Objective(s): Traumatic brain injury (TBI) is one of the most common causes of death and disability in modern societies. The role of steroids and melatonin is recognized as a neuroprotective factor in traumatic injuries. This study examined the role of melatonin receptors in the neuroprotective effects of estrogen. Materials and Methods: Seventy female ovariectomized Wistar rats were divided into five groups and two subgroups. All animals underwent brain trauma. The groups were as follow: ۱) trauma, ۲) melatonin receptor antagonist vehicle + estrogen, ۳) MT۱ melatonin receptor antagonist + estrogen, ۴) MT۲ melatonin receptor antagonist+ estrogen, ۵) MT۳ melatonin receptor antagonist+ estrogen. Brain edema
(۲۴ hr), intracranial pressure (ICP) (-۱, ۰, ۱, ۴ and ۲۴ hr) and blood–brain barrier (BBB) permeability (۵ hr) and aquaporin (AQP۴) expression (۲۴ hr) were evaluated after TBI. Results: MT۱, MT۲ and MT۳ melatonin receptors had anti-edema effects while MT۱ and MT۲ have a role in protecting BBB by estrogen. Furthermore, the activity of MT۳ and MT۲ melatonin receptors weakened the effect of estrogen on ICP. However, melatonin receptors had no role in the effect of estrogen on AQP۴ protein. Conclusion: Based on the above results, it seems that melatonin receptors appear to influence the effect of estrogen in TBI
without altering AQP۴ expression. The role of the receptors is different in this interaction.