Combination of ezetimibe and sericin attenuates cadmium chloride-induced neurotoxicity in an experimental rat model by suppressing oxidative stress and neuroinflammation.
Temgire Pooja, Navik Umashanker, Kumar Puneet
Abstract
BACKGROUND: Cadmium chloride (CdCl2)-induced neurotoxicity is a global health concern, associated with oxidative stress, neuroinflammation, and downregulation of IGF-1R/GLP-1R/Nrf2/HO-1 signaling pathway. Agents targeting this pathway may offer a promising strategy to mitigate neurotoxic effects. Therefore, we proposed that ezetimibe, a lipid-lowering drug, and sericin, a natural silk protein with antioxidant and anti-inflammatory properties, were evaluated for their potential to mitigate CdCl2-induced neurotoxicity in experimental rats. METHODS: Seventy adult Wistar rats were allocated to receive control, CdCl2 (5 mg/kg), CdCl2 with ezetimibe (10 and 20 mg/kg), and sericin (200 and 400 mg/kg), or in combination for 28 days. Behavioral assessments, muscle coordination, and cognitive dysfunction were performed. Animals were sacrificed on day 29, and hippocampal tissue was used to perform oxidative stress markers, including malondialdehyde (MDA), nitrite, glutathione (GSH), estimation of acetylcholinesterase, and neurochemicals (serotonin, norepinephrine), neuroinflammatory markers, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), nuclear factor kappa B (NF-κB), immunohistochemistry of glial fibrillary acidic protein (GFAP), mitochondrial complex-I activity, and protein expression of IGF-1R, GLP-1R, Nrf2, NF-κB, and HO-1. RESULTS: CdCl2 exposure resulted in motor and cognitive deficits, increased oxidative stress, neuroinflammation, and mitochondrial dysfunction. Ezetimibe and sericin, specifically the combination group, showed more pronounced effects; they improved motor behavior, maintained redox homeostasis, restored neurotransmitter levels, reduced neuroinflammation, and increased mitochondrial complex-I activity. Moreover, they restored the protein expression of IGF-1R, GLP-1R, Nrf2, NF-κB, and HO-1. CONCLUSION: The results demonstrate that ezetimibe and sericin, alone and in combination, can counteract Cd2+-induced neurotoxicity.
Key Findings
- Cadmium chloride exposure induced motor and cognitive deficits, oxidative stress, neuroinflammation, and mitochondrial dysfunction in rats.
- Ezetimibe and sericin treatment, especially in combination, improved motor behavior, restored redox balance, neurotransmitter levels, and mitochondrial complex-I activity.
- The combination therapy restored protein expression of IGF-1R, GLP-1R, Nrf2, NF-κB, and HO-1, indicating modulation of oxidative stress and inflammatory pathways.
Clinical Significance
This study suggests that ezetimibe and sericin could be potential therapeutic agents to mitigate cadmium-induced neurotoxicity by targeting oxidative stress and neuroinflammation pathways, which may have implications for treating neurotoxic effects in humans.
Citation
Temgire Pooja, Navik Umashanker, Kumar Puneet. Combination of ezetimibe and sericin attenuates cadmium chloride-induced neurotoxicity in an experimental rat model by suppressing oxidative stress and neuroinflammation. Molecular biology reports. 2026-Nov-06.