Resveratrol Protects the Prefrontal Cortex Against Methamphetamine Neurotoxicity: Association with SIRT1 and Changes in miR-22, miR-9, and miR-138 Expression

Abstract

Background: Methamphetamine (METH) is a well-known psychostimulant that induces neurotoxicity and cognitive decline. Resveratrol is a natural phenolic compound found in grapes and berries. Sirtuin-1 (SIRT1) is an important protein involved in neuroprotective pathways. Several microRNAs are dysregulated following METH use, which can affect gene expression. Objectives: This study evaluated the contribution of SIRT1 and its associated microRNAs to resveratrol-mediated neuroprotection against METH-induced neurotoxicity, cognitive decline, and neuronal damage in the prefrontal cortex (PFC). Methods: Rats received METH (5 mg/kg) for 14 days. Resveratrol was administered orally before METH injection. Object-based attention and Y-maze tests were performed to assess attention and working memory, respectively. SIRT1 gene expression and protein levels were assessed using quantitative PCR and immunoblotting. miRNAs related to SIRT1 were predicted, and changes in their levels were examined. Morphological changes in PFC tissue were evaluated using histological analysis. Results: Chronic METH use induced PFC damage and impaired attention and working memory. It also decreased SIRT1 levels and upregulated miR-22 - 3p, miR-9 - 5p, miR-138 - 5p, and miR-133a-3p in the PFC. Administration of resveratrol prevented METH-induced PFC damage and improved cognition. Resveratrol treatment reduced levels of miR-22 - 3p, miR-9 - 5p, and miR-138 - 5p, accompanied by increased SIRT1 levels. Conclusions: Resveratrol treatment exerted protective effects in the PFC against METH toxicity. These effects were associated with increased SIRT1 and altered expression of several SIRT1-related microRNAs, including miR-22 - 3p, miR-9 - 5p, and miR-138 - 5p. However, further research is needed to clarify the roles of SIRT1 and associated microRNAs in resveratrol-mediated neuroprotection.