Non-hypotensive dose of telmisartan and nimodipine produced synergistic neuroprotective effect in cerebral ischemic model by attenuating brain cytokine levels

• Published in: Pharmacology, biochemistry and behavior Vol. 122; pp. 61 - 73
• Main Authors: Justin, A., Sathishkumar, M., Sudheer, A., Shanthakumari, S., Ramanathan, M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014
• Subjects: Animals; AT1 receptor; Behaviour; Benzimidazoles - administration & dosage; Benzoates - administration & dosage; Brain - drug effects; Brain - metabolism; Brain Ischemia - metabolism; Brain Ischemia - prevention & control; Calcium channel blocker; Cytokines; Cytokines - antagonists & inhibitors; Cytokines - metabolism; Drug Synergism; Drug Therapy, Combination; Excitatory amino acids; Hypotension - metabolism; Male; Neuroprotective Agents - administration & dosage; Nimodipine - administration & dosage; Rats; Rats, Sprague-Dawley; Transient ischemia; eNOS; Na2HPO4; BBB; Transient ischemia; NF-kB; KH2PO4; TBARs; BSA; TBA; KCl; CMC; iNOS; PPAR-γ; DNPH; IL; MgCl2; Cytokines; Behaviour; ANSA; Calcium channel blocker; IR; i.p; AT1 receptor; TCA; RH; ROS; NaCl; Na+; ELISA; NM; MCAo; NADPH; NO; NaH2PO4; NaOH; CNS; K2HPO4; K; EAAs; BHT; HCl; SD; NADH; ANOVA; NMDA; SO; GSH; AT1; HPLC; HPTLC; SSA; JNK/c-Jun; DTNB; EDTA; GS; NED; UV–Vis; TNF-α; Ca2; DNA; PMS; Excitatory amino acids; TM; ATP; GLT-1; AT receptor
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2014.03.009

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 2h of occlusion. The drugs were administered 30min prior to the surgery and continued throughout the study period. After 24h 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 & 10mg/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 (5mg/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 Ca2+ dependent glutamate toxicity in neurons. The advantage of TM therapy in ischemic state can be explored clinically due to its dual effect in hypertension. •Telmisartan at non-hypertensive dose shown neuroprotection in ischemic condition.•Telmisartan neuroprotective effect attributed to anti-inflammatory property.•IL1β/IL6 exhibited positive correlation with glutamate in neuroprotective activity.•Cytokines and excitatory amino acids had positive correlation in ischemic state.•Telmisartan and nimodipine combination favors energy restoration.