Abstract 3327: The Combination Therapy of Chemical Chaperone and n-NOS inhibitor Affords Enhanced Neuroprotection in a Rodent model of Ischemic Stroke associated with Comorbid Type 2 diabetes
Ischemic stroke involves complex and multiple pathomechanisms along with underlying comorbidities. Combination therapies have long been recommended by STAIR committee for the successful stroke treatment. The augmentation of nitrosative and endoplasmic reticulum (ER) stress has been postulated in pathogenesis of cerebral ischemia/reperfusion (I/R) injury associated with diabetes. We investigated whether combination of tauroursodeoxycholic acid (TUDCA), a chemical chaperone and 3-bromo- 7-nitroindazole (3-BNI), nNOS inhibitor would protect against diabetes-exacerbated focal cerebral I/R injury. Transient focal cerebral ischemia was induced in high fat diet-fed and low-dose streptozotocin-treated type 2 diabetic rats. Histological (brain infarct, oedema volume) and functional outcomes (neurological score) were evaluated after 2 hours/22 hours of I/R in diabetic rats. Further, immunohistochemical and TUNEL analyses were performed for detecting the changes in in-situ expression of ER stress/apoptosis markers [GRP78 and CHOP/GADD153] and DNA fragmentation in penumbral brain region, respectively. The diabetic rats after cerebral I/R showed significant increase in brain infarct, oedema volume and functional neurological deficits compared with sham-operated rats. Acute administration of TUDCA (100 mg/kg) or 3-BNI (10 mg/kg) per se exhibited no significant neuroprotective effects as compared to vehicle-treated diabetic I/R rats. Interestingly, the combination of TUDCA (100 mg/kg) and 3-BNI (10 mg/kg) showed synergistic and enhanced neuroprotection as evidenced by significantly greater reduction in brain infarction, oedema volume and functional neurological deficits as compared to respective monotherapy. Further, there was marked lowering of apoptotic DNA fragmentation accompanied in parallel with enhanced reduction of GRP78 and CHOP/GADD153 immunoreactivity. The effects were observed independent of changes in blood glucose level. The results of our study demonstrates the enhanced neuroprotection with combination of TUDCA and 3-BNI in ischemic stroke model associated with comorbid type 2 diabetes which may be attributed to greater attenuation of ER stress/apoptosis.
- © 2012 by American Heart Association, Inc.