The role of iron-induced oxidative stress in acute ischemic stroke and the potential role for fasciculations in their therapy.

摘要

Reactive oxygen species (ROS) play an important role in the pathogenesis of acute ischemic stroke. To understand the pathophysiological mechanisms underlying oxidative stress, we wanted to elucidate the effect of iron overload on infarct size after middle cerebral artery occlusion (MCAO) and to evaluate the neuroprotective effect of tempol. Rats were administered iron and tempol before MCAO, control rats received saline. Iron increased infarct size as compared to control values and pretreatment with tempol inhibited the action of iron. We measured ROS generated by exogenous iron in brain tissue and peripheral vasculature. Although the ROS production in the brain of iron treated rats did not increase, ROS generation in the carotid arteries was significantly increased compared to controls. We propose that ROS, generated in the cerebral vasculature contributes to oxidative stress during an ischemic episode. Iron generates OH- radicals through the Fenton reaction and the enzyme NADPH oxidase generates O2- . We studied the neuroprotective efficacy of inhibiting these processes by using deferroxamine and apocynin. Apocynin and deferoxamine treatment reduced the infarct size in spontaneously hypertensive rats (SHRs) compared to untreated SHRs. Hence, we believe that the extent of neuroprotection seen in the hypertensive rats, in the presence of elevated blood pressures, is a function of elevated ROS generation. We also wanted to investigate the neuroprotective efficacy of atypical antioxidants such as tamoxifen. We studied whether therapeutic doses of tamoxifen, could protect against ischemic stroke. Adult rats were bilaterally ovariectomized and implanted subcutaneously with placebo or tamoxifen time-release pellets (0.1, 0.8, or 2.4 mg/kg/day) and subjected to MCAO. MCAO produced a large infarct (∼53%) in control animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct size (∼70% reduction) as compared to the controls. Lastly, we investigated the role of PSA-NCAM in axonal fasciculations which are deployed by the growing axons to reach their target site. We also provide evidence to show that PSA-NCAM plays a permissive role in mediating axonal fasciculations in culture. Since PSA-NCAM induction takes place in the neurons of the cerebral cortex and caudate after MCAO, understanding the role of PSA-NCAM in cell-cell interactions may lead to development of significant strategies for post-injury repair in stroke.