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An in vivo and in silico probing of the protective potential of betaine against sodium fluoride-induced neurotoxicity.
| BMC Pharmacology and Toxicology | Owumi SE, Oluwawibe BJ, Chimezie J, Babalola JJ, Ogunyemi OM, Gyebi GA, Otunla MT, Altayyar A, Arunsi UO, Irozuru CE, Owoeye OO. | 25(1):87.
Cerebellum Cerebrum Neurotoxicity Protective effect Apoptosis Brain Brain Cellular/Tissue Effects Animal Study
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Abstract

Excessive fluoride exposure beyond the tolerable limit may adversely impacts brain functionality. Betaine (BET), a trimethyl glycine, possesses antioxidant, anti-inflammatory and anti-apoptotic functions, although the underlying mechanisms of the role of BET on fluoride-induced neurotoxicity remain unelucidated. To assess the mechanism involved in the neuro-restorative role of BET on behavioural, neurochemical, and histological changes, we employed a rat model of sodium fluoride (NaF) exposure. Animals were treated with NaF (9 mg/kg) body weight (bw) only or co-treated with BET (50 and 100 mg/kg bw) orally uninterrupted for 28 days. We obtained behavioural phenotypes in an open field, performed negative geotaxis, and a forelimb grip test, followed by oxido-inflammatory, apoptotic, and histological assessment. Behavioural endpoints indicated lessened locomotive and motor and heightened anxiety-like performance and upregulated oxidative, inflammatory, and apoptotic biomarkers in NaF-exposed rats. Co-treatment with BET significantly enhanced locomotive, motor, and anxiolytic performance, increased the antioxidant signalling mechanisms and demurred oxidative, inflammatory, and apoptotic biomarkers and histoarchitectural damage in the cerebrum and cerebellum cortices mediated by NaF. The in-silico analysis suggests that multiple hydrogen bonds and hydrophobic interactions of BET with critical amino acid residues, including arginine (ARG380 and ARG415) in the Keap1 Kelch domain, which may disrupt Keap1-Nrf2 complex and activate Nrf2. This may account for the observed increased in the Nrf2 levels, elevated antioxidant response and enhanced anti-inflammatory response. The BET-Keap1 complex was also observed to exhibit structural stability and conformational flexibility in solvated biomolecular systems, as indicated by the thermodynamic parameters computed from the trajectories obtained from a 100 ns full atomistic molecular dynamics simulation. Therefore, BET mediates neuroprotection against NaF-induced cerebro-cerebellar damage through rats’ antioxidant, anti-inflammatory, and anti-apoptotic activity, which molecular interactions with Keap1-Nrf2 may drive.

Fig. 15

Fig. 15

Proposed mechanistic mode of action of betaine neuroprotective effect against NaF-induced neurotoxicity in male Wistar rats. BET confers protection to the cerebellum and cerebrum rats treated with NaF by enhancing redox balance and resolving inflammation. BET achieves this by suppressing the accumulation of ROS, as evidenced through increased levels of phase-1 antioxidants, including SOD, CAT, and GPx, which can detoxify O2.? and H2O2. Furthermore, BET increased the levels of phase-2 antioxidants GST, GSH, and TSH, crucial in detoxifying lipid hydroperoxides and primary oxidative products like MDA. Failure to upregulate these antioxidant molecules may result in MDA accumulation in rats’ cerebrum and cerebellum. Aside from regulating redox balance, BET also resolves inflammation by suppressing the levels of pro-inflammatory mediators while increasing the level of anti-inflammatory markers. Furthermore, BET prevented the manifestation of apoptosis in the cerebellum and cerebrum of rats by inhibiting the activity of caspase 3. Created by Arunsi Uche O. using BioRender, https://app.biorender.com/

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FULL-TEXT STUDY ONLINE AT
https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-024-00812-
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