Cinnamophilin offers prolonged neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after transient focal cerebral ischemia

OBJECTIVE: We have previously shown that cinnamophilin ([8R, 8′S]-4, 4′-dihydroxy-3, 3′-dimethoxy-7-oxo-8, 8′-neolignan) exhibited potent antioxidant, radical-scavenging, and anti-inflammatory actions and reduced acute ischemic brain damage, even when it was given up to 6 hrs postinsult. Here, we characterized the long-lasting neuroprotection of cinnamophilin against gray and white matter damage and its beneficial effects on electrophysiological and functional outcomes in a model of stroke. DESIGN: Prospective laboratory animal study. SETTING: Research laboratory in a university teaching hospital. SUBJECTS: Adult male Sprague-Dawley rats (240-290 g). INTERVENTIONS: Under controlled conditions of normoxia, normocarbia, and normothermia, spontaneously breathing, halothane-anesthetized (1.0-1.5%) rats were subjected to transient middle cerebral artery occlusion for 90 mins. Cinnamophilin (80 mg/kg) or vehicle was given intravenously at reperfusion onset. MEASUREMENTS AND MAIN RESULTS: Physiological parameters, including arterial blood gases and cortical blood perfusion, somatosensory-evoked potentials, and neurobehavioral outcomes, were serially examined. Animals were euthanized at 7 days or 21 days postinsult. Gray matter and white matter (axonal and myelin) damage were then evaluated by quantitative histopathology and immunohistochemistry against phosphorylated component-H neurofilaments and myelin basic protein, respectively. After the follow-up period of 7 and 21 days, our results showed that cinnamophilin significantly decreased gray matter damage by 31.6% and 34.9% (p <.05, respectively) without notable adverse effects. Additionally, cinnamophilin effectively reduced axonal and myelin damage by 46.3-68.6% (p <.05) and 25.2-28.1% (p <.05), respectively. Furthermore, cinnamophilin not only improved the ipsilateral field potentials (p <.05, respectively), but also reduced the severity of contralateral electrophysiological diaschisis (p <.05). Consequently, cinnamophilin improved sensorimotor outcomes up to 21 days postinsult (p <.05, respectively). CONCLUSIONS: Administration with cinnamophilin provides long-lasting neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after ischemic stroke. The results suggest a need for further studies to characterize the potential of cinnamophilin in the field of ischemic stroke.