Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: We investigated the role of thrombin in early brain injury after subarachnoid hemorrhage (SAH). METHODS: The standard intravascular perforation model was used to produce experimental SAH in Sprague Dawley rats. Low-dose (0.3 mg/h) and high-dose (0.9 mg/h) argatroban, a direct thrombin inhibitor, were evaluated for effects on brain edema, blood-brain barrier (BBB) disruption, apoptotic cell death, inflammatory marker, and neurological outcomes after SAH. RESULTS: Both doses of argatroban attenuated BBB disruption; however, only high-dose was effective in lowering edema in all brain regions, reducing cell death, and inflammatory marker expression, and improving neurological outcomes. CONCLUSIONS: Thrombin inhibition by argatroban improves neurological outcomes and provides neuroprotection against acute events after SAH such as BBB disruption, brain edema, and cell death.

Dual effects of melatonin on oxidative stress after surgical brain injury in rats.

The purpose of this study was to evaluate the effect of melatonin on oxidative stress occurring in the brain after routine lobectomy neurosurgery procedures. Different concentrations of melatonin (5, 15 and 150 mg/kg) were administered 1 hr before lobectomy in a rodent surgical brain injury (SBI) model. Neurological outcomes were assessed 24 hr before the killing of the rodents, for evaluation of brain water content (brain edema) and lipid peroxidation (oxidative stress). The results showed that lower doses (5 and 15 mg/kg) failed to reduce brain edema, but the 15 mg/kg dose did lower oxidative stress and improved several neurological parameters. High concentration of melatonin (150 mg/kg) significantly increased brain edema and elevated oxidative stress when compared with the vehicle-treated group. Furthermore, high-dose melatonin also worsened neurological outcomes compared with other groups. The study suggests that melatonin has dual effects: low-dose melatonin may provide neuroprotective effects against SBI but a high dose may aggravate some parameters after SBI.

Melatonin decreases mortality following severe subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood-brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague-Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.

Effects of melatonin in early brain injury following subarachnoid hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the BBB. Previous studies have shown that melatonin provides neuroprotection in other models of CNS injury. METHODS: This experiment evaluates melatonin as a neuroprotectant against early brain injury following SAH. The endovascular perforation model of SAH was performed in male Sprague Dawley rats followed by the administration of melatonin two hours after the insult. Mortality and brain water content were assessed 24 after SAH. FINDINGS: A significant reduction in 24 h mortality was seen following treatment with 150 mg/kg of melatonin. Brain water content was evaluated in the high dose treatment group to see if a reduction in brain edema was associated with reduced mortality. High dose melatonin tended to reduce brain water content following SAH. CONCLUSIONS: Large doses of melatonin significantly reduced mortality and brain water content in rats following SAH.

The antioxidant effects of melatonin in surgical brain injury in rats.

BACKGROUND: Surgical brain injury (SBI) to normal brain tissue can occur as inevitable sequelae of neurosurgical operations. SBI can contribute to post-operative complications such as brain edema following blood-brain barrier (BBB) disruption leading to neurological deficits. Melatonin is a commonly used drug with known antioxidant properties and neuroprotective effects in experimental animal studies (Chen et al., J Pineal Res 41:175-182, 2006; Chen et al., J Pineal Res 40(3):242-250, 2006; Cheung, J Pineal Res 34:153-160, 2003; Lee et al., J Pineal Res 42(3):297-309, 2007; Reiter et al., Exp Biol Med (Maywood) 230(2):104-117, 2005). METHODS: We tested different concentrations of melatonin (5 mg/kg, 15 mg/kg and 150 mg/kg) administered 1 hour before surgery for neuroprotection against SBI using a rodent model. Post-operative assessment included brain water content (brain edema), lipid peroxidation assays (oxidative stress), and neurological assessment. FINDINGS: The results showed a trend in decreasing brain edema with lower doses of melatonin (5 mg/kg and 15 mg/ kg), however, high concentration of melatonin (150 mg/kg) significantly increased brain edema compared to all other groups. This deleterious effect of high-dose melatonin was also observed in lipid-peroxidation assay wherein lower-dose melatonin (15 mg/kg) attenuated oxidative stress, but high-dose melatonin (150 mg/kg) increased oxidative stress as compared to vehicle-treated group. Furthermore, high-dose melatonin also worsened neurological outcomes compared to other groups whereas; the low-dose melatonin group (15 mg/kg) showed some improved neurological parameters. CONCLUSIONS: The study suggests that low-dose melatonin may provide neuroprotective effects against SBI. Further studies are needed to confirm this. More importantly, the findings of the study stress the need to carefully reassess safety issues with high doses of melatonin, which is considered to be a practically non-toxic drug.