Role of nitric oxide synthase on brain GABA transaminase activity and GABA levels

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In an attempt to clarify the controversial role of nitric oxide (NO) in seizures, the effects of NO on brain GABA transaminase (GABA-T) activity and GABA levels were investigated. To this aim, the effects of the substrate (l-arginine) and inhibitors (Nω-nitro-l-arginine methyl ester, 7-nitroindazole) of NO synthase (NOS) on GABA-T activity and GABA levels in vitro and ex vivo were analyzed. In vitro NO diminished GABA-T activity and increased GABA. Ex vivo NO modified GABA-T activity and GABA levels biphasically. Inhibition of endothelial and neuronal NOS (eNOS and nNOS) had opposite effects on GABA-T activity and GABA levels, even during seizures induced by pentylenetetrazole. Different effects of NO on GABA-T activity and on GABA levels, depending on the NOS isoform involved, may explain its contradictory role in seizures, the endothelial NOS acting as an anticonvulsant and the neuronal NOS as a proconvulsant. nNOS inhibitors may represent a new generation of antiepileptics.

1. M. Hoffman, A new role for gases: neurotransmission, Science 28 (1991) 1788–1788;

2. S. Moncada, R. M. Palmer and E. A. Higgs, Nitric oxide: physiology, pathophysiology, and pharmacology, Pharmacol. Rev. 43 (1991) 109–142.

3. K. S. Raevskii, V. G. Bashkatova and A. F. Vanin, The role of nitric oxide in brain glutaminergic pathology, Vestn. Ross. Akad. Med. Nauk 1 (2000) 11–15.

4. M. Banach, B. Piskorska, S. J. Czuczwar and K. K. Borowicz, Nitric oxide, epileptic seizures, and action of antiepileptic drugs, CNS Neurol. Disord. Drug Targets 10 (2011) 808–819;

5. J. Garthwaite and C. L.Boulton, Nitric oxide signaling in the central nervous system, Annu. Rev. Physiol. 57 (1995) 683–706;

6. A. Kumar, S. Lalitha and J. Mishra, Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice, Epilepsy Behav. 29 (2013) 103–111;

7. K. Kuriyama and S. Ohkuma, Role of nitric oxide in central synaptic transmission: effects on neurotransmitter release, Jpn. J. Pharmacol. 69 (1995) 1–8;

8. M. J. Owens and C. B. Nemeroff, Pharmacology of valproate, Psychopharmacol. Bull. 37 (2003) 17–24.

9. Q. P. Wang, F. Jammoul, A. Duboc, J. Gong, M. Simonutti, E. Dubus, C. M. Craft, W. Ye, J. A. Sahel and S. Picaut, Treatment of epilepsy: the GABA-transaminase inhibitor, vigabatrin, induces neuronal plasticity in the mouse retina, Eur. J. Neurosci. 27 (2008) 2177–2187;

10. M. Qume and L. J. Fowler, Effect of chronic treatment with the GABA transaminase inhibitors g-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus, Br. J. Pharmacol. 122 (1997) 539–545;

11. N. Rahimi, M. Sadeghzadeh, M. Javadi-Paydar, M. R. Heidary, F. Jazaeri and A. R. Dehpour, Effects of D-penicillamine on pentylenetetrazole-induced seizures in mice: involvement of nitric oxide/NMDA pathways, Epilepsy Behav. 39 (2014) 42–47;

12. Q. Wang, E. Mergia, D. Koesling and T. Mittmann, Nitric oxide/cGMP signaling via guanylyl cyclase isoform 1 modulates glutamate and GABA release in somatosensory cortex of mice, Neuroscience 30 (2017) 180–189;

13. J. P. Pin, B. J. Van-Vliet and J. Bockaert, NMDA-and kainate-evoked GABA release from striatal neurons differentiated in primary culture: differential blocking by phencyclidine, Neurosci. Lett. 87 (1988) 87–92;

14. J. G. Valtschanoff, R. J. Weinberg, V. N. Kharazia, H. H. Schmidt, M. Nakane and A. Rustioni, Neurons in rat cerebral cortex that synthesize nitric oxide: NADPH diaphorase histochemistry, NOS immunocytochemistry, and colocalization with GABA, Neurosci. Lett. 157 (1993) 157–161.

15. G. Lonart, J. Wang and K. M. Johnson, Nitric oxide induces neurotransmitter release from hippocampal slices, Eur. J. Pharmacol. 220 (1992) 271–272;

16. G. Segovia and F. Mora, Role of nitric oxide in modulating the release of dopamine, glutamate, and GABA in striatum of the freely moving rat, Brain Res. Bull. 45 (1998) 275–279;

17. A. R. Jayakumar, R. Sujatha, V. Paul, C. Asokan, S. Govindasamy and R. Jayakumar, Role of nitric oxide on GABA, glutamic acid, activities of GABA-T and GAD in rat brain cerebral cortex, Brain Res. 837 (1999) 229–235;

18. V. Paul and P. Ekambaram, Effects of sodium nitroprusside, a nitric oxide donor, on gamma-aminobutyric acid concentration in the brain and on picrotoxin-induced convulsions in combination with phenobarbitone in rats, Pharmacol. Biochem. Behav. 80 (2005) 363–370.

19. J. Rodrigo, D. R. Springall, O. Uttenthal, M. L. Bentura, F. Abadia-Molina, V. Riveros-Moreno, R. Martinez-Moreno, J. M. Polak and S. Moncada, Localization of nitric oxide synthase in the adult rat brain, Philos. Trans. Royal Soc. London B, Biol. Sci. 345 (1994) 175–221;

20. S. Gotti, M. Sica, C. Viglietti-Panzica and G. Panzica, Distribution of nitric oxide synthase immunoreactivity in the mouse brain, Microsc. Res. Tech. 68 (2005) 13–35.

21. P. K. Moore, P. Wallace, Z. Gaffen, S. L. Hart and R. C. Babbedge, Characterization of the novel nitric oxide synthase inhibitor 7-nitro indazole and related indazoles: antinociceptive and cardiovascular effects, Br. J. Pharmacol. 110 (1993) 219–224;

22. M. J. Jung, B. Lippert, B. W. Metcalf, P. J. Schechter, P. Bohlen and A. Sjoerdsma, The effect of 4-amino hex-5-ynoic acid (gamma-acetylenic GABA, gamma-ethynyl GABA) a catalytic inhibitor of GABA transaminase, on brain GABA metabolism in vivo, J. Neurochem. 28 (1977) 717–723;

23. V. Paul and A. R. Jayakumar, A role of nitric oxide as an inhibitor of gamma-aminobutyric acid transaminase in rat brain, Brain Res. Bull. 51 (2000) 43–46.

24. J. Orzelska, S. Talarek S, J. Listos and S. Fidecka, Divergent effects of l-arginine-NO pathway modulators on diazepam and flunitrazepam responses in NOR task performance, Behav. Brain Res. 284 (2015) 179–186;

25. S. J. Getting, J. Segieth, S. Ahmad, C. S. Biggs and P. S. Whitton, Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo, Brain Res. 717 (1996) 196–199;

26. J. J. Luszczki, A. Sacharuk, A. Wojciechowska, M. M. Andres-Mach, M. Dudra-Jastrzebska, M. Mohamed, K. M. Sawicka, J. Kozinska and S. J. Czuczwar, 7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model, Pharmacol. Rep. 58 (2006) 660–671.

27. N. Y. Lukomskaya, N. I. Rukoyatkina, L. V. Gorbunova, V. E. Gmiro and L. G. Magazanik, Studies of the roles of NMDA and AMPA glutamate receptors in the mechanism of corasole convulsions in mice, Neurosci. Behav. Physiol. 34 (2004) 783–789;

28. G. Mohseni, S. Ostadhadi, R. Akbarian, M. Chamanara, A. Norouzi-Javidan and A. R. Dehpour, Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors, Epilepsy Behav. 65 (2016) 49–55;

29. R. M. Jafari, M. H. Ghahremani, N. Rahimi, A Shadboorestan, A. Rashidian, J. Esmaeili, S. Ejtemaei Mehr and A. R. Dehpour, The anticonvulsant activity and cerebral protection of chronic lithium chloride via NMDA receptor/nitric oxide and phospho-ERK, Brain Res. Bull. 137 (2017) 1–9;

30. S. Danjo, Y. Ishihara, M. Watanabe, Y. Nakamura and K. Itoh, Pentylentetrazole-induced loss of blood-brain barrier integrity involves excess nitric oxide generation by neuronal nitric oxide synthase, Brain Res. 1530 (2013) 44–53;

Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

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