal populations will be discussed.

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by severe motor, cognitive and psychiatric impairments. While motor deficits often confirm diagnosis, cognitive dysfunctions usually manifest early in the disease process and are consistently ranked among the leading factors that impact the patients' quality of life. The genetic component of HD, a mutation in the huntingtin (HTT) gene, is traditionally presented as the main contributor to disease pathology. However, accumulating evidence suggests the implication of the microtubule-associated tau protein to the pathogenesis and therefore, proposes an alternative conceptual framework where tau and mutant huntingtin (mHTT) act conjointly to drive neurodegeneration and cognitive dysfunction. This perspective on disease etiology offers new avenues to design therapeutic interventions and could leverage decades of research on Alzheimer's disease (AD) and other tauopathies to rapidly advance drug discovery. In this mini review, we examine the breadth of tau-targeting treatments currently tested in the preclinical and clinical settings for AD and other tauopathies, and discuss the potential application of these strategies to HD.

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Induced pluripotent stem cell (iPSC)-based models are powerful tools to study neurodegenerative diseases such as Parkinson's disease. The differentiation of patient-derived neurons and astrocytes allows investigation of the molecular mechanisms responsible for disease onset and development. In particular, these two cell types can be mono- or co-cultured to study the influence of cell-autonomous and non-cell-autonomous contributors to neurodegenerative diseases. We developed a streamlined procedure to produce high-quality/high-purity cultures of dopaminergic neurons and astrocytes that originate from the same population of midbrain floor-plate progenitors. This unit describes differentiation, quality control, culture parameters, and troubleshooting tips to ensure the highest quality and reproducibility of research results. © 2019 The Authors. Basic Protocol 1: Differentiation of iPSCs into midbrain-patterned neural progenitor cells Support Protocol: Quality control of neural progenitor cells Basic Protocol 2: Differentiation of neural progenitor cells into astrocytes Basic Protocol 3: Differentiation of neural progenitor cells into dopaminergic neurons Basic Protocol 4: Co-culture of iPSC-derived neurons and astrocytes.

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Ethnopharmacological relevance: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta and the presence in surviving neurons of Lewy body inclusions enriched with aggregated forms of the presynaptic protein α-synuclein (aSyn). Although current therapies provide temporary symptomatic relief, they do not slow the underlying neurodegeneration in the midbrain. In this study, we analyzed contemporary herbal medicinal practices used by members of the Lumbee tribe to treat PD-related symptoms, in an effort to identify safe and effective herbal medicines to treat PD.

Aim of the study: The aims of this study were to (i) document medicinal plants used by Lumbee Indians to treat PD and PD-related symptoms, and (ii) characterize a subset of plant candidates in terms of their ability to alleviate neurotoxicity elicited by PD-related insults and their potential mechanisms of neuroprotection.

Materials and methods: Interviews of Lumbee healers and local people were carried out in Pembroke, North Carolina, and in surrounding towns. Plant samples were collected and prepared as water extracts for subsequent analysis. Extracts were characterized in terms of their ability to induce activation of the nuclear factor E2-related factor 2 (Nrf2) antioxidant response in cortical astrocytes. An extract prepared from Sambucus caerulea flowers (elderflower extract) was further examined for the ability to induce Nrf2-mediated transcription in induced pluripotent stem cell (iPSC)-derived astrocytes and primary midbrain cultures, to ameliorate mitochondrial dysfunction, and to alleviate rotenone- or aSyn-mediated neurotoxicity.

Results: The ethnopharmacological interviews resulted in the documentation of 32 medicinal plants used to treat PD-related symptoms and 40 plants used to treat other disorders. A polyphenol-rich extract prepared from elderflower activated the Nrf2-mediated antioxidant response in cortical astrocytes, iPSC-derived astrocytes, and primary midbrain cultures, apparently via the inhibition of Nrf2 degradation mediated by the ubiquitin proteasome system. Furthermore, the elderflower extract rescued mitochondrial functional deficits in a neuronal cell line and alleviated neurotoxicity elicited by rotenone and aSyn in primary midbrain cultures.

Conclusions: These results highlight potential therapeutic benefits of botanical extracts used in traditional Lumbee medicine, and they provide insight into mechanisms by which an elderflower extract could suppress neurotoxicity elicited by environmental and genetic PD-related insults.

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Ethnopharmacological relevance: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder affecting 5% of the population over the age of 85 years. Current treatments primarily involve dopamine replacement therapy, which leads to temporary relief of motor symptoms but fails to slow the underlying neurodegeneration. Thus, there is a need for safe PD therapies with neuroprotective activity. In this study, we analyzed contemporary herbal medicinal practices used by members of the Pikuni-Blackfeet tribe from Western Montana to treat PD-related symptoms, in an effort to identify medicinal plants that are affordable to traditional communities and accessible to larger populations.

Aim of the study: The aims of this study were to (i) identify medicinal plants used by the Pikuni-Blackfeet tribe to treat individuals with symptoms related to PD or other CNS disorders, and (ii) characterize a subset of the identified plants in terms of antioxidant and neuroprotective activities in cellular models of PD.

Materials and methods: Interviews of healers and local people were carried out on the Blackfeet Indian reservation. Plant samples were collected, and water extracts were produced for subsequent analysis. A subset of botanical extracts was tested for the ability to induce activation of the Nrf2-mediated transcriptional response and to protect against neurotoxicity elicited by the PD-related toxins rotenone and paraquat.

Results: The ethnopharmacological interviews resulted in the documentation of 26 medicinal plants used to treat various ailments and diseases, including symptoms related to PD. Seven botanical extracts (out of a total of 10 extracts tested) showed activation of Nrf2-mediated transcriptional activity in primary cortical astrocytes. Extracts prepared from Allium sativum cloves, Trifolium pratense flowers, and Amelanchier arborea berries exhibited neuroprotective activity against toxicity elicited by rotenone, whereas only the extracts prepared from Allium sativum and Amelanchier arborea alleviated PQ-induced dopaminergic cell death.

Conclusions: Our findings highlight the potential clinical utility of plants used for medicinal purposes over generations by the Pikuni-Blackfeet people, and they shed light on mechanisms by which the plant extracts could slow neurodegeneration in PD.

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are debilitating, incurable neurodegenerative disorders. Intensive research efforts have been focused on characterizing a role for the diet in AD and PD, with a view toward identifying dietary components that could reduce the risk of disease or slow neurodegeneration in the brains of patients. Various plant constituents, including isothiocyanates, sulfur compounds, and polyphenols, have been examined in terms of their ability to alleviate neurotoxicity in cellular and animal models of AD or PD. Mechanisms by which these phytochemicals carry out their neuroprotective effects include activation of cellular antioxidant responses mediated by the transcription factors Nrf2 and PGC-1α, stimulation of mitochondrial biogenesis, and attenuation of glial activation. A number of dietary plant constituents have been linked epidemiologically to reduced AD or PD risk and are known to penetrate the blood–brain barrier, suggesting that they could be of therapeutic benefit to patients.

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Parkinson’s disease (PD) is a complex neurodegenerative disorder that involves a constellation of motor and nonmotor symptoms. Although several medications are moderately effective in attenuating motor symptoms during the early stages of PD, there are currently no therapies available to slow the underlying neurodegeneration, in large part because the molecular underpinnings of the disease are incompletely understood. In this chapter, we review neuropathological, toxicological, and genetic data supporting the premise that mitochondrial dysfunction and autophagic impairment play a central role in PD pathogenesis. Moreover, we examine findings suggesting that the interplay between these two toxic phenomena contributes to neurodegeneration in the brains of PD patients. Finally, we discuss how insights into the roles of mitochondrial and autophagic impairment in PD can set the stage for developing disease-modifying therapies.

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Ethnopharmacological relevance: Nepal is a hotspot for cultural and biological diversities. The tremendous diversity of ecosystems and climates and the blend of medicinal practices inherited from Ayurvedic and Traditional Tibetan Medicine are well suited to a study aimed at discovering information about medicinal plants to treat Parkinson's disease (PD). In addition, this study across Nepal's altitudinal range is relevant to understanding how cultural and ecological environments influence local traditional medicines. The aim of the study is to document the uses of medicinal plants in three different eco-geographical areas of Nepal (Chitwan-Panchase-Mustang) to treat symptoms related to PD. A second goal is to analyze the impact of culture and environment on the evolution of traditional medicine.

Materials and methods: The study was conducted in five communities located in three different eco-geographical environments and at altitudes ranging from 300m to 3700m. We interviewed a total of 56 participants (local people, folk, Ayurvedic and Amchi healers) across the three research areas. We conducted open-ended interviews to document the uses of medicinal plants to treat PD-related symptoms. Information provided by the interviewees suggested that the medicinal plants are also used to treat symptoms related to other disorders. We determined the informant consensus factor as well as the importance of specific plant species to (i) identify plants that are the best candidates to be analyzed experimentally for their potential to treat PD and (ii) perform a cross-cultural comparison of the three areas of study.

Results: This study reports the local uses of 35 different plant species along the Chitwan-Panchase-Mustang altitudinal range. We identify a total of eight plant species that were used in all three research areas, and more specifically one species used to treat PD-like symptoms. We identify a potential dual protective activity of medicinal plants used to treat PD-related symptoms as recent literature suggests that these plants also have anti-cancer properties. In addition, we document that the presence of Ayurvedic healers could influence local practices and that local practices could influence local Ayurvedic practices.

Conclusions: This study documents the uses of medicinal plants to treat symptoms related to PD and other disorders across the Chitwan-Panchase-Mustang altitudinal range. PD is a neurodegenerative disease affecting a growing number of people worldwide. No cures are available to slow the death of the neurons, and there is a critical need to work towards innovative therapeutic strategies. We identify medicinal plants based on traditional practices to help develop a cure for PD. The three areas of study were chosen for their ecological and cultural diversities, and two of these are included in conservation programs (Panchase Protected Forest and Annapurna Conservation Area). The documentation of community-natural resource relationships is another step in the preservation of traditional practices and local biodiversity and a reflection of communities' rights in the design of conservation programs.