7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN) attenuates inflammation and oxidative stress via MAPK, and Nrf2/HO-1 signaling in Traumatic brain injury

Abstract

Traumatic brain injury (TBI) is an acquired neurological insult that has become a major cause of mortality.Hence, immediate and appropriate medical attention is essential. The present study investigated the neuroprotective effect of 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid against a weight drop model of traumatic brain injury (TBI). During the in-vitro analysis, ECN demonstrated neuroprotective potential by remarkably improving the cell viability and also provided significant protection in case of nitric oxide-evoked oxidative stress in HT22 cells. The administration of ECN significantly improved the neurological severity score, and mechanical/periorbital allodynia following TBI, when compared with the TBI-group. The level of brain edema and blood-brain barrier (BBB) disruption were also significantly reduced by ECN treatment. ECN also restored constitutional changes in the protein/lipid profile; simultaneous with histological changes in the brain in contrast to the TBI-group. It significantly ameliorated neuronal loss and also minimized the intracerebral hemorrhages arising from traumatic insult. ECN exhibited potent anti-inflammatory effects, by altering the expression of extracellular-signal-regulated kinase (ERK), p38, and activating protein-1 (AP-1) proteins. It also exhibited antioxidant effects by increasing the production levels of nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Furthermore, ECN also produced an anti-apoptotic effect by downregulation of caspase3 and upregulation of B-cell lymphoma 2 (Bcl-2). It also increased the levels of antioxidants while reducing the levels of oxidative stress and inflammatory markers in comparison to the TBI-group. In short, it was concluded that ECN exhibited protective anti-inflammatory, antioxidant, and anti-apoptotic effects against trauma-induced brain injury. © 2025 Elsevier B.V., All rights reserved.