Androgen is Responsible for Enhanced Susceptibility of Melatonin Against Traumatic Brain Injury in Females

Background: Numerous publications have demonstrated that melatonin administration is associated with mortality reduction and improvement in neurological outcomes after traumatic brain injury (TBI). However, there are significant sex differences in several diseases associated with melatonin. We aimed to determine whether androgen was responsible for enhanced susceptibility of melatonin against TBI in females, as well as potential molecular mechanisms.

Methods: Weight-drop was used to establish a rodent model of TBI. Melatonin (10 mg/kg) and testosterone (1 mg/kg) were administered three times every day for three days after TBI using subcutaneous injection, respectively. Seven days after TBI, an open field assay was used to evaluate locomotor and exploratory activities. Neuronal amount, neuronal apoptosis, and expression of phosphorylated extracellularly regulated protein kinases 1/2 (ERK1/2), c-jun N-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (p38MAPK) in neurons were assessed using immunofluorescence assay seven days after TBI. The expression of caspase-3, Bax, and Bcl-2 in the frontal cortex was detected using western blot.

Results: Compared with female rats, melatonin administration exhibited more neuroprotective effects (including improved locomotor and exploratory activities, elevated neuronal amount, and reduced neuronal apoptosis) in male rats exposed to TBI. Moreover, testosterone significantly improved locomotor and exploratory activities, elevated neuronal amount, decreased neuronal apoptosis, downregulated phosphorylation of JNK1/2- and p38MAPK-positive neurons, but upregulated phosphorylation of ERK1/2-positive neurons in the frontal cortex, and reduced the expressions of cleaved caspase-3, Bax, but increased Bcl-2 expressions in female rats exposed to TBI.

Conclusions: Androgen was responsible for the enhanced susceptibility to TBI under melatonin supplementation in females through a mechanism that may be associated with MAPK pathway regulation.