MODULATION OF EPILEPTIC ACTIVITY IN RATS: FOCUS ON SLEEP, PHYSICAL EXERCISE AND NITRIC OXIDE-MEDIATED NEUROTRANSMISSION IN A MODEL OF HOMOCYSTEINE THIOLACTONE SEIZURES
Abstract
Epilepsy is a chronic neurological disorder characterized by recurrent epileptic seizures. Understanding of its mechanisms of initiation and development, as well as modulating factors, are of great scientific interest. Experimental models of epilepsy are useful in understanding these mechanisms.
Homocysteine, an amino acid endogenously generated in the body, together with its reactive metabolite homocysteine thiolactone (HCT), is recognized as a risk factor for variety of diseases. HCT-induced seizures are model of generalized epilepsy in which coexistence of two types of epileptic activity were documented. Complex interplay between sleep and epilepsy is still only poorly understood. Also, relationship between physical exercise and epilepsy is quite intriguing, especially underlying mechanism involved in this relationship. The role of nitric oxide (NO)-mediated neurotransmission in development of the epileptic activity is highly contradictor in the existing scientific literature.
In this review article we addressed modulation of epileptic activity in rats focusing sleep, physical activity and NO-mediated signaling. Firstly, we considered concepts of experimental models of epileptic activity with unique features of HCT seizures. Secondly, modulating effects of sleep and regular physical exercise training on epileptic activity, along with works from the authors, are discussed. Finally, the anticonvulsive effects of NO derived by nNOS and iNOS in HCT seizures are reviewed.
Key words: homocysteine, seizures, sleep, physical activity, nitric oxide
References
Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006; 367: 1087–100.
Badawy RA, Harvey AS, Macdonell RA. Cortical hyperexcitability and epileptogenesis: understanding the mechanisms of epilepsy - part 1. J Clin Neurosci 2009; 16(3): 355-65.
Loscher W. Current status and future directions in the pharmacotherapy of epilepsy. Trends Pharmacol Sci 2002; 23, 113–118.
Stanojlović OP, Zivanović DP. Experimental models of epilepsy. Med Pregl 2004;57 (7-8):359-62.
Hoffer LJ. Homocysteine remethylation and trans-sulfuration. Metabolism 2004; 53: 1480-3.
Djuric D, Jakovljević V, Rašić-Marković A, Đurić A, Stanojlović A. Homocysteine, folic acid and coronary artery disease: possible impact on prognosis and therapy. Indian J Chest Di Allied Sci 2008;50: 39-48.
Jakubowski H. Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci. 2004; 61: 470–87.
Perla-Kajan J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids 2007;32: 561–72.
Herrmann W, Obeid R. Homocysteine: a biomarker in neurodegenerative diseases. Clin Chem Lab Med 2011; 49: 435-41.
Troen AM. The central nervous system in animal models of hyperhomocysteinemia. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29:1140-51.
Stanojlović O, Rašić–Marković A, Hrnčić D, et al. Two types of seizures in homocysteine thiolactone – treated adult rats, behavioral and encephalographic study. Cell Mol Neurobiol 2009; 29: 329-39.
Malow B. Sleep and epilepsy. Neurol Clin 1996; 14 (4): 765-89.
Matos G, Andersen ML, do Valle AC, Tufik S. The relationship between sleep and epilepsy: evidence from clinical trials and animal models. J Neurol Sci. 2010; 295(1-2): 1-7.
Hrnčić D, Rašić-Marković A, Bjekić-Macut J, et al. Gaseous neurotansmitter nitric oxide: its role in experimental models of epilepsy. Arch Biol Sci 2012; 64(3): 1207-16.
Sardo P, Carletti F, D'Agostino S, Rizzo V, Ferraro G. Involvement of nitric oxide-soluble guanylyl cyclase pathway in the control of maximal dentate gyrus activation in the rat. J Neural Transm. 2006; 113 (12): 1855-61.
Royes LF, Fighera MR, Furian AF, et al. Involvement of NO in the convulsive behavior and oxidative damage induced by the intrastriatal injection of methylmalonate. Neuroscience Letters 2005; 376: 116-20.
Royes LF, Fighera MR, Furian AF, et al. The role of nitric oxide on the convulsive behavior and oxidative stress induced by methylmalonate: an electroencephalographic and neurochemical study. Epilepsy Res 2007; 73: 228-37.
Stanojlović O, Zivanović D, Mirković S, Mikhaleva I. Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures. Pharmacol Biochem Behav 2004: 77(2) 227-34.
Stanojlović O, Hrnčić D, Živanović D, Šušić V. Anticonvulsant, but not antiepileptic action of valproate on audiogenic seizure in metaphit – treated rats. Clin Exp Pharmacol Physiol 2007; 34: 1010-5.
Hrnčić D, Stanojlović O, Živanović D, Šušić V. Delta sleep – inducing peptide potentiates anticonvulsive activity of valproate against metaphit – provoked audiogenic seizures in rats. Pharmacol. 2006; 77: 78-84.
Hrnčić D, Vučević D, Rašić A, et al. Moderate body hypothermia alleviates behavioral and EEG manifestations of audiogenic seizures in metaphit – treated rats. Canad J Physiol Pharmacol 2007; 85: 1032-37.
Vučević D, Hrnčić D, Radosavljević T, et al. Correlation between electrocorticographic and motor phenomena in lindane-induced experimental epilepsy in rats. Canad J Physiol Pharmacol. 2008; 86: 173-9.
Mladenović D, Hrnčić D, Vučević D, et al. Ethanol suppresed seizures in lindane- treated rats. Electroencephalographic and behavioral studies. J Physiol Pharmacol 2007; 58:641-54.
Hrnčić D, Rašić-Marković A, Sušić V, Djurić D, Stanojlović O. Influence of NR2B-Selective NMDA Antagonist on Lindane-Induced Seizures in Rats. Pharmacol 2009; 84: 234-9.
Rašić-Marković A, Djuric D, Hrnčić D, et al. High dose of ethanol decreases total spectral power density in seizures induced by D,L – homocysteine thiolactone in adult rats. Gen Physiol Bioph 2009; 28: 25-33.
Rašić-Marković A, Hrnčić D, Djurić D, et al. The effect of N-methyl-D-aspartate receptor antagonists on D, L-homocysteine thiolactone induced seizures in adult rats. Acta Physiol Hung 2011; 98 (1): 17-26.
Rasić-Marković A, Stanojlović O, Hrnčić D, et al. The activity of erythrocyte and brain Na+/K+ and Mg2+-ATPases in rats subjected to acute homocysteine and homocysteine thiolactone administration.Mol Cell Biochem 2009; 327: 39-45.
Rašić-Marković A, Hrnčić D, Macut D, Stanojlović O, Djuric D. Anticonvulsive Effect of Folic Acid in Homocysteine Thiolactone-Induced Seizures. Cell Mol Neurobiol. 2011; 31 (8): 1221-28.
Martins RC, Andersen ML, Tufik S. The reciprocal interaction between sleep and type 2 diabetes mellitus: facts and perspectives. Braz J Med Biol Res 2008;41:180-7.
Stanojlović O, Hrnčić D, Rašić-Marković A, Macut Dj, Djurić D, Šušić V. Sleep peptides in experimental models of epilepsy. Glas Srp Akad Nauka Med.2011; (51): 141-9.
Jouvet M. Paradoxical sleep as a programming system. J Sleep Res 1998; 7:1-5.
Matos G, Tufik S, Scorza FA, Cavalheiro EA, Andersen ML. Sleep, epilepsy and translational research: what can we learn from the laboratory bench? Prog Neurobiol 2011; 95 (3): 396-405.
Susic V, Markovic O. Potentiation of metaphite – induced audiogenic seizures by REM sleep deprivation in rats. Physiol Behav 1993; 54: 331-8.
Méndez M, Radtke RA. Interactions between sleep and epilepsy. J Clin Neurophysiol 2001; 18: 106-27.
Crespel A, Baldy-Moulinier M, Coubes P. The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia 1998; 39, 150–7.
Derry CP, Duncan S. Sleep and epilepsy. Epilepsy Behav 2013; 26 (3): 394-404.
Mallick BN, Singh A. REM sleep loss increases brain excitability: role of noradrenaline and its mechanism of action. Sleep Med Rev 2011; 15: 165-78.
Jouvet D, Vilmont P, Delorme F, Jouvet M. Etude de la privation selective de la phase paradoxale de sommeil chez le chat. C R Soc Biol Fil 1964; 158: 756-9.
Tufik S, Andersen ML, Bittencourt LR, Mello MT. Paradoxical sleep deprivation: neurochemical, hormonal and behavioral alterations. Evidence from 30 years of research. An Acad Bras Cienc 2009; 81: 521-38.
Nunes JR GP, Tufik S, Nobrega JN. Decreased muscarinic receptor binding in rat brain after paradoxical sleep deprivation: an autoradiographic study. Brain Res 1994; 645: 247-52.
McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med 2007; 8: 302-30.
Tufik S, Troncone LRP, Braz S. Does REM sleep deprivation induce subsensitivity of presynaptic dopamine or postsynaptic acetylcholine receptors in the rat brain? Eur J Pharmacol 1987; 140: 215-19.
Mohamed SH, Ezz HAS, Khadrawy AY, Noor AN. Neurochemical and electrophysiological changes induced by paradoxical sleep deprivation in rats. Behav Brain Res 2011; 225: 39-46
Hrnčić D, Rašić-Marković A, Macut-Bjekic J, Šušić V, Djuric D, Stanojlović O. Paradoxical sleep deprivation potentiates epilepsy induced by homocysteine thiolactone in rats. Exp Biol Med 2013; 238 (1): 77-83.
Dubow JS, Kelly JP. Epilepsy in sports and recreation. Sports Med 2003; 33: 499–516.
Ablah E, Haug A, Konda K, Tinius AM, Ram S, Sadler T, Liow K. Exercise and epilepsy: a survey of Midwest epilepsy patients. Epilepsy Behav 2009; 14: 162–66.
Elliott JO, Lu B, Moore JL, McAuley JW, Long L. Exercise, diet, health behaviors, and risk factors among persons with epilepsy based on the California Health Interview Survey, 2005. Epilepsy Behav. 2008; 13: 307–15.
Gordon KE, Dooley JM, Brna PM. Epilepsy and activity- A population based study. Epilepsia 2010; 51: 2254-59.
Wong J, Wirrell E. Physical activity in children/teens with epilepsy compared with that in their siblings without epilepsy. Epilepsia 2006; 47: 631-9.
Fountain NB, May AC. Epilepsy and athletics. Clin Sports Med 2003; 22: 605–16.
Kuijer A. Epilepsy and exercise, electroencephalographical and biochemical studies. Advances in Epileptology: The 10th Epilepsy International Symposium. Raven Press, New York 1980; 543.
Ogunyemi AO, Gomez MR, Klass DW. Seizures induced by exercise. Neurology 1988; 38: 633-4.
Ramsden M, Berchtold NC, Patrick Kesslak J, Cotman CW, Pike CJ. Exercise increases the vulnerability of rat hippocampal neurons to kainate lesion. Brain Res 2003; 971: 239-44.
Arida RM, Jesus VA, Cavalheiro EA. Effect of physical exercise on kindling development. Epilepsy 1998; 30: 127–132.
Arida RM, Scorza FA, dos Santos NF, Peres CA, Cavalheiro EA. Effect of physical exercise on seizure occurrence in a model of temporal lobe epilepsy in rats. Epilepsy Res 1999; 37: 45-52.
Souza MA, Oliveira MS, Furian AF, et al. Swimming training prevents pentylenetetrazol-induced inhibition of Na+, K+-ATPase activity, seizures, and oxidative stress. Epilepsia 2009; 50: 811-23.
Arida RM, Sanabria ER, da Silva AC, Faria LC, Scorza FA, Cavalheiro EA. Physical training reverts hippocampal electrophysiological changes in rats submitted to the pilocarpine model of epilepsy. Physiol Behav 2004: 83(1): 165-71.
Eriksen HR, Ellertsen B, Grønningsaeter H, Nakken KO, Løyning Y, Ursin H. Physical exercise in women with intractable epilepsy. Epilepsia 1994; 35: 1256-64.
Nakken KO, Løyning A, Løyning T, Gløersen G, Larsson PG. Does physical exercise influence the occurrence of epileptiform EEG discharges in children? Epilepsia 1997; 38: 279-84.
Contarteze RV, de Alencar Mota CS, et al. Exercise test and glucose homeostasis in rats treated with alloxan during the neonatal period or fed a high calorie diet. J Diabetes 2009; 1:65-72.
Hrncic D, Rasic-Markovic A, Lekovic J, et al. Exercise Decreases Susceptibility to Homocysteine Seizures: the Role of Oxidative Stress. Int J Sports Med. 2013, in press.
Elfering SL, Sarkela TM, Giulivi C. Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem. 2002; 277: 38079–86.
Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994; 298: 249-58.
Zhou L, Zhu D. Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications. Niric Oxide 2009; 20: 223-30.
González-Hernández T, García-Marín V, Pérez-Delgado MM, González-González ML, Rancel-Torres N, González-Feria L. Nitric oxide synthase expression in the cerebral cortex of patients with epilepsy. Epilepsia 2000; 41: 1259-68.
Murashima YL, Yoshii M, Suzuki J . Role of nitric oxide in the epileptogenesis of EL mice. Epilepsia 2000; 41: 195-99.
Pannu R, Singh I. Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochemistry International 2006; 49: 170-82.
Rondouin G, Bockaert J, Lerner-Natoli M. L-Nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats. NeuroReport. 1993; 4: 1187-90.
Rondouin G, Lerner-Natoli M, Manzoni O, Lafon-Cazal M, Bockaert J. A nitric oxide (NO) synthase inhibitor accelerates amygdala kindling. NeuroReport 1992; 3: 805-56.
Paul V, Ekambaram P. Effects of sodium nitroprusside, a nitric oxide donor, on γ-aminobutyric acid concentration in the brain and on picrotoxin-induced convulsions in combination with phenobarbitone in rats. Pharmacol Biochem Behav. 2005; 80: 363-70.
Ayyildiz M, Yildirim M, Agar E. The involvement of nitric oxide in the anticonvulsant effects of alpha-tocopherol on penicillin-induced epileptiform activity in rats. Epilepsy Res 2007; 73: 166-72.
Tutka P, Barczyński B, Arent K, Mosiewicz J, Mróz T, Wielosz M. Different effects of nitric oxide synthase inhibitors on convulsions induced by nicotine in mice. Pharmacol Rep 2007; 59: 259-67.
Urbanska EM, Drelewska E, Borowicz KK, Blaszczak P, Kleinrok Z, Czuczwar SJ. NG-nitro-L-arginine, a nitric oxide synthase inhibitor, and seizure susceptibility in four seizure models in mice. J Neural Transm 1996; 103: 1145-52.
Proctor MR, Fornai F, Afshar JK, Gale K. The role of nitric oxide in focally-evoked limbic seizures. Neurosci 1997; 76: 1231-6.
Lu W, Chen G, Cheng JS. NMDA antagonist displays anticonvulsant effect via NO synthesis inhibition penicillin treated rat hippocampal slices. Neuroreport 1998; 9: 4045-9.
Borowicz KK, Luszczki J, Kleinrok Z, Czuczwar SJ. 7- Nitroindazole, a nitric oxide synthase inhibitor, enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetrazol- induced convulsions. J Neural Transm 2000; 107: 1117-26.
Sardo P, Carletti F, D'Agostino S, Rizzo V, Ferraro G. Involvement of nitric oxide-soluble guanylyl cyclase pathway in the control of maximal dentate gyrus activation in the rat. J Neural Transm 2006; 113 (12): 1855-61.
Hrnčić D, Rašić-Marković A, Krstić D, Macut D, Djuric D, Stanojlović O. The Role of Nitric Oxide in Homocysteine Thiolactone-Induced Seizures in Adult Rats. Cell Mol Neurobiol 2010;30:219-31.
Hrnčić D, Rašić-Marković A, Krstić D, et al. Inhibition of the neuronal nitric oxide synthase potentiates homocysteine thiolactone-induced seizures in adult rats. Med Chem 2012; 8(1): 59-64.
Hrnčić D, Rašić-Marković A, Macut D, Sušic V, Djuric D, Stanojlovic O. Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase. Hum Exp Toxicol 2013, in press, on line first.
Luszczki JJ, Sacharuk A, Wojciechowska A, et al. 7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Pharmacol Rep 2006; 58 (5), 660-71.
Lesani A, Javadi-Paydar M, Khodadad TK, et al. Involvement of the nitric oxide pathway in the anticonvulsant effect of tramadol on pentylenetetrazole-induced seizures in mice. Epilepsy Behav 2010; 19(3), 290-5.
Adabi-Mohazab R, Javadi-Paydar M, Delfan B, Dehpour AR. Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice. Epilepsy Res 2012; 101 (1-2): 28-35.
Bahremand A, Nasrabady SE, Ziai P, et al. Involvement of nitric oxide-cGMP pathway in the anticonvulsant effects of lithium chloride on PTZ-induced seizure in mice. Epilepsy Res 2010; 89(2-3): 295-302.
Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993; 364: 626–32.
Getting SJ, Segieth J, Ahmad S, Biggs CS, Whitton PS. Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo. Brain Res. 1996 22; 717 (1-2): 196-9.
Paul V, Ekambaram P. Effects of sodium nitroprusside, a nitric oxide donor, on γ-aminobutyric acid concentration in the brain and on picrotoxin-induced convulsions in combination with phenobarbitone in rats. Pharmacol Biochem Behav 2005; 80: 363-70.
Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni N. Biochemistry of homocysteine in health and diseases. Ind J Biochem Biophys 2006; 43: 275-83.
Rauhala P, Lin AM, Chiueh CC. Neuroprotection by S nitrosoglutathione of brain dopamine neurons from oxidative stress. FASEB J 1998; 12: 165-73.