Cinnamophilin attenuates gray and white matter damage and improves neurobehavioral and electrophysiological recoveries following transient focal cerebral ischemia

Introduction: Optimal functional integration requires not only the preservation of the cortex and the subcortical cytoarchitectures, but also an integrity of the anatomical, electrophysiological and metabolic links between gray and white matter [1-2]. Cinnamophilin (CINN; 20-80 mg/kg) dose-dependently protects against ischemic lesion via decreasing postischemic oxidative damage in mice [2]. We herein evaluate whether CINN could decrease gray and white matter damage and, therefore, enhance the restoration of neurobehavioral and electrophysiological outcomes following transient focal cerebral ischemia. Methods: Male Sprque-Dawley rats, weighing 240-280 gm, were subjected to intraluminal suture occlusion for 60 minutes. CINN (80 mg/kg) or vehicle was given intravenously at 1 hour after reperfusion. Physiological parameters, including core temperature, local cortical perfusion and arterial blood gases, were measured before, during and after cerebral ischemia-reperfusion, whereas the somatosensory potentials evoked from each forepaw and hindpaw region were recorded prior to the ischemic insult and at 7 days after reperfusion. Postmortem gray matter damage was determined by quantitative image analysis of Nissl-stained sections. White matter damage was evaluated immunohistochemically by SMI-31 and myelin basic protein (MPB). Results: CINN (80 mg/kg, i.v., n=9) given 2 h after the ischemic insult significantly reduced infarct volumes (27.3±7.3% vs. 39.9±5.8%, P<0.005) and improved neurobehavioral outcome by 47.4% (P<0.001), compared with those in control animals (n=9). CINN treatment was also noted to result in more surviving neurons in cortical (582±203 vs. 207±100, per mm2, P<0.001) and subcortical (201±67 vs. 646±153, per mm2, P<0.001) regions, compared to controls. In addition, CINN not only significantly improved somatosensory responses evoked from the contralateral, non-affected fore- and hindpaw by 33.2% and 26.9% (P<0.001, respectively), but also significantly improved contralateral transcallosal diaschisis evoked from the affected forepaw by 8% (P<0.05). Furthermore, we have observed that CINN significantly preserved more phosphorylated component-H of neurofilaments by 33.1% (52.6±12.4% vs. 19.6±12.7%, P<0.005) and improved the integrity of myelin by 28.2% (61.4±7.4% vs. 44.1±16.2, P<0.05) in the ischemic hemisphere. Conclusion: Delayed treatment with CINN not only protects against gray and white matter damage, but also offers the advantage of enhancing neurohavioral and electrophysiological outcomes following transient focal cerebral ischemia in rats. These findings support that the agent may be worthwhile for further investigation for its clinical implications in the treatment of ischemic stroke.