Abstract
Background: Intracerebral hemorrhage (ICH) resulting from the rupture of blood vessels in the brain leads to serious brain tissue damage by leakage of blood components. Formation of hematoma in the brain is followed by several kinds of reparative processes including recovery of blood flow with angiogenesis in the damaged region as well as microglia / macrophage-mediated phagocytosis of blood constituents and dead cell debris. Therefore, enhancement of these reparative mechanisms may contribute to the improvement of long-term prognosis after ICH. Because nicotine has been reported to promote angiogenesis in peripheral tissues under pathological conditions such as hindlimb ischemia and lung cancer, here we examined the effect of nicotine on angiogenesis in the brain after ICH.
Methods: Collagenase was injected into the striatum of male C57BL/6J mice to induce ICH. Nicotine (2 mg/kg) was intraperitoneally administered three times at 24-h interval, the first dose given at 3 h after ICH induction. Alternatively, nicotine (100 μg/ml) in drinking water was made freely available to mice after ICH surgery. Blood vessels within the hematoma region were identified by immunohistochemistry against an endothelial cell marker CD31 at 1 and 2 weeks after ICH. At the same time, the neuroprotective effect of nicotine was examined by immunohistochemistry against a neuronal marker NeuN.
Results: In the absence of drug treatment, the area occupied by blood vessels in the hematoma region exhibited gradual recovery during 2-weeks period after ICH, which reflected spontaneous occurrence of angiogenesis in the damaged brain tissue. We found that intraperitoneal administration of nicotine tended to enhance the increase of blood vessels in the hematoma. Notably, nicotine given through the drinking water produced a more potent effect in enhancing angiogenesis than intraperitoneal doses, and the effect reached a statistically significant level. Moreover, nicotine given through the drinking water significantly increased the number of surviving neurons in the hematoma at 1 week after ICH, although the neuroprotective effect did not last for 2 weeks.
Conclusions: Nicotine promotes angiogenesis in the brain after ICH, which might in part contribute to the enhancement of neuronal survival in the hematoma.
