JNK inhibition mitigates sepsis-associated encephalopathy via attenuation of neuroinflammation, oxidative stress and apoptosis

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, leading to cognitive dysfunction and neuronal damage. C-Jun N-terminal kinases (JNKs), a subset of the MAP kinase family, have attracted substantial interest for their role in cellular events during sepsis conditions. Previous investigations have established the involvement of JNK signaling against memory impairment and abnormal synaptic plasticity. However, the present study is the first to investigate the effects of JNK inhibition in sepsis-associated cerebral injury and cognitive impairments. This study investigated the neuroprotective effects of SP600125, a selective JNK inhibitor, in cecal ligation and puncture (CLP) mouse model of sepsis. CLP-induced sepsis resulted in significant cognitive impairments, as assessed by the open field test, inhibitory avoidance test, morris water maze, and novel object recognition test. Additionally, septic mice exhibited increased serum levels of neuronal injury markers (S100B and NSE), pro-inflammatory cytokines (TNF-alpha and IL-1 beta), and oxidative stress markers (MDA), along with decreased antioxidant levels (GSH, SOD, and CAT). Histological analysis revealed neuronal pyknosis, degeneration, and loss of Nissl bodies in the cortex and hippocampus of septic mice. Furthermore, sepsis-induced blood-brain barrier dysfunction was evident from increased cerebral edema. Treatment with SP600125 (10, 30, and 50 mg/kg) significantly attenuated CLP-induced cognitive deficits, neuronal injury, neuroinflammation, oxidative stress, and apoptosis in a dose-dependent manner. The present study provides preliminary evidence that JNK inhibition by SP600125 exerts neuroprotective effects against sepsis-induced encephalopathy in vivo via suppression of neuroinflammation, oxidative stress, and apoptosis.