Neuroprotective Effects of Some Nutraceuticals against Manganese-Induced Parkinson’s Disease in Rats: Possible Modulatory Effects on TLR4/NLRP3/NF-κB, GSK-3β, Nrf2/HO-1, and Apoptotic Pathways

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, and anti-apoptotic nutraceuticals. We investigated the potential protective effects of these nutraceuticals alone or in combinations against MnCl2-induced PD in rats. Seven groups of adult male Sprague Dawley rats were categorized as follows: group (I) was the control, while groups 2–7 received MnCl2 either alone (Group II) or in conjunction with oral doses of sesamol (Group III), thymol (Group IV), CoQ10 (Group V), WG (Group VI), or their combination (Group VII). All rats were subjected to four behavioral tests (open-field, swimming, Y-maze, and catalepsy tests). Biochemical changes in brain levels of monoamines, ACHE, BDNF, GSK-3β, GABA/glutamate, as well as oxidative stress, and apoptotic and neuroinflammatory biomarkers were evaluated, together with histopathological examinations of different brain regions. Mn increased catalepsy scores, while decreasing neuromuscular co-ordination, and locomotor and exploratory activity. It also impaired vigilance, spatial memory, and decision making. Most behavioral impairments induced by Mn were improved by sesamol, thymol, WG, or CoQ10, with prominent effect by sesamol and thymol. Notably, the combination group showed more pronounced improvements, which were confirmed by biochemical, molecular, as well as histopathological findings. Sesamol or thymol showed better protection against neuronal degeneration and some behavioral impairments induced by Mn than WG or CoQ10, partly via interplay between Nrf2/HO-1, TLR4/NLRP3/NF-κB, GSK-3β and Bax/Bcl2 pathways.

miR‐107‐5p ameliorates neurological damage, oxidative stress, and immune responses in mice with Alzheimer's disease by suppressing the Toll‐like receptor 4 (TLR4)/nuclear factor‐kappaB(NF‐κB) pathway

“…Furthermore, besides TLR4‐dependent processes, we did not explore other potential mechanisms in this study. For instance, the nuclear factor‐erythroid 2‐related factor 2 (Nrf2) pathway reduces OS by manipulating antioxidant proteins such as heme oxygenase‐1, mitigating inflammation, and inhibiting Aβ and tau phosphorylation, which enhances memory, learning, and cognitive abilities 34,35 . Research has also reported that miR‐146a induces OS through the MAPK signaling pathway, exacerbating cognitive impairment and AD pathology 36 .…”

Thymol as a Potential Neuroprotective Agent: Mechanisms, Efficacy, and Future Prospects

“…23 Similarly, Abu-Elfotuh et al found that oral thymol administration at the final dose of 15 mg/kg/day for 5 weeks (i.e., 35 days) could effectively improve neuronal degeneration and behavioral impairments in rats via the inhibition of oxidative stress, apoptotic cell death, and neuroinflammatory response in the brain tissues of rats with Parkinson's Disease. 28 Thymol has also shown promise in mitigating cognitive deficits and brain damage induced by heavy metals or high-fat diets. 28−31 Furthermore, studies also showed that a thymol diet of up to 500 mg/kg in rats exhibited no toxicity, indicating higher safety.…”

The gut microbiota metabolite butyrate mitigates MPTP/MPP+‐induced Parkinson's disease by inhibiting the JAK2/STAT3 signaling pathway

“…4 Progressive loss of dopaminergic neurons in the midbrain, a main cause of PD, may result in concomitant dopamine depletion and α-synuclein accumulation. 5 Besides, it is believed that neuroinflammation and oxidative stress also act key roles in PD pathogenesis, 6 suggesting anti-oxidative and anti-inflammatory agents might offer a promising therapeutic potential for PD. Since current drugs for PD treatment mainly target PD symptoms and cannot prevent the loss of dopaminergic neurons, 7 the discovery and development of novel neuroprotective and disease-modifying agents for PD are still needed.…”

“…Clinically, major PD symptoms include motor dysfunctions (e.g., bradykinesia, rest tremor, and muscular rigidity) 4 . Progressive loss of dopaminergic neurons in the midbrain, a main cause of PD, may result in concomitant dopamine depletion and α‐synuclein accumulation 5 . Besides, it is believed that neuroinflammation and oxidative stress also act key roles in PD pathogenesis, 6 suggesting anti‐oxidative and anti‐inflammatory agents might offer a promising therapeutic potential for PD.…”