title: Non-hypotensive dose of telmisartan and nimodipine produced synergistic neuroprotective effect in cerebral ischemic model by attenuating brain cytokine levels.
abstract: The hypothesis of the present study is that the anti-inflammatory property of telmisartan (TM), an AT1 blocker that may exert neuroprotection through attenuation of excitatory amino acids by controlling cytokines and reactive oxygen species, release during ischemia. The neuroprotective effect of TM and its combination with nimodipine (NM) were studied in rats by using middle cerebral artery occlusion method followed by ischemic reperfusion (IR) after 2 h of occlusion. The drugs were administered 30 min prior to the surgery and continued throughout the study period. After 24 h of IR the neurological deficit was assessed, and the locomotor activity and open field behaviour were assessed on the seventh day. On the ninth day, the brains were isolated for neurochemical and cytokine measurements and histopathological studies. The results have shown that treatment of TM (5 & 10 mg/kg) gradually reduced the glutamate, aspartate and glutamine synthetase levels. It also restored the ATP, Na(+)K(+)ATPase, glutathione and synapse integrity in the different regions of the brain in comparison to ischemic brain. TM ameliorated the pro-inflammatory cytokine (IL-1β, IL-6, TNF-α), lipid peroxide and nitric oxide levels. Anti-inflammatory cytokine IL-10 level was found to be concurrently increased. Combination therapy of TM with NM (5 mg/kg) has shown additive effects in the above said parameters. Further a positive correlation between glutamate and cytokine release was observed, and it indicated that synaptic clearance of glutamate can be regulated by cytokines. It can be concluded that TM induces neuroprotective activity through amelioration of pro-inflammatory cytokine release during cerebral ischemia. The additive effect of NM on TM neuroprotective effect would be through controlling cytokine release, ATP restoration by cerebrovasodilation, and along with prevention of Ca(2+) dependent glutamate toxicity in neurons. The advantage of TM therapy in ischemic state can be explored clinically due to its dual effect in hypertension.
authors.affiliation: Department of Biotechnology, PSG College of Technology, Peelamedu, Coimbatore, TN 641004, India.
authors.forename: A
authors.initials: A
authors.lastname: Justin
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore, TN 641004, India.
authors.forename: M
authors.initials: M
authors.lastname: Sathishkumar
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore, TN 641004, India.
authors.forename: A
authors.initials: A
authors.lastname: Sudheer
authors.affiliation: Department of Pathology, PSG Institute of Medical Sciences & Research, Peelamedu, Coimbatore, TN 641004, India.
authors.forename: S
authors.initials: S
authors.lastname: Shanthakumari
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore, TN 641004, India. Electronic address: muthiah.in@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007022:Hypotension / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009553:Nimodipine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077333:Telmisartan
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D016207:Cytokines; D018696:Neuroprotective Agents; D009553:Nimodipine; D000077333:Telmisartan
keywords: AT(1) receptor; Behaviour; Calcium channel blocker; Cytokines; Excitatory amino acids; Transient ischemia