The induction of oxidative stress and
inflammation has been closely linked in
traumatic brain injury (TBI). Transcriptional factors of signal transducers and activators of transcription (STAT)
proteins are redox sensitive and participate in the regulation of
cytokine signaling. Previous studies demonstrated that
melatonin protects neurons through its antioxidative and anti-inflammatory effects in various neuropathological conditions. However, the effect of
melatonin on STAT activity after TBI has not yet been explored. In this study, we used a controlled weight-drop TBI model and found that
brain contusion induced oxidative stress (a decreased level of total
glutathione and an increased ratio of
oxidized glutathione to total
glutathione), a reduction in STAT1
DNA-binding activity, and consequently neuronal loss in a
contusion depth-dependent manner. A significant increased
mRNA expression of suppressor of
cytokine signaling (SOCS3), inducible
nitric oxide synthetase (iNOS), and interleukine-6 (IL-6), but a decreased
protein expression of
protein inhibitor of activated STAT (PIAS1), was found 24 hr after
brain contusion. SOCS3 and PIAS1 are endogenous negative regulators of STAT1. Moreover, the combination of intraperitoneal and local (presoaked in
gelfoam and placed on the traumatic cortex) administration of
melatonin had the most pronounced influence in inhibiting all effects except the PIAS1 downregulation induced by
brain contusion. The results suggest that SOCS-3 upregulation and oxidative stress may contribute to the STAT1 inactivation after TBI.
Melatonin protects neurons from TBI by reducing oxidative stress, STAT1 inactivation, and upregulation of SOCS-3 and pro-inflammatory
cytokines.