Faculty, Staff and Student Publications

Language

English

Publication Date

11-20-2024

Journal

Biochemical Journal

DOI

10.1042/BCJ20240217

PMID

39466125

PMCID

PMC11957353

PubMedCentral® Posted Date

9-20-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Existing literature suggests that infection-specific mechanisms may play a significant role in the onset and progression of dementia, as opposed to the broader phenomenon of systemic inflammation. In addition, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach for sepsis, given their anti-inflammatory and antioxidant properties. We investigated the neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the prefrontal cortex (PFC) and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats were subjected to sepsis by cecal ligation and puncture or left non-manipulated. The animals were treated with simvastatin or vehicle for 4 days before and 10 days after surgery. The treatment preserved the non-associative memory (P <  0.05), recovered expression of Smad-3 in the hippocampus (P <  0.05), and prevented increased expression of calpain-1 (hippocampus: P <  0.0001; PFC: P <  0.05) and GSKβ (hippocampus: P <  0.0001; PFC: P <  0.0001) in the brain structures of the sepsis survivor animals. These animals also showed mitochondrial dysfunction and decreased axon terminals in the RE. Simvastatin seems to restore energy metabolism by improving the electron transfer system (ETS) values in the hippocampus (P <  0.01) and the oxidative phosphorylation/ETS (P/E) ratio in the PFC (P <  0.05), in addition to preventing the reduction of axon terminals in survivor animals. These results suggest a potential neuroprotective effect and the importance of considering HMG-CoA reductase inhibitors as a possible adjuvant therapy in sepsis.

Keywords

Animals, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Rats, Wistar, Rats, Sepsis, Male, Simvastatin, Neuroinflammatory Diseases, Hippocampus, Prefrontal Cortex, Neuroprotective Agents, Cognition

Published Open-Access

yes

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