title: Possible involvement of nitrergic and opioidergic systems in the modulatory effect of acute chloroquine treatment on pentylenetetrazol induced convulsions in mice.
abstract: Chloroquine has long been used for the treatment of malaria and rheumatological disorders. Accumulating evidence suggests potential use of chloroquine as a neuroprotective agent. Several studies have reported that endogenous opioids and nitric oxide (NO) system mediate the chloroquine effects. In the present study, the involvements of endogenous opioids and NO in the modulatory effects of chloroquine on pentylenetetrazol-induced seizures were assessed in mice. Chloroquine 5mg/kg significantly increased the seizure threshold, but this effect was reversed with naltrexone 1mg/kg. Acute co-administration of l-NAME (non-selective NO synthase (NOS) inhibitor, 5mg/kg) or 7-NI (selective neuronal NOS inhibitor, 40 mg/kg) with the effective dose of chloroquine completely inhibited its anticonvulsant effects. Acute single injection of a sub-effective dose of l-arginine (NO precursor, 60 mg/kg) with a sub-effective dose of chloroquine 2.5mg/kg increased the seizure threshold but administration of L-arginine 60 mg/kg with chloroquine 10mg/kg decreased the seizure threshold. Moreover, the combination of the lower doses of naltrexone (0.1mg/kg) and 7-NI (15 mg/kg) showed additive effects in blocking the chloroquine-induced anticonvulsant properties. Chloroquine 5mg/kg enhanced the hippocampal nitrite levels. Chloroquine at the dose of 20mg/kg decreased the seizure threshold. This effect was inhibited through L-NAME (5mg/kg), 7-NI (40 mg/kg) and naltrexone (1mg/kg) administration with this dose of chloroquine. In conclusion, NO signaling probably through neuronal NOS, but not inducible NOS could be involved in the opioid-dependent anticonvulsant effects of chloroquine in this model of seizures in mice. It seems that nitric oxide and opioid systems are involved in modulatory effect of chloroquine on seizures induced by pentylenetetrazol.
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; Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Kerman, Iran.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Hassanipour
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.
authors.forename: Armin
authors.initials: A
authors.lastname: Shirzadian
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.
authors.forename: Mahdi Mashhadi-Akbar
authors.initials: MM
authors.lastname: Boojar
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.
authors.forename: Aminreza
authors.initials: A
authors.lastname: Abkhoo
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.
authors.forename: Alireza
authors.initials: A
authors.lastname: Abkhoo
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.
authors.forename: Sina
authors.initials: S
authors.lastname: Delazar
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.
authors.forename: Shayan
authors.initials: S
authors.lastname: Amiri
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.
authors.forename: Nastaran
authors.initials: N
authors.lastname: Rahimi
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; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Sattar
authors.initials: S
authors.lastname: Ostadhadi
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; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: Dehpour@sina.tums.ac.ir.
authors.forename: Ahmad-Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001120:Arginine / Q000494:pharmacology; D002738:Chloroquine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D006146:Guanidines; D007191:Indazoles; D009573:Nitrites; D009569:Nitric Oxide; D009271:Naltrexone; D002738:Chloroquine; D001120:Arginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester; D010433:Pentylenetetrazole
keywords: Chloroquine; Clonic seizure threshold; Mice; Nitric oxide; Opioid; Pentylenetetrazole