Melatonin is a strong
anti-oxidant that has beneficial effects against early
brain injury (EBI) following a
subarachnoid hemorrhage (SAH) in rats; protection includes the reduction of both mortality and neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model have not been clearly identified. This study examined the influence of
melatonin on
brain edema secondary to disruption of the blood-brain barrier (BBB) and the relationship between these effects and pro-inflammatory
cytokines in EBI following SAH using the filament perforation model of SAH in male Sprague-Dawley rats.
Melatonin (150 mg/kg) or vehicle was given via an
intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH.
Melatonin treatment markedly attenuated
brain edema secondary to BBB dysfunctions by preventing the disruption of
tight junction protein expression (ZO-1,
occludin, and
claudin-5).
Melatonin treatment also repressed cortical levels of pro-inflammatory
cytokines (IL-1β, IL-6, and TNF-α), which were increased in EBI 24 hr after SAH. To further identify the mechanism of this protection, we demonstrated that administration of
melatonin attenuated matrix
metallopeptidase 9 expression/activity and
vascular endothelial growth factor expression, which are related to the inflammatory response and BBB disruption in EBI after SAH. Taken together, this report shows that
melatonin prevents disruption of
tight junction proteins which might play a role in attenuating
brain edema secondary to BBB dysfunctions by repressing the inflammatory response in EBI after SAH, possibly associated with regulation of pro-inflammatory
cytokines.