Hesperidin Attenuates Mercury Chloride-Induced Neurotoxicity in Rats by Modulating Oxidative Stress, Neuroinflammation, Apoptosis, Autophagy and ER Stress

Mercury chloride (HgCl₂) is a well-known environmental toxicant that can induce neurotoxicity through oxidative stress, neuroinflammation, endoplasmic reticulum (ER) stress, dysregulated autophagy, and apoptosis. This study evaluated the potential neuroprotective effects of hesperidin (HES), a bioactive flavonoid with antioxidant and anti-inflammatory properties, against HgCl₂-induced brain injury in rats. Sixty male Sprague Dawley rats received 1.23 mg/kg HgCl₂ intraperitoneally for 7 days, while HES was administered orally at doses of 100, 200, or 400 mg/kg. HgCl₂ exposure resulted in elevated lipid peroxidation, impaired antioxidant status, increased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and reduced IL-10 levels. Upregulation of Bax and caspase-3, downregulation of Bcl-2 and BDNF, along with increased GFAP immunoreactivity, indicated enhanced neuronal apoptosis and astrocyte activation. Furthermore, increased Beclin-1, LC3A/B, and ER stress-related markers (GRP78, PERK, ATF4, XBP1, IRE1, CHOP) suggested disturbances in cellular homeostasis. HES treatment—most notably at 400 mg/kg—attenuated oxidative stress, improved antioxidant enzyme activities, reduced pro-inflammatory responses while partially restoring IL-10, and modulated apoptosis, autophagy, and ER stress-associated pathways. In addition, increased BDNF levels following HES administration may indicate improved neuronal plasticity. Collectively, these findings suggest that hesperidin may have therapeutic potential as a neuroprotective agent against HgCl₂-induced neurotoxicity by modulating multiple molecular pathways involved in oxidative damage, inflammation, apoptosis, autophagy, and ER stress.