Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice |
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| Affiliation: | 1. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;2. Students'' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran;3. Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran;4. Institut universitaire en santé mentale de Québec, Québec City, Québec, Canada;5. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;6. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran;1. Department of Neurology, University Hospital, Zagreb, Croatia;2. Departamento de Psiquiatría, Universidad Maimónides, Buenos Aires, Argentina;3. Department of Anatomy and Neurobiology, Washington University, St. Louis, MO, USA;4. Department of Neurology, Washington University, St. Louis, MO, USA;5. Department of Psychiatry, Washington University, St. Louis, MO, USA;6. Department of Radiology, Washington University, St. Louis, MO, USA;7. Department of Neurology, Penn State University, Hershey, PA, USA;1. Health Economics and Outcomes Research, AbbVie, North Chicago, IL, USA;2. Department of Pharmacy, Clinical and Administrative Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;3. Department of Pharmacy, Clinical and Administrative Sciences, The University of Oklahoma Health Sciences Center, Tulsa, OK, USA;4. Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;5. Department of Neurology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA |
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| Abstract: | Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders.Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine–nitric oxide pathway or not.Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P < 0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine–nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature. |
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