Antioxidant Effects of Vitamin E and L-Carnitine on Hippocampal Histology, Epigenetics, and Cognition in Morphine-Exposed Mice.

Chronic exposure to morphine induces oxidative stress and alters the hippocampal expression of genes encoding enzymes involved in epigenetic modifications (e.g., DNA methyltransferases; DNMTs and Histonedeacetylases; HDACs) and apoptosis-related signaling (e.g., Bax and Bcl-2). This study examined the effects of vitamin E and L-carnitine supplementation on cognitive function and hippocampal gene expression following morphine administration in adult male NMRI mice. Morphine was administered subcutaneously twice daily at escalating doses: 10 mg/kg for 10 days, 20 mg/kg from day 10 to 20, and 30 mg/kg from day 20 to 45. Antioxidants (vitamin E at 200 mg/kg, L-carnitine at 100 mg/kg, or both) were administered starting on day 10. Behavioral tests, including the open field test, elevated plus maze, and novel object recognition, were conducted on days 43-45. Hippocampal analyses assessed mRNA expression of DNMT3A, DNMT3B, HDAC1, HDAC2, Bax, and Bcl-2, as well as malondialdehyde (MDA) levels, total antioxidant capacity (TAC), and CA1 Nissl staining. Morphine-treated mice exhibited increased anxiety-like behavior, though this effect was not consistently reversed by antioxidants, and memory impairment compared to saline controls. Antioxidant treatment partially mitigated these behavioral deficits. Biochemically, morphine elevated MDA and reduced TAC levels, while antioxidant administration attenuated these markers toward control levels. Histologically, morphine increased CA1 cellular damage, which was attenuated by antioxidants. At the molecular level, morphine increased Bax mRNA and decreased Bcl2 mRNA expression; antioxidant treatment partially reversed these changes. Morphine also increased DNMT3B mRNA expression, which was reversed by antioxidants. Additionally, HDAC1 and HDAC2 mRNA expression decreased with morphine treatment and was enhanced by vitamin E and L-carnitine. These findings suggest that vitamin E and L-carnitine may attenuate morphine-induced hippocampal dysfunction through modulation of oxidative stress and altered gene expression, supporting their potential as adjunctive therapies for opioid-related cognitive impairment.