Peculiarities of influence of NO-synthase inhibitors on behavioral parameters of rats

Abstract

Aim. A comparative study of the influence of nitric oxide synthase (NO-synthase) inhibitors on the parameters of anxiety, motor activity and pain sensitivity of rats.

Materials and Methods. The work was conducted on male rats of Wistar line. The anxiety level and locomotor activity of rats were studied in the «elevated plus maze» (EPM) test. Pain sensitivity of the animals was tested on the «hotplate» apparatus. In the work, selective inhibitor of inducible isoform of NO-synthase – aminoguanidine – at a dose of 50 mg/kg, and non-selective inhibitor of this enzyme – N-nitro-L-arginine – at a dose of 50 mg/kg, were used. Rats of the control group were introduced the equivalent quantity of normal saline.

NO-synthase inducible inhibitor – aminoguadinine did not produce any influence on the anxiety level, but led to reduction of the horizontal motor activity of rats. Introduction of non-selective NO-synthase inhibitor – N-nitro-L-arginine – was accompanied by reduction of the anxiety and of the locomotor activity of animals in the EPM test. Both investigated NO-synthase inhibitors induced alteration of pain sensitivity of rats in the form of hypoalgesia. Here, the most pronounced nociceptive effect was observed with introduction of non-selective NO-synthase inhibitor.

Conclusion. In the work the evidence of participation of inducible isoform of NO-synthase in realization of the motor activity and pain sensitivity processes in rats is shown. In result of the conducted experiments it was found that introduction of non-selective NO-synthase inhibitor N-nitro-L-arginine was accompanied by evident alterations of anxious behavior, locomotor activity and nociceptive sensitivity of rats. The results obtained confirm the important role of the system of regulation of nitric oxide synthesis in neurochemical mechanisms of behavioral reactions in rats.

Keywords

NO-synthase inhibitors / anxiety / motor activity / analgesic effect / rats

References

[1] Moncada S, Bolaños JP. Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry. 2006;97(6):1676-89. doi:10.1111/j.1471 -4159.2006.03988.x

[2] Moncada S., Bolaños J.P. Nitric oxide, cell bioenergetics and neurodegeneration // Journal of Neurochemistry. 2006. Vol. 97, №6. P. 1676-1689. doi:10.1111/j.1471-4159.2006.03988.x

[3] Garthwaite J. NO as a multimodal transmitter in the brain: discovery and current status. British Journal of Pharmacology. 2019;176(2):197-211. doi:10.1111/ bph. 14532

[4] Garthwaite J. NO as a multimodal transmitter in the brain: discovery and current status // British Journal of Pharmacology. 2019. Vol. 176, №2. P. 197-211. doi:10.1111/bph.14532

[5] Philippu A. Nitric oxide: a universal modulator of brain function. Current Medicinal Chemistry. 2016;23(24): 2643-52. doi:10.2174/0929867323666160627120408

[6] Philippu A. Nitric oxide: a universal modulator of brain function // Current Medicinal Chemistry. 2016. Vol. 23, №24. P. 2643-2652. doi:10.2174/092986 7323666160627120408

[7] Kikuchi R, Ambe K, Kon H, et al. Nitric oxide synthase (NOS) isoform expression after peripheral nerve transec-tion in mice. The Bulletin of Tokyo Dental College. 2018;59(1):15-25. doi:10.2209/tdc publication.2017-0007

[8] Kikuchi R., Ambe K., Kon H., et al. Nitric oxide synthase (NOS) isoform expression after peripheral nerve tran-section in mice // The Bulletin of Tokyo Dental College. 2018. Vol. 59, №1. P. 15-25. doi:10.2209/tdcpublication.2017-0007

[9] Fadyukova O.E., Kuzenkov V.S., Koshelev V.B., et al. Semax prevents from the excess nitric oxide production caused by incomplete global ischemia in rat brain. Eksperimental’naya i Klinicheskaya Far-makologiya. 2001;64(2):31-4. (In Russ).

[10] Fadyukova O.E., Kuzenkov V.S., Koshelev V.B., et al. Semax prevents from the excess nitric oxide production caused by incomplete global ischemia in rat brain // Экспериментальная и клиническая фармакология. 2001. Т. 64, №2. С. 31-34.

[11] Sharma Sh, Puttachary S, Thippeswamy T. Glial source of nitric oxide in epileptogenesis: a target for disease modification in epilepsy. Journal of Neuroscience Research. 2019;97(11):1363-77. doi:10. 1002/jnr.24205

[12] Sharma Sh., Puttachary S., Thippeswamy T. Glial source of nitric oxide in epileptogenesis: а target for disease modification in epilepsy // Journal of Neuroscience Research. 2019. Vol. 97, №11. P. 1363-1377. doi:10.1002/jnr.24205

[13] Tripathy D, Chakraborty J, Mohanakumar KP. Antagonistic pleiotropic effects of nitric oxide in the pathophysi-ology of Parkinson's disease. Free Radical Research. 2015;49(9):1129-39. doi:10.3109/10 715762.2015.1045505

[14] Tripathy D., Chakraborty J., Mohanakumar K.P. Antagonistic pleiotropic effects of nitric oxide in the patho-physiology of Parkinson's disease // Free Radical Research. 2015. Vol. 49, №9. P. 1129-1139. doi:10.3109/10715762.2015.1045505

[15] Gilhotra N, Jain H, Dhingra D. Differential effects of nitric oxide synthase inhibitors on anxiety in unstressed and stressed mice. Indian Journal of Experimental Biology. 2010;48(4):365-72.

[16] Gilhotra N., Jain H., Dhingra D. Differential effects of nitric oxide synthase inhibitors on anxiety in unstressed and stressed mice // Indian Journal of Experimental Biology. 2010. Vol. 48, №4. P. 365-372.

[17] Gulati K, Rai N, Ray A. Nitric oxide and anxiety. Vitamins and Hormones. 2017;103:169-92. doi:10. 1016/bs.vh.2016.09.001

[18] Gulati K., Rai N., Ray A. Nitric Oxide and Anxiety // Vitamins and Hormones. 2017. Vol. 103. P. 169-192. doi:10.1016/bs.vh.2016.09.001

[19] Kumar A, Chanana P. Role of nitric oxide in stress-induced anxiety: from pathophysiology to therapeutic target. Vitamins and Hormones. 2017;103:147-67. doi:10.1016/bs.vh.2016.09.004

[20] Kumar A., Chanana P. Role of nitric oxide in stress-induced anxiety: from pathophysiology to therapeutic target // Vitamins and Hormones. 2017. Vol. 103. P. 147-167. doi:10.1016/bs.vh.2016.09.004

[21] Miclescu A, Gordh T. Nitric oxide and pain: 'So-mething old, something new'. Acta Anaesthesiolo-gica Scandi-navica. 2009;53(9):1107-20. doi:10.1111/ j.1399-76.2009.02054.x

[22] Miclescu A., Gordh T. Nitric oxide and pain: 'Something old, something new' // Acta Anaesthe-siologica Scandi-navica. 2009. Vol. 53, №9. P. 1107-1120. doi:10.1111/j.1399-6576.2009.02054.x

[23] Pradhan AA, Bertels Z, Akerman S. Targeted Nitric Oxide Synthase Inhibitors for Migraine. Neuro-therapeutics. 2018;15:391-401. doi:10.1007/s13311 -018-0614-7

[24] Pradhan A.A., Bertels Z., Akerman S. Targeted Nitric Oxide Synthase Inhibitors for Migraine // Neurotherapeu-tics. 2018. Vol. 15. P. 391-401. doi:10.1007/s13311-018-0614-7

[25] Camargo EA, Santana DG., Silva CI, et al. Inhibition of inducible nitric oxide synthase-derived nitric oxide as a therapeutical target for acute pancreatitis induced by secretory phospholipase A2. European Journal of Pain. 2014;18(5):691-700. doi:10.1002/ j.1532-2149.2013.00414.x

[26] Camargo E.A., Santana D.G., Silva C.I., et al. Inhibition of inducible nitric oxide synthase-derived nitric oxide as a therapeutical target for acute pancreatitis induced by secretory phospholipase A2 // European Journal of Pain. 2014. Vol. 18, №5. P. 691-700. doi:10.1002/j.1532-2149.2013.00414.x

[27] Bashkatova V, Philippu A. Role of nitric oxide in psychostimulant-induced neurotoxicity. AIMS Neuroscience. 2019;6(3):191-3. doi:10.3934/Neuroscience. 2019.3.191

[28] Bashkatova V., Philippu A. Role of nitric oxide in psychostimulant-induced neurotoxicity // AIMS Neuro-science. 2019. Vol. 6, №3. P. 191-203. doi:10.3934/ Neuroscience.2019.3.191

[29] Pellow S, Chopin P, File E, et al. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods. 1985;14(3):149-67. doi:10.1016/ 0165-0270(85)90031-7

[30] Pellow S., Chopin P., File E., et al. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat // Journal of Neuroscience Methods. 1985. Vol. 14, №3. P. 149-167. doi:10.1016/0165-0270(85)90031-7

[31] Bondarenko DA, Dyachenko IA, Skobtsov DI, et al. In vivo models of studying of analgetic activity. Biomedi-cine. 2011;(2):84-94. (In Russ).

[32] Бондаренко Д.А., Дьяченко И.А., Скобцов Д.И., и др. In vivo модели для изучения анальгетической актив-ности // Биомедицина. 2011. №2. С. 84-94.

[33] Celik T, Zagli U, Kayir H, et al. Nitric oxide synthase inhibition blocks amphetamine-induced locomotor activity in mice. Drug and Alcohol Dependence. 1999; 56(2):109-13. doi:10.1016/s0376-8716 (99)00031-9

[34] Celik T., Zagli U., Kayir H., et al. Nitric oxide synthase inhibition blocks amphetamine-induced loco-motor activ-ity in mice // Drug and Alcohol Dependence. 1999. Vol. 56, №2. P. 109-113. doi:10. 1016/s0376-8716(99)00031-9

[35] Joung HY, Jung EY, Kim K, et al. The differential role of NOS inhibitors on stress-induced anxiety and neuroen-docrine alterations in the rat. Beha-vioural Brain Research. 2012;235(2):176-81. doi:10. 1016/j.bbr.2012.07.037

[36] Joung H.Y., Jung E.Y., Kim K., et al. The differential role of NOS inhibitors on stress-induced anxiety and neuro-endocrine alterations in the rat // Beha-vioural Brain Research. 2012. Vol. 235, №2. P. 176-181. doi:10.1016/j.bbr.2012.07.037

[37] Cinelli MA, Do HT, Miley GP, et al. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Medic-inal Research Reviews. 2020;40(1): 158-89. doi:10.1002/med.21599

[38] Cinelli M.A., Do H.T., Miley G.P., et al. Inducible nitric oxide synthase: regulation, structure, and inhibition // Medicinal Research Reviews. 2020. Vol. 40, №1. P. 158-189. doi:10.1002/med.21599

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