title: Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury.
abstract: Recently glutamate transporters have emerged as a potential therapeutic target in a wide range of acute and chronic neurological disorders, owing to their novel mode of action. The modulation of GLT-1, a major glutamate transporter has been shown to exert neuroprotection in various models of ischemic injury and motoneuron degeneration. Therefore, an attempt was made to explore its neuroprotective potential in cerebral ischemia/reperfusion injury using ceftriaxone, a GLT-1 modulator. Pre-treatment with ceftriaxone (100mg/kg. i.v) for five days resulted in a significant reduction (P<0.01) in neurological deficit as well as cerebral infarct volume after 1h of ischemia followed by 24h of reperfusion injury. It also caused a significant (P<0.05) upregulation of GLT-1 mRNA, protein and glutamine synthetase (GS) activity. Furthermore, inhibition of ceftriaxone-mediated increased glutamine synthetase activity by dihydrokainate (DHK), a GLT-1 specific inhibitor, confirms the specific effect of ceftriaxone on GLT-1 activity. In addition, ceftriaxone also induced a significant (P<0.01) increase in [(3)H]-glutamate uptake, mediated by GLT-1 in glial enriched preparation, as evidenced by use of DHK and DL-threo-beta-benzyloxyaspartate (DL-TBOA). Thus, the present study provides overwhelming evidence that modulation of GLT-1 protein expression and activity confers neuroprotection in cerebral ischemia/reperfusion injury.
authors.affiliation: Division of Pharmacology, Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, India.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Verma
authors.forename: Vikas
authors.initials: V
authors.lastname: Mishra
authors.forename: Dinakar
authors.initials: D
authors.lastname: Sasmal
authors.forename: Ram
authors.initials: R
authors.lastname: Raghubir
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002443:Ceftriaxone / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D002544:Cerebral Infarction / Q000150:complications / Q000473:pathology; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis; D018698:Glutamic Acid / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009457:Neuroglia / Q000378:metabolism; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D018696:Neuroprotective Agents; D018698:Glutamic Acid; C020889:dihydrokainic acid; D002443:Ceftriaxone; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid