Abstract
In addition to significant antioxidant properties, melatonin exhibits neuroprotective effects against various neurological diseases including traumatic brain injury (TBI) and ischemic stroke. Several potential mechanisms have been reported in the neuroprotection of melatonin among patients with TBI. Notably, the heme oxygenase-1 (HO-1)/cAMP response element-binding protein (CREB) signaling pathway is implicated in the development of a depressive state. Moreover, the activity of CREB in the nucleus accumbens (NAc) participates in reward and motivation, further contributing to depression induced by TBI. This study aims to explore whether melatonin could mitigate TBI-induced depression by activating of HO-1/CREB signal in a rodent model of weight-drop. As a consequence, melatonin (10 mg/kg) attenuated TBI-induced elevated immobility time in the force swim test, decreased time spent sniffing the novel rat in 3-chambered social test, and downregulated phosphorylated CERB in the NAc. However, a special inhibitor of HO-1 (SnPP) via intracerebroventricular injection partially reversed the neuroprotective effects of melatonin. Furthermore, melatonin decreased the number of summarized intersects in the astrocyte, A1-type astrocytes, IL-6-positive astrocytes in the NAc after TBI exposure, nevertheless, these changes could partially be restored by SnPP. Therefore, our findings demonstrate a novel neuroprotective mechanism for melatonin against TBI which can be a potential neuroprotective agent for the treatment of TBI-induced depression.