Combined Vitamin D and Resveratrol Treatment Attenuates Motor Deficits and Neurodegeneration in a 6‐OHDA Mouse Model of Parkinson's Disease in Male Mice: A Focus on Sirt1 and Lingo‐1 Pathways in the Ventral Tegmental Area
Aug 2026· Brain and Behavior· Vol 16· 0 citations· 47 references
Medicine
TL;DR
Given the neuroprotective properties of Vitamin D3 and resveratrol, this study examined whether their combined administration could modulate Sirt1 and Lingo‐1 expression and attenuate neurodegeneration in a 6‐hydroxydopamine (6‐OHDA) model of PD.
Abstract
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration, leading to severe motor impairments. Lingo‐1 negatively regulates neuronal survival, while Sirtuin‐1 (Sirt1) supports mitochondrial function and oxidative stress resistance. Given the neuroprotective properties of Vitamin D3 (VitD3) and resveratrol, this study examined whether their combined administration could modulate Sirt1 and Lingo‐1 expression and attenuate neurodegeneration in a 6‐hydroxydopamine (6‐OHDA) model of PD.
Currently, effective disease-modifying treatments for Parkinson’s disease (PD) remain lacking. Although exercise has been confirmed to exert neuroprotective effects against PD, its specific molecular mechanisms remain unclear. In particular, the causal role of the Nuclear Factor E2-related Factor 2 (Nrf2)–antioxidant response element (ARE) signaling axis in this process has not been clearly elucidated. This study aimed to provide direct causal evidence that regular treadmill exercise protects the substantia nigra pars compacta (SNc)–striatal dopaminergic system by activating the Nrf2-ARE pathway. The results showed that exercise significantly improved motor function deficits in PD mice, preserved the number of TH-positive neurons, and restored striatal dopamine homeostasis. Mechanistically, exercise activated the Nrf2-ARE pathway, thereby inhibiting the accumulation of mitochondrial ROS (mtROS) and the activation of pro-inflammatory amoeboid microglia in the substantia nigra. Crucially, the improvements in behavioral, neuropathological, and neurochemical indicators induced by exercise were completely reversed, returning to levels comparable to those in the sedentary model group. In conclusion, this study provides clear pharmacological evidence that the neuroprotective effect of regular treadmill exercise against chronic PD strictly depends on the Nrf2-ARE pathway. These findings indicate that Nrf2 is a key mechanistic node linking exercise and neuroprotection, providing reliable preclinical evidence for Nrf2-targeted disease-modifying strategies in PD rehabilitation.
Shu-Wei Zhang, Dong Yang, Chang-Fa Tang et al.· International Journal of Mol...· 0 citations
Alzheimer's disease is the most prevalent form of dementia globally, with postmenopausal women bearing a disproportionately higher risk attributable to the loss of estrogen's neuroprotective effects. The rat model combining bilateral ovariectomy and chronic D-galactose induction has been validated as a preclinical representation of sporadic postmenopausal AD, producing a clinicopathological profile encompassing elevated oxidative stress markers (increased MDA and decreased SOD activity), hippocampal amyloid-β42 accumulation, acetylcholinesterase hyperactivity, decreased expression of BDNF and Nrf2, elevated GSK-3β expression, and hippocampal histopathological degeneration. This review integrates these clinicopathological profiles across five interconnected domains: oxidative, amyloid, cholinergic, molecular, and histopathological and evaluates preclinical evidence for zinc as a multi-target therapeutic agent. Principal mechanisms identified include Nrf2-ARE pathway activation, M1/M2 microglial polarization modulation, support of BDNF expression, and indirect protection of cholinergic neuronal integrity. An observation across preclinical studies is that the relationship between zinc dosage and neuroprotection conforms to a U-shaped or inverted-U-shaped dose-response curve, making systematic dose-response evaluation essential for identifying optimal therapeutic doses. Key research gaps identified include the absence of systematic dose-response studies using zinc in the OVX+D-galactose model, limited exploration of therapeutic zinc administration following AD-like pathology establishment, and the uncharacterized role of the Nrf2 pathway under conditions of combined estrogen deficiency and D-galactose-induced oxidative stress. Addressing these gaps is essential for establishing zinc as a safe, accessible, and clinically relevant neuroprotective strategy for postmenopausal women at elevated Alzheimer's disease risk.
Novi Dewi Tanjung· Jurnal Biomedika dan Kesehat...· 0 citations
Parkinson's disease is characterized by degeneration of dopaminergic neurons in the midbrain, primarily affecting the substantia nigra, while conventional treatments provide only symptomatic relief with adverse long-term effects. In contrast, herbal drugs exhibit multi-targeted neuroprotective properties, potentially addressing oxidative stress, neuro-inflammation, and neuronal apoptosis with better tolerability. Present study explores the neuroprotective potential of Ayurvedic polyherbal formulation, Neurogrit Gold (NG) in a Drosophila melanogaster model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Phytometabolite profiling of NG by HPLC and GC-FID identified several phytometabolites and fatty acids, including Cordifolioside, Magnoflorine, and Palmatine, Palmitic acid, Stearic acid, Oleic acid, Linoleic acid and γ-Linolenic acid. Present study demonstrated that NG enhanced climbing activity, improved cognition and food sensing behaviour in Drosophila exposed to MPTP. Additionally, NG prevented MPTP-induced phenotypic alterations and locomotory deficits in Drosophila larvae, as evidenced by increased larval volume and crawling activity. NG prevented MPTP-induced reduction in brain size of Drosophila larvae and prevented the impairment in their ability to locate food and preserved self-righting behaviour. Moreover, NG enhanced anti-oxidant defence mechanisms, indicated by increased GSH levels, SOD activity while suppressing ROS levels in Drosophila heads. These NG-mediated beneficial effects were found to be associated with modulation in gene expression of parkin, Tyrosine hydroxylase (TH) and Dopamine transporter (DAT). Collectively, this study provides preclinical evidence on the neuroprotective potential of Neurogrit Gold, positioning it as a promising natural candidate for further investigation in advanced animal models of Parkinson's disease.
Parkinson's disease (PD) remains a neurodegenerative disorder without effective disease-modifying therapies, largely due to its multifactorial pathogenesis. We report that the natural flavonoid Astragalin (AST) concurrently addresses three core pathological processes in PD, namely dopaminergic neuron degeneration, α-synucleinopathy, and neuroinflammation, through coordinated modulation of interconnected molecular pathways. In both subacute MPTP- and chronic rotenone-induced murine PD models, AST preserved 85% of nigral tyrosine hydroxylase-positive neurons, fully prevented motor deficits, and suppressed phosphorylated α-synuclein (α-Syn) accumulation and Lewy body-like inclusion formation. Mechanistically, AST activated the BDNF-TrkB/AKT pro-survival pathway, enhanced NRF2-mediated antioxidant defense, and suppressed neuroinflammatory cascades by dual inhibition of Notch1/HES-1 and COP1-C/EBPβ signaling, leading to attenuated microglial and astrocytic activation. These findings position AST as a promising multi-target therapeutic neuroprotective candidate with disease-modifying potential, providing a structural scaffold for developing combination-inspired anti-PD strategies.
Jun Wang, Jie-Yu He, Qin Huang et al.· Free Radical Biology & Medic...· 0 citations
Short-chain fatty acids regulate intestinal homeostasis and modulate the gut–brain axis, suggesting they may be applicable in adjunctive treatments for Parkinson’s disease (PD). However, the therapeutic efficacy of sodium butyrate (NaB) in PD remains unclear. Using appropriate PD animal models may aid in clarifying the therapeutic effects of NaB and facilitate the development of NaB-based PD treatment strategies. We comprehensively evaluated the therapeutic effects of oral NaB in rats with 6-hydroxydopamine (6-OHDA)-induced PD.
We induced hemiparkinsonism in rats by administering unilateral 6-OHDA in the medial forebrain bundle. At 24 h after confirming lesion development, some rats were randomized to receive oral NaB (administered daily) over 4 weeks. Behavioral assessments—comprising gait analysis, open-field activity, and apomorphine-induced rotations—were performed longitudinally in weeks 1 and 4. Finally, dopaminergic neuronal degeneration was evaluated to correlate functional recovery with structural neuroprotection.
The 4-week oral NaB intervention significantly alleviated 6-OHDA-induced motor deficits (i.e., locomotor activity, akinesia, and gait) and anxiety-like behavior; however, it did not alleviate apomorphine-induced rotations. Tyrosine hydroxylase immunohistochemical staining confirmed these findings, indicating that the dopaminergic neuron survival rate was significantly higher in the NaB-treated groups than in the sham control group.
Early long-term oral NaB treatment afforded neuroprotection and alleviated motor and non-motor deficits (such as gait and central time in the open field) in rats with 6-OHDA-induced PD. Our model indicates the therapeutic potential of oral NaB and provides a translational framework for investigating the mechanisms of NaB therapy in PD and associated neurological disorders.
Acute liver failure (ALF) is a life-threatening condition often leading to hepatic encephalopathy (HE), a neuropsychiatric disorder characterized by cognitive deficits and motor dysfunction due to elevated ammonia levels and neuroinflammation. This study investigates the therapeutic potential of resveratrol (RSV), a SIRT1 activator, in mitigating the cognitive and motor impairments associated with ALF-induced HE. SIRT1 is an NAD+-dependent class III histone deacetylase and mammalian ortholog of yeast Sir2, linking longevity, caloric restriction, neuroprotection, metabolism, inflammation, and oxidative stress regulation. It deacetylates PGC-1α and represses PPARγ, thereby enhancing mitochondrial function, insulin sensitivity, fat oxidation, gluconeogenesis, and DNA repair via p53. Using an ALF rat model induced by thioacetamide (TAA), the study demonstrates that RSV pretreatment significantly reduces ammonia levels and restores neurotransmitter balance in the brain. Specifically, RSV modulates the glutamate-NMDAR-NOS-cGMP pathway, reducing excitotoxicity by downregulating NR2B and upregulating NR2A receptor subunits. Additionally, in the downstream pathway, RSV ameliorates oxidative stress and neuroinflammation by normalizing iNOS and nNOS expression, reducing nitric oxide (NO) production, and restoring cGMP levels, thus improving spatial memory and motor coordination. Further, the neurobehavioral tests, including T-maze, rotarod, and traction control, confirm RSV's protective role in HE by mitigating the neurobehavioral deficits. These findings suggest that targeting SIRT1 with resveratrol may offer a promising therapeutic approach for HE management during ALF, by providing neuroprotection and improving cognitive and motor function.
