Title : Exogenous CGRP mitigates neuroinflammation and cognitive impairment in sepsis- associated encephalopathy via regulating C-Jun N-terminal kinase
Abstract:
During sepsis, the CNS is particularly vulnerable to injury mediated by inflammatory and oxidative processes, which can cause sepsis-associated encephalopathy (SAE), a diffuse brain impairment. Sepsis-induced pathological consequences lead to short and long-term neurobehavioural deficits, such as cognitive impairment, motor deficits, memory, and attention deficits. The successful implementation of the CGRP treatment improves SAE and its associated behavioral impairments, which leads to the development of novel therapeutic agents in managing sepsis encephalopathy. The cecal ligation and puncture (CLP) method was used to induce sepsis. Behavioral changes were assessed on days 7-12 by open field test, inhibitory avoidance task, Novel object recognition test, and Morris-water maze test. After sacrifice, neuronal injury and inflammation were assessed by S100β, NSE, TNF-α, and IL-1β in the serum. Biochemical changes were explored by estimating malondialdehyde, superoxide dismutase, and reduced glutathione in the mouse brain. Cerebral edema was evaluated by the wet/dry ratio method, and histopathological changes were assessed via cresyl violet staining of the mouse brain. The protein expression levels of CGRP, TRPV1, p-JNK, and the neuronal apoptotic markers caspase-3 and Bcl-2 were assessed using specific Elisa kits and western blotting. CGRP preconditioning at low doses significantly improves cerebral injury and cognitive function. However, CGRP administration at a high dose did not exhibit any significant beneficial effect but rather showed cerebral injury and cognitive defects. Respectively, It has been observed that the mice TRPV1 antagonist markedly attenuates the CGRP-induced effects. Moreover, CGRP treatment significantly attenuated the CLP-induced cognitive dysfunction and significantly improved neuro-inflammation, oxidative damage, neuro-apoptosis, and brain histopathology to protect against sepsis-induced cerebral injury and cognitive dysfunction. Based on the observed responses, it could be suggested that CGRP preconditioning protects against septic encephalopathy by preventing neuroinflammation, oxidative stress, and apoptosis by regulating C-Jun N-terminal kinase.
