title: Hypoxia/ischemia a key player in early post stroke seizures: modulation by opioidergic and nitrergic systems.
abstract: Stroke is a leading cause of death, disability, and socioeconomic loss worldwide. All attempts at pharmacological reduction of the complications of stroke (e.g. post-stroke seizure, and brain׳s vulnerability to hypoxic/ischemic injury) have failed. Endogenous opioids and nitric oxide (NO) overproduction has been documented in brain hypoxia/ischemia (H/I), which can exert pro-convulsive effects. In this study, we aimed to examine the possible involvement of opioidergic and nitrergic pathways in the pathogenesis of post-stroke seizure. H/I was induced by right common carotid ligation and sham-operated mice served as controls. We demonstrated that right common carotid ligation decreases the threshold for clonic seizures induced by pentylenetetrazole (PTZ), a GABA antagonist. Furthermore, pro-convulsive effect of H/I following right common carotid ligation was blocked by naltrexone (NTX) (3mg/kg), NG-Nitro-l-arginine methyl ester (l-NAME) (10mg/kg), and aminoguanidine (AG) (100mg/kg) administration (P<0.001). Interestingly, co-administration of non-effective doses of NTX and l-NAME (1 and 0.5mg/kg, respectively) reverses epileptogenesis of H/I (P<0.001). In the same way, co-administration of non-effective doses of NTX and AG (1 and 5mg/kg, respectively), reverses epileptogenesis of H/I (P<0.001). Indeed, the histological studies performed on mice exposed to H/I confirmed our previous data. These findings suggest hyper-susceptibility to PTZ induced seizure following H/I is mediated by interaction of opioidergic, and iNOS/NO pathways. Therefore, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Students׳ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Maziar
authors.initials: M
authors.lastname: Gooshe
authors.affiliation: Pharmacology and Applied Medicine, Department of Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran; International Campus, ICTUMS, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Amir Hossein
authors.initials: AH
authors.lastname: Abdolghaffari
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Students׳ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali Reza
authors.initials: AR
authors.lastname: Aleyasin
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Chabouk
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sina
authors.initials: S
authors.lastname: Tofigh
authors.affiliation: Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Gholam Reza
authors.initials: GR
authors.lastname: Hassanzadeh
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Borna
authors.initials: B
authors.lastname: Payandemehr
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Partoazar
authors.affiliation: Department of Physiology, School of Medicine, Tehran University of Medical Science, Tehran, Iran.
authors.forename: Yaser
authors.initials: Y
authors.lastname: Azizi
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000150:complications*; D015687:Cell Hypoxia / Q000187:drug effects; D004357:Drug Synergism; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000150:complications* / Q000378:metabolism*; D020521:Stroke / Q000150:complications*
chemical_list: D000701:Analgesics, Opioid; D018756:GABA Antagonists; D009569:Nitric Oxide; D009271:Naltrexone; D019331:NG-Nitroarginine Methyl Ester; D010433:Pentylenetetrazole
keywords: Hypoxia/ischemia; Nitrergic system; Opioidergic system; Post stroke seizure