Melatonin has beneficial effects against early brain injury (EBI) by modulating cerebral oxidative stress after experimental subarachnoid hemorrhage (SAH); however, few investigations relate to the precise underlying molecular mechanisms. To date, the relation between melatonin and nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) pathway has not been studied in SAH models. This study was undertaken to evaluate the influence of melatonin on Nrf2-ARE pathway in rats after SAH. Adult male SD rats were divided into four groups: (i) control group (n=18); (ii) SAH group (n=18); (iii) SAH+vehicle group (n=18); and (iv) SAH+melatonin group (n=18). The rat SAH model was induced by injection of 0.3mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20s. In SAH+melatonin group, melatonin was administered i.p. at 150mg/kg at 2 and 24hr after the induction of SAH. Brain samples were extracted at 48hr after SAH. Treatment with melatonin markedly increased the expressions of Nrf2-ARE pathway-related agents, such as Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase α-1. Administration of melatonin following SAH significantly ameliorated EBI, including brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and neurological deficits. In conclusion, post-SAH melatonin administration may attenuate EBI in this SAH model, possibly through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.

Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s. Behavioral problems, mood, cognition, particularly memory, attention, and executive function are commonly impaired by TBI. Spending to assist, TBI survivors with disabilities are estimated to be costly per year. Such impaired functional outcomes following TBI can be improved via various rehabilitative approaches. The objective of the present paper is to review the current rehabilitation treatment of traumatic brain injury in adults.

The current research aimed to investigate the role of hypoxia-inducible factor-1α (HIF-1α), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) dysfunction and cerebral edema formation in a rat subarachnoid hemorrhage (SAH) model. The SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2-methoxyestradiol (an inhibitor of HIF-1α), was administered intravenously at 2 and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions, BBB impairment, and brain edema. Following SAH, remarkable edema and BBB extravasations were observed. Compared with the control group, the SAH animals have significantly upregulated expressions of HIF-1α, AQP-4, and MMP-9, in addition to decreased amounts of laminin and tight junction proteins. Brain edema was repressed after inhibition of AQP-4, MMP-9, or HIF-1α. Although BBB permeability was also ameliorated after inhibition of either HIF-1α or MMP-9, it was not modulated after inhibition of AQP-4. Inhibition of MMP-9 reversed the loss of laminin. Finally, inhibition of HIF-1α significantly suppressed the level of AQP-4 and MMP-9, which could induce the expression of laminin and tight junction proteins. Our results suggest that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular signaling pathway involving AQP-4 and MMP-9. Pharmacological intervention of this pathway in patients with SAH may provide a novel therapeutic strategy for early brain injury.

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