2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia/reperfusion protects the brain

Zheng Zhang; Jin-Long Yang; Lin-Lei Zhang; Zhen-Zhen Chen; Jia-Ou Chen; Yun-Gang Cao; Man Qu; Xin-Da Lin; Xun-Ming Ji; Zhao Han

doi:10.4103/1673-5374.241461

2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia/reperfusion protects the brain

Neural Regen Res. 2018 Dec;13(12):2111-2118. doi: 10.4103/1673-5374.241461.

Authors

Zheng Zhang¹, Jin-Long Yang², Lin-Lei Zhang³, Zhen-Zhen Chen⁴, Jia-Ou Chen³, Yun-Gang Cao³, Man Qu³, Xin-Da Lin³, Xun-Ming Ji³, Zhao Han⁵

Affiliations

¹ Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
² Department of Neurology, Shan Xian Central Hospital, Heze, Shandong Province, China.
³ Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
⁴ Department of Children Rehabilitation, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
⁵ Department of Neurosurgery; China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.

Abstract

We previously demonstrated that administering 2-(2-benzofuranyl)-2-imidazolin (2-BFI), an imidazoline I2 receptor agonist, immediately after ischemia onset can protect the brain from ischemic insult. However, immediate administration after stroke is difficult to realize in the clinic. Thus, the therapeutic time window of 2-BFI should be determined. Sprague-Dawley rats provided by Wenzhou Medical University in China received right middle cerebral artery occlusion for 120 minutes, and were treated with 2-BFI (3 mg/kg) through the caudal vein at 0, 1, 3, 5, 7, and 9 hours after reperfusion. Neurological function was assessed using the Longa's method. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride assay. Morphological changes in the cortical penumbra were observed by hematoxylin-eosin staining under transmission electron microscopy . The apoptosis levels in the ipsilateral cortex were examined with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression of Bcl-2 and BAX was detected using immunohistochemistry. We found the following: Treatment with 2-BFI within 5 hours after reperfusion obviously improved neurological function. Administering 2-BFI within 9 hours after ischemia/reperfusion decreased infarct volume and alleviated apoptosis. 2-BFI administration at different time points after reperfusion alleviated the pathological damage of the ischemic penumbra and reduced the number of apoptotic neurons, but the protective effect was more obvious when administered within 5 hours. Administration of 2-BFI within 5 hours after reperfusion remarkably increased Bcl-2 expression and decreased BAX expression. To conclude, 2-BFI shows potent neuroprotective effects when administered within 5 hours after reperfusion, seemingly by up-regulating Bcl-2 and down-regulating BAX expression. The time window provided clinical potential for ischemic stroke by 2-BFI.

Keywords: 2-(2-benzofuranyl)-2-imidazoline; BAX; Bcl-2; apoptosis; ischemia/reperfusion; nerve regeneration; neural regeneration; neuroprotection; time window.