Neuroprotection following acute ischemic stroke: efficacy of preconditioning and antioxidants.

The recently published article in Neurological Sciences by Lu et al. [1] titled ‘Erythromycin pretreatment induces tolerance against focal cerebral ischemia through up-regulation of nNOS but not down-regulation of HIF-1a in rats’ was very interesting. The authors evaluated the effect of preconditioning with erythromycin, a macrolide class antibiotic, on stroke outcomes in a rat focal cerebral ischemia model. This study found that erythromycin preconditioning significantly attenuated cerebral infarct volume, cerebral edema, and neurological deficits. Additionally, neuronal nitric oxide synthase (nNOS) expression was upregulated and hypoxia-inducible factor1a (HIF-1a) expression was downregulated in the erythromycin preconditioning cohort. Thus, this study supports further investigation regarding the neuroprotective effects of preconditioning for ischemic stroke. Another recent article by Vakili et al. [2] evaluated the neuroprotective effects of crocin, a carotenoid antioxidant, against hypoxia, reperfusion, and cerebral edema following ischemic stroke. In an ischemic stroke model in rats, the authors performed middle cerebral artery occlusion (MCAO) for 1 h using nylon suture. The suture was then withdrawn for 23 h to simulate post-stroke reperfusion. Regional cerebral blood flow was monitored using laser Doppler flowmetry with a probe through an ipsilateral temporal burr hole. Crocin was administered at varying doses (range 15–120 mg/kg) and at different time points (range 1 h before to 6 h after MCAO) to establish a dose– response relationship as well as the therapeutic time window. The animals were monitored for neurological outcomes 24 h after MCAO and prior to killing. The harvested brains were assessed for infarct volume, cerebral edema as measured by brain water content, oxidative stress as measured by malondialdehyde (MDA) content, and activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx). The authors found that the optimal dose of crocin was 60 mg/kg, which resulted in a mean decrease in infarct volume of 74 %. The higher crocin dose of 120 mg/kg did not result in a further reduction of infarct volume, and lower doses resulted in a lower magnitude of reduction in infarct volume. Similarly, crocin 60 mg/kg resulted in the best neurological outcomes 24 h post-stroke. Crocin administration within 1 h of MCAO significantly reduced cerebral edema. There was no effect of crocin on cerebral edema outside of the 1-h therapeutic window. Treatment with crocin significantly decreased MDA content and significantly increased SOD and GPx activity thereby suggesting that crocin affords neuroprotection by ameliorating oxidative cerebral injury and activating antioxidant enzymes. The relatively brief time window in which preconditioning agents or antioxidants must be administered to provide neuroprotection in vivo may not be translatable into clinical practice. In the aforementioned study, crocin only provided neuroprotection within a 1-h therapeutic window which is challenging, if not virtually impossible, to clinically achieve. Similarly, we cannot derive, based on the presently available studies of preconditioning for ischemic stroke, the effective time window in which preconditioning must be performed to yield clinical benefit. Furthermore, studies abound purporting the neuroprotective role of D. Ding (&) Department of Neurosurgery, University of Virginia, P.O. Box 800212, Charlottesville, VA 22908, USA e-mail: dmd7q@hscmail.mcc.virginia.edu