3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor modulates biomarkers related to Alzheimer's disease pathology in a sepsis-surviving rat model

Abstract Sepsis survivors have persistent neurological changes, including cognitive and behavioral dysfunction, which are associated with increased production of neurodegenerative biomarkers and morphological changes in areas with mnemonic functions. 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach in sepsis, given their anti-inflammatory and antioxidant properties. Here we investigated the possible neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the hippocampus, prefrontal cortex, and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats (280 ± 30 g) were submitted to sepsis by cecal ligation and puncture (CLP, n = 28) or left as non-manipulated (control, n = 24). The animals were treated with simvastatin (20 mg/kg) or vehicle four days before and ten days after surgery. The treatment recovered expression of Smad-3 in hippocampus (F(3, 28) = 6.22; P < 0.05), and prevented increased expression of calpain-1 (hippocampus (F(3, 28) = 16.06; P < 0.0001; prefrontal cortex: F(3, 28) = 10.54; P < 0.05) and GSKβ (hippocampus: F(3, 28) = 62.79; P < 0.0001; prefrontal cortex: F(3, 28) = 15.35; P < 0.0001) in the brain structures of the sepsis survivor animals. Septic animals showed mitochondrial dysfunction and a decrease in axon terminals in the RE. Simvastatin seems to restore energy metabolism by improve of the ETS values in the hippocampus (F(3, 12) = 7.533; P < 0.01) and the P/E ratio in the prefrontal cortex (F(3, 12) = 5.818; P < 0.05), in addition to preventing the reduction of axon terminals in survivor animals. These results together suggest a potential neuroprotective effect of simvastatin and raise the importance of considering HMG-CoA reductase inhibitors as a possible adjuvant therapy in sepsis.