title: Neuroprotective effect of lercanidipine in middle cerebral artery occlusion model of stroke in rats.
abstract: Oxidative stress, inflammation and apoptotic neuronal cell death are cardinal mechanisms involved in the cascade of acute ischemic stroke. Lercanidipine apart from calcium channel blocking activity possesses anti-oxidant, anti-inflammatory and anti-apoptotic properties. In the present study, we investigated neuroprotective efficacy and therapeutic time window of lercanidipine in a 2h middle cerebral artery occlusion (MCAo) model in male Wistar rats. The study design included: acute (pre-treatment and post-treatment) and sub-acute studies. In acute studies (pre-treatment) lercanidipine (0.25, 0.5 and 1mg/kg, i.p.) was administered 60min prior MCAo. The rats were assessed 24h post-MCAo for neurological deficit score (NDS), motor deficit paradigms (grip test and rota rod) and cerebral infarction via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The most effective dose was found to be at 0.5mg/kg, i.p., which was considered for further studies. Regional cerebral blood flow (rCBF) was monitored till 120min post-reperfusion to assess vasodilatory property of lercanidipine (0.5mg/kg, i.p.) administered at two different time points: 60min post-MCAo and 15min post-reperfusion. In acute studies (post-treatment) lercanidipine (0.5mg/kg, i.p.) was administered 15min, 120min and 240min post-reperfusion. Based on NDS and cerebral infarction via TTC staining assessed 24h post-MCAo, effectiveness was evident upto 120min. For sub-acute studies same dose/vehicle was repeated for next 3days and magnetic resonance imaging (MRI) was performed 96h after the last dose. Biochemical markers estimated in rat brain cortex 24h post-MCAo were oxidative stress (malondialdehyde, reduced glutathione, nitric oxide, superoxide dismutase), blood brain barrier damage (matrix metalloproteinases-2 and -9) and apoptotic (caspase-3 and -9). Lercanidipine significantly reduced NDS, motor deficits and cerebral infarction volume as compared to the control group. Lercanidipine (60min post-MCAo) significantly increased rCBF (86%) as compared to vehicle treated MCAo group (64%) 120min post-reperfusion, but failed to show vasodilatation with 15min post-reperfusion group. Lercanidipine (13.78±2.78%) significantly attenuated percentage infarct volume as evident from diffusion-weighted (DWI) and T2-weighted images as compared to vehicle treated MCAo group (25.90±2.44%) investigated 96h post-MCAo. The apparent diffusion coefficient (ADC) was also significantly improved in lercanidipine group as compared to control group. Biochemical alterations were significantly ameliorated by lercanidipine till 120min post-reperfusion group and MMP-9 inhibition observed even with 240min group. Thus, lercanidipine revealed significant neuroprotective effect mediated through attenuation of oxidative stress, inflammation and apoptosis.
authors: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors: Sangeetha
authors: S
authors: Gupta
authors: Department of NMR & MRI Facility, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors: Uma
authors: U
authors: Sharma
authors: Department of NMR & MRI Facility, All India Institute of Medical Sciences, New Delhi, 110029, India.
authors: Naranamangalam R
authors: NR
authors: Jagannathan
authors: Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India. Electronic address: yk.ykgupta@gmail.com.
authors: Yogendra Kumar
authors: YK
authors: Gupta
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004095:Dihydropyridines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017078:Laser-Doppler Flowmetry; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009422:Nervous System Diseases / Q000209:etiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004095:Dihydropyridines; D018696:Neuroprotective Agents; D053148:Caspase 3; D053453:Caspase 9; D020778:Matrix Metalloproteinase 2; C060343:lercanidipine
keywords: Anti-apoptotic; Anti-inflammatory; Anti-oxidant; Calcium channel blocker; Lercanidipine; MCAo; Neuroprotection; Stroke