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The gut microbiota plays a pivotal role in maintaining host health and has increasingly been linked to the pathogenesis of neurodegenerative diseases through the microbiota-gut-brain axis. Parkinson's disease (PD), characterized by dopaminergic dysfunction, neuro inflammation, and pathological alpha-synuclein (α-synuclein) aggregation, is frequently accompanied by gut microbial dysbiosis. Probiotics isolated from human infants could offer distinct neuroprotective and immunomodulatory benefits, yet their effects on integrated gut-brain axis models remain underexplored. In this study, we investigated the therapeutic potential of Lactobacillus acidophilus SLAM_LAA02 (L. acidophilus SLAM_LAA02), a novel infant-derived strain, in modulating PD-related behavioral and neuropathological features via modulation of the gut-brain axis. Following comprehensive safety and functional assessments, we first assessed L. acidophilus SLAM_LAA02 in Caenorhabditis elegans, where supplementation extended lifespan, enhanced antimicrobial defense, improved behavioral responses, and reduced α-synuclein expression in transgenic worms. We then evaluated its effects in a rotenone-induced mouse model that reflects early-stage PD-like features. L. acidophilus SLAM_LAA02 administration ameliorated motor dysfunction, modulated neuroinflammatory signaling, restored gut microbial diversity, and improved intestinal barrier-associated outcomes. These changes were accompanied by a notable reduction in α-synuclein expression and upregulated neuroprotective gene expression, including brain-derived neurotrophic factor (BDNF). Together, these findings suggest that L. acidophilus SLAM_LAA02 exhibits neuroprotective and gut-modulating properties across complementary model systems, supporting its potential as a promising probiotic candidate for alleviating early PD-related dysfunctions through the gut-brain axis. Show less

This review aims to elucidate the molecular mechanisms underlying the neuroprotective effects of acupuncture in preclinical models of Parkinson's disease (PD). In PD animal models, acupuncture inhibits oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) and lipid peroxidation. It regulates autophagy either independently of mammalian target of rapamycin (mTOR) or via mTOR activation, promoting alpha-synuclein (α-synuclein) clearance. Acupuncture also suppresses apoptosis (modulating Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2)) and pyroptosis (inhibiting NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD)). It enhances neurogenesis through brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and glial cell line-derived neurotrophic factor (GDNF) signaling, promoting neural stem cell proliferation and differentiation. Furthermore, acupuncture reduces neuroinflammation by decreasing microglial activation, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It also modulates gut microbiota composition (e.g., increasing butyrate-producing bacteria like Butyricimonas and reducing pro-inflammatory Erysipelotrichaceae and Bacteroides) and influences lipid metabolism, thereby mitigating dopaminergic neuron loss and motor deficits. Preclinical evidence demonstrates that acupuncture exerts multi-target neuroprotective effects against PD through pathways involving oxidative stress, autophagy, apoptosis/pyroptosis, neurogenesis, neuroinflammation, and gut microbiota-lipid metabolism crosstalk. However, limitations include a focus on preventive rather than reversal effects, lack of long-term efficacy data, and heterogeneity in acupoint selection. Further mechanistic and standardization studies are warranted. Show less

The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease. Show less

Pulmonary fibrosis is a common and life-threatening complication of Parkinson's disease (PD), yet the molecular mechanisms linking the two diseases remain unclear, creating a critical gap in targeted therapeutic strategies for comorbid patients. Angiotensin-converting enzyme 2 (ACE2) plays a key role in neuroprotection and lung homeostasis; its deficiency exacerbates PD-related neuroinflammation and α-synuclein aggregation, while also promoting pulmonary inflammation and fibrotic remodeling. Clarifying how ACE2 deficiency drives PD-exacerbated pulmonary fibrosis is therefore an urgent unmet need. This study explored the underlying mechanisms using MPTP-induced PD mouse models and bioinformatics analyses of PD/idiopathic pulmonary fibrosis (IPF) datasets from the GEO database. In MPTP-induced PD mice, ACE2 deficiency significantly worsened motor/non-motor dysfunction, dopaminergic neuron loss, microglial/astrocytic activation, and lung fibrosis (evidenced by elevated α-SMA/TGF-β and increased collagen deposition). Bioinformatics identified 41 overlapping differentially expressed genes (DEGs) between PD and IPF, enriched in critical pathways: downregulated FoxO1 (impairing antioxidant defense) and upregulated TNF, JAK1-STAT3, and AGE-RAGE (amplifying inflammation/fibrosis). ROC analysis validated hub genes (e.g., BDNF, FOSL2) with good diagnostic value (AUC > 0.7), and molecular docking identified Smilagenin, Fostamatinib, Olopatadine, and Amlexanox as potential therapeutics. This study confirms ACE2 deficiency is a central driver of PD-exacerbated pulmonary fibrosis via the FoxO1/TNF/JAK1-STAT3/AGE-RAGE pathways, providing novel biomarkers and drug candidates to address the clinical need for managing this comorbidity. Show less

BackgroundHigh intensity interval training (HIIT) involves vigorous intensity exercise bouts interspersed with low intensity bouts. Despite growing interest, the optimal dosage and clinical adaptability of HIIT in Parkinson's disease (PD) remain unclear. This scoping review synthesized the literature on systemic adaptations underlying HIIT in PD and developed a clinical framework while considering chronotropic incompetence, orthostatic hypotension, and disease progression.MethodsThree databases were searched for studies that incorporated HIIT interventions in PD. The Template for Intervention Description and Replication checklist was used to characterize the quality of intervention reporting.ResultsA total of 285 studies were screened, of which 10 studies were included. HIIT was administered 2-3 times/week for 30-60 min/session over 8-12 weeks. Seven studies used moderate-volume HIIT and three studies used high-volume HIIT protocols. The quality of intervention reporting was fair to good. HIIT improved cardiorespiratory fitness, motor severity, and functional mobility in PD, however, improvements were comparable to moderate intensity continuous training (MICT). HIIT may facilitate neuroplasticity by increasing brain-derived neurotrophic factor levels and dopamine transporter uptake. We recommend that HIIT programs for individuals with autonomic dysfunction use individualized heart rate targets, and perceived exertion for determining exercise intensity, and incorporate longer duration programs (>12 weeks).ConclusionHIIT is a well-tolerated intervention that may improve cardiorespiratory fitness, disease severity, and certain neurobiological markers in mild-moderate PD, with benefits similar to MICT. Larger trials comparing different HIIT volumes are needed to identify optimal exercise volume to inform individualized exercise prescription. Show less

Parkinson's disease (PD) is a common neurodegenerative disorder involving multiple pathological processes. Bergapten (BeG) exhibits various pharmacological activities, including anti-inflammatory, antioxidant and neuroprotective effects, but its mechanism of action in PD remains unclear. This study aimed to investigate the neuroprotective effects and underlying mechanisms of BeG in PD models. An in vitro neuroinflammation model was established using LPS-treated astrocytes. In-vitro studies demonstrated that BeG counteracted LPS-induced astrocyte activation by reducing the expressions of GFAP, inflammatory mediators (IL-6, TNF-α, IL-1β), and A1 polarization markers. It alleviated ERS (as indicated by reduced levels of GRP78, CHOP) and apoptosis (as shown by changes in Bax, caspase-3) while enhancing Bcl-2. Mechanistically, BeG suppressed LCN2 expression and JAK2/STAT3 phosphorylation, with LCN2 overexpression attenuating its protective effects. In MPTP-treated mice, BeG improved motor function, preserved dopaminergic neurons, and reduced astrocyte activation and A1 polarization. It increased neurotrophic factors (BDNF, GDNF) while decreasing inflammation, ER stress and apoptotic markers. The inhibition of the LCN2/JAK2/STAT3 pathway was consistently observed in both models, suggesting its central role in BeG's neuroprotective mechanism. These findings suggest that BeG exerts neuroprotective effects in PD by inhibiting the LCN2/JAK2/STAT3 signaling pathway, thereby effectively inhibiting astrocyte activation-mediated neuroinflammation and ERS. Show less

Lilium brownii is a plant that can be used for medicinal and food purposes. 1-O-p-coumaroyl-3-O-feruloyl glycerol (CF) is a phenolic acid glycerol dimer isolated from Lilium brownii. This study aims to evaluate the neuroprotective effects of CF and elucidate the possible molecular mechanisms underlying its neuroprotective effects through in vivo and in vitro models of Parkinson's disease. 1-methyl-4-phenylpyridinium ions (MPP Following CF administration, the apoptosis rate and reactive oxygen species (ROS) levels in PC12 cells were significantly reduced. CF markedly upregulated the expression of proteins including dopamine, tyrosine hydroxylase, brain-derived neurotrophic factor (BDNF), while simultaneously downregulating the expression of proteins such as α-synuclein. Molecular docking results demonstrated favorable affinity between CF and proteins including p62. This compound not only ameliorated motor and cognitive impairments in Parkinson's disease mice but also markedly increased neuronal numbers within the substantia nigra region of these animals. CF exerts a neuroprotective effect in Parkinson's disease by modulating the p62-Keap1-Nrf2 signalling pathway. Show less

Brain-derived neurotrophic factor (BDNF) plays an important role in the survival of dopaminergic neurons. Clinical studies have suggested that serum BDNF levels are reduced in patients with Parkinson's disease (PD). However, no study has investigated peripheral BDNF levels and BDNF Val66Met polymorphism in the prodromal stage of PD and their relationship with disease conversion. In total, 120 patients with video-polysomnography confirmed isolated REM sleep behavior disorder (iRBD) and 120 healthy controls (HCs) were enrolled. Genetic analyses were performed, and plasma levels of BDNF were measured. All patients with iRBD underwent comprehensive clinical testing, and 107 iRBD patients were prospectively followed up. Plasma BDNF levels were significantly lower in the iRBD group than in HCs (18,878.85 pg/mL vs. 24,649.85 pg/mL, p = 0.002), but no differences were observed in BDNF Val66Met carrier rates between the two groups. Plasma BDNF levels did not differ significantly between BDNF Val66Met carriers and noncarriers. Notably, higher plasma BDNF levels were associated with an increased risk of short-term disease conversion (hazard ratio = 3.418, 95% CI: 1.520-7.684, p = 0.003), whereas BDNF Val66Met carrier rates showed no such association. Our findings suggest that plasma BDNF is significantly associated with iRBD and may likely serve as a prognostic biomarker for the development of neurodegenerative disease. However, the BDNF Val66Met polymorphism may not be involved in the pathogenesis of iRBD as well as phenoconversion in the studied population. Show less

ObjectiveTo evaluate the effects of a combined psychological and functional exercise intervention on emotion, quality of life, and brain-derived neurotrophic factor (BDNF) levels in patients with Parkinson's disease (PD).MethodsIn this randomized controlled trial, 172 patients with PD were randomly assigned into 2 groups with 86 patients in each group. The control group received routine care, while the intervention group received a 12-week intervention combining psychological support with functional exercise in addition to routine care. Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Parkinson's Disease Questionnaire-39 (PDQ-39), Barthel Index, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and serum BDNF levels were assessed before and after the intervention. Adherence rates were also determined for each group. Spearman correlation analysis was used to examine associations between changes in BDNF (ΔBDNF) and changes in HAMA (ΔHAMA) and HAMD (ΔHAMD) scores.ResultsAt the end of the 12-week clinical trial, the intervention group demonstrated significantly lower HAMA, HAMD, PDQ-39, and MDS-UPDRS scores ( Show less

Brain-derived neurotrophic factor (BDNF) has been suggested to support dopaminergic neuron's endurance and dopamine release. Its Val66Met polymorphism might modify Parkinson's disease (PD) evolution, although evidence in Asian populations remains limited. This study aimed to explore how the BDNF rs6265 genotypes are associated with the clinical characteristics and longitudinal progression patterns of PD patients in a Korean population. A total of 247 patients were enrolled and followed for a mean duration of 50.9 ± 23.9 months. Baseline and/or periodic assessments captured motor severity, non-motor burden, cognition, orthostatic stress, cardiac denervation, and presynaptic dopamine transporter availability. The repeated measures were manipulated to infer any genotypic differences in the trajectories of each clinical domain. Genotype frequencies were 31.2% (77/247) for Val/Val and 68.8% (170/247) for Met-allele carriers. Baseline clinical characteristics and presynaptic dopamine transporter availability were comparable between genotypes; however, Val homozygotes showed more preserved myocardial innervation and poorer non-frontal cognitive performance. Longitudinal analyses demonstrated genotype-specific increases in motor and cognitive severity. Compared to Met-allele carriers, the homozygous Val group exhibited accelerated motor progression and more rapid decline in frontal domain after three years of follow-up. The differences in myocardial denervation at diagnosis, cognitive profiles, and motor progression might suggest a potential modulatory role of BDNF polymorphism in PD progression in the Korean population. Show less

Parkinson's disease (PD) is a progressive neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra and is associated with neuroinflammation, apoptosis, oxidative stress, and motor impairment. Imipramine, a tricyclic antidepressant, has a wide range of biological effects such as anti-inflammatory, anti-apoptotic, and free radical scavenging activities. The present study was designed to investigate the neuroprotective effect of imipramine in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). Male Wistar rats were treated with daily intraperitoneal administration of imipramine (20 mg/kg, for 14 days) starting 72 h after 6-OHDA injection (20 μg/rat; 4 μl in the right medial forebrain bundle (MFB)). The motor performance was assessed using the rotarod, beam, pole, and apomorphine-induced rotation tests. The protein levels of neurotrophic factors (BDNF, GDNF, and NT3) and factors involved in oxidative stress (MDA, CAT, SOD, GST, and GSH) were measured in the striatum by ELISA technique. The neuronal survival was also evaluated by Nissl staining. Our results showed that 6-OHDA caused motor impairments and neuronal cell death. It also significantly reduced the protein levels of neurotrophic factors and induced an oxidative stress response in the striatum of rats. Whereas, imipramine treatment effectively reduced 6-OHDA-induced motor deficits and neuronal cell death. This improvement was accompanied by an increase in neurotrophic factors, especially GDNF, as well as a reduction in oxidative stress through increased SOD levels. These findings provide direct evidence that imipramine treatment contributes to improve of neuronal cell death and motor deficits, perhaps by increasing the striatal levels of SOD and GDNF, which play a key role in the survival of dopaminergic neurons. Further studies are also needed to elucidate the precise underlying molecular mechanisms of neuroprotective effects of imipramine. Show less

Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases. Show less

Aim: To summarise current knowledge on the effects of intermittent fasting on cognitive functions and neuroprotective mechanisms, with particular attention to Alzheimer's disease and Parkinson's disease. Materials and Methods: A narrative review based on twelve peer-reviewed publications on the effects of intermittent fasting on cognitive function, neuroprotection, and circadian rhythms. Preclinical data and selected clinical studies indicate that intermittent fasting improves memory, attention, and executive functions, which is associated with activation of autophagy, reduction of oxidative stress, improved mitochondrial function, and increased levels of brain-derived neurotrophic factor. In Parkinson's disease, intermittent fasting limits alpha-synuclein aggregation and protects dopaminergic neurons, whereas in Alzheimer's disease it reduces beta-amyloid deposition and enhances synaptic plasticity. Intermittent fasting also influences the gut-brain axis and circadian rhythm alignment, which may further support neuroprotection. Conclusions: Intermittent fasting is a promising adjunct strategy in the management of neurodegenerative diseases. However, well-designed, randomised clinical trials are needed to confirm its effectiveness and safety. Show less