Neuroprotective effects of ROCK inhibition on hippocampal energy metabolism in a rat model of metabolic syndrome.

OBJECTIVES: Metabolic syndrome (MS) is associated with insulin resistance, hyperglycemia, and dyslipidemia, leading to impaired neuronal energy metabolism and hippocampal dysfunction. Rho-associated kinase (ROCK) has been implicated in metabolic and neuroinflammatory dysregulation; however, its role in MS-induced hippocampal energy imbalance remains unclear. This study aimed to determine whether pharmacological ROCK inhibition with fasudil restores hippocampal energy metabolism in a rat model of fructose-induced MS. MATERIALS AND METHODS: Male Lewis rats were divided into control, MS, and MS+fasudil groups. Plasma and hippocampal metabolic parameters were assessed using biochemical assays. Activities of glycolytic enzymes, Krebs cycle enzymes, and mitochondrial respiratory chain complexes I--IV were measured. Phosphatidylinositol 3-kinase/Protein kinase B/Mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway components, including phosphorylated PI3K, AKT, mTOR, Phosphatase and tensin homolog (PTEN), and Ras homolog enriched in brain (Rheb), were analyzed by Western blotting. RESULTS: MS disrupted glucose homeostasis and significantly suppressed the activities of glycolytic, mitochondrial, and respiratory chain enzymes in the hippocampus. These changes were accompanied by reduced phosphorylation of PI3K, AKT, and mTOR, increased PTEN expression, and decreased Rheb levels, indicating impaired PI3K/AKT/mTOR signaling. Fasudil treatment normalized plasma and hippocampal glucose levels, restored enzymatic activities across major energy-producing pathways, and reactivated PI3K/AKT/mTOR signaling by reducing PTEN and restoring AKT and Rheb activity. CONCLUSION: These findings demonstrate that ROCK overactivation contributes to central insulin resistance and hippocampal energy dysfunction in MS. ROCK inhibition with fasudil effectively reverses these alterations, highlighting ROCK as a potential therapeutic target for preserving hippocampal metabolic function in MS.