2-(2-benzofuranyl)-2-imidazoline and Brain-Ischemia

We showed previously that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor (I2R) exerts neuroprotective effects in ischemia stroke via an unknown mechanism. The present study was to investigate whether 2-BFI can protect the neurovascular unit (NVU) using a rat model of 90 min focal cerebral ischemia.. Rats were randomly divided into three groups: thesham-operated group; the vehicle control group and the 2-BFI group which received 2-BFI (3 mg/kg) immediately after the start of middle cerebralartery occlusion (MCAO). Neurological deficit score, infarct size, apoptosis level, brain water content and Evans Blue extravasation were assessed at 24 h after stroke. Expressions of occludin and zonula occludens 1 (ZO-1), collagen IV, aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9) and MMP-2 were assessed by Western blotting.. 2-BFI treatment was associated with significant improvement of neurological performance and decreased infarct volume at 24 h after stroke. Apoptosis level reduced significantly by 2-BFI compared to the vehicle group (34.3 ± 5.4% vs 56.1 ± 7.9%, p < 0.05). Significant decreased of brain water content (79.5 ± 2.6% vs 84.62 ± 2%, p < 0.05) and Evans Blue extravasation (1.2 ± 0.5 vs 2.5 ± 0.41 µg/g, p < 0.05) of ipsilateral hemisphere was observed in 2-BFI group compared to vehicle group. Expressions of occludin, ZO-1 and collagen IV were significantly higher while MMP-9 level significantly lower in 2-BFI group. AQP-4 and MMP-2 showed no difference between 2-BFI and the vehicle groups.. These results suggest that the neuroprotective effects of 2-BFI in acute ischemic brain damage are at least partly due to the drug's ability to improve the functions of NVU.

Topics: Animals; Apoptosis; Benzofurans; Brain; Brain Edema; Brain Ischemia; Capillary Permeability; Disease Models, Animal; Imidazoles; Male; Motor Activity; Neurons; Neuroprotection; Neuroprotective Agents; Random Allocation; Rats, Sprague-Dawley

Stroke is caused by vascular dysfunction and currently there are no effective therapeutics to stroke induced brain damage. In contrast to an intense emphasis on neuroprotection, relatively few studies have addressed means of vascular protection in cerebral ischemia. Here we discovered that the ligand to immidazolin receptor, 2-BFI, not only provided potent neuroprotection during middle cerebral artery occlusion in rat, which confirmed our previous reports, but also protected the integrity of the cerebral vasculature. Treatment with 2-BFI twice daily after the occlusion of the middle cerebral artery for 14 d significantly improved the neurological deficits, reduced brain infarction, and importantly, protected the cerebral vasculature as evidenced by the increased expression of an endothelial marker, von Willebrand factor, and better preservation of the cerebral vasculature, as viewed under a confocal microscope on rat brain perfused with FITC-labeled dextran. These results indicated that 2-BFI contributes to protection of neurovasculature. Understanding the molecular mechanisms could eventually lead to development of more effective therapies for stroke.

Topics: Animals; Benzofurans; Brain Ischemia; Cerebrum; Imidazoles; Imidazoline Receptors; Infarction, Middle Cerebral Artery; Ligands; Male; Middle Cerebral Artery; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; von Willebrand Factor

The aim of this study was to determine whether 2-(2-benzofuranyl)-2-imidazoline, an imidazoline I(2) receptor ligand, could protect against cell death from brain injury and improve the functional outcome after focal cerebral ischemia in rats.. Transient focal ischemia was induced by suture occlusion of the middle cerebral artery. Rats were intraperitoneally treated with a vehicle, 2-(2-benzofuranyl)-2-imidazoline or idazoxan immediately after focal ischemia. Infarct volume was assessed by 2,3,5-triphenyltrazolium chloride staining and neurobehavioral deficits were monitored. The volume of cell death in the penumbra after ischemia was determined by immunostaining using anti-cleaved caspase-3 antibody and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL).. Both 2-(2-benzofuranyl)-2-imidazoline and idazoxan significantly improved the neurological score compared with the vehicle at 24 hours after focal ischemia. Treatment with 2-(2-benzofuranyl)-2-imidazoline or idazoxan also significantly reduced infarct volume and the number of both caspase-3- and TUNEL-positive cells in the penumbra compared with vehicle-treated rats (p<0.01 and p<0.05, respectively).. The results suggest the neuroprotective role of 2-(2-benzofuranyl)-2-imidazoline and idazoxan in focal cerebral ischemia, and may therefore represent useful targets for developing new treatments for stroke.

Topics: Animals; Benzofurans; Brain Injuries; Brain Ischemia; Caspase 3; Disease Models, Animal; Idazoxan; Imidazoles; Imidazoline Receptors; In Situ Nick-End Labeling; Male; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Tetrazolium Salts