2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats.
Stroke is the third leading cause of death and disability in North America and is becoming the most frequent cause of death in the rapid developing China. Protecting neurons in order to minimize brain damage represents an effective approach towards stroke therapeutics. Our recent study demonstrated that 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a ligand for imidazoline I(2) receptors, is potently neuroprotective against stroke, possibly through transiently antagonizing NMDA receptor activities. In this study, we further investigated the characteristics and mechanisms of 2-BFI-mediated neuroprotection using a rat stroke model of transient occlusion of the middle cerebral artery. Here, we show that 2-BFI was most effective at the dose of 3mg/kg in vivo, with significantly reduced brain infarct size and improved neurological deficits. Lower doses of 2-BFI at 1.5mg/kg, or higher dose of 2-BFI at 6 mg/kg, were either not effective, or toxic to the brain, respectively. Treating stroke rats with 3mg/kg 2-BFI significantly reduced the number of TUNEL positive cells and preserved the integrity of subcellular structures such as nuclear membranes and mitochondria as shown under the electron microscope, confirming neuroprotection. Most interestingly, 2-BFI-treated brains exhibited significant expression of Bcl-2, a gene with a known function in neuroprotection. Taken together, these studies not only demonstrated that 2-BFI at 3mg/kg was effective in neuroprotection, but also, for the first time, showed that 2-BFI provided neuroprotection through up-regulating the neuroprotective gene Bcl-2. 2-BFI can be further developed as a therapeutic drug for stroke treatment.
Han
Zhao
Z
Division of Stroke Medicine, The First Affiliate Hospital of Wenzhou Medical College, No. 2 Fuxue Lane, Wenzhou City, Zhejiang Province 325000, PR China.
Zhang
Hong-Xia
HX
Tian
Ji-Sha
JS
Zheng
Rong-Yuan
RY
Hou
Sheng T
ST
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D003243:Consciousness / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008854:Microscopy, Electron; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects*; D016138:Walking
D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; C487767:imidazoline receptor 2; C103723:2-(2-benzofuranyl)-2-imidazoline