Neuroprotective effects of Takinib on an experimental traumatic brain injury rat model via inhibition of transforming growth factor beta-activated kinase 1

Abstract

Abstract Transforming growth factor β-activated kinase 1 (TAK1) remarkably controls several signaling pathways regulating inflammation and apoptosis and represents an important target for pharmacologically treating traumatic brain injury (TBI). Takinib, a small molecule TAK1 inhibitor with potent anti-inflammatory activity, has shown promising activity in preclinical studies. The research dealt with evaluating the potential neuroprotective impact of takinib on a TBI rat model. A modified Feeney’s weight-drop model was employed to cause TBI in mature male Sprague-Dawley rats. One day after induction of TBI in the rats, they received an intracerebroventricular injection of takinib, and their histopathology and behavior were assessed. The results of this study demonstrated that takinib suppressed TBI progression in rats by decreasing TAK1, p-TAK1, nuclear p65, and ionized calcium-binding adaptor molecule 1 levels while upregulating the NF-κB inhibitor expression. Takinib significantly inhibited the production of two pro-inflammatory factors, tumor necrosis factor-α, and interleukin-1β. Furthermore, takinib remarkably upregulated the expression of tight junction proteins zonula occludens-1 and claudin-5 and reduced cerebral edema. Takinib effectively suppressed apoptosis via downregulation of cleaved caspase 3 and Bax and reduction of TUNEL-positive stained cell count. Thus, an enhancement of neuronal function and survival was observed post-TBI. These findings highlight the medicinal value of takinib in the management of TBI and offer an experimental justification for investigating TAK1 as a possible pharmacological target.