RESEARCH PAPER
Evidence for the involvement of the GABA- ergic pathway in the anticonvulsant and antinociception activity of Propoxazepam in mice and rats
 
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Bogatsky Physical-chemical instityte of NAS, Odessa, Ukraine
CORRESPONDING AUTHOR
Vitalii Larionov   

Bogatsky Physical-chemical instityte of NAS of Ukraine, Lyustdorfskaya doroga 86, 65080, Odessa, Ukraine
 
J Pre Clin Clin Res. 2019;13(3):99–105
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Propoxazepam (3-alcoxyderivative of 1.4-benzodiazepine), in the tail-flick test and picrotoxin-induced convulsions showed significant analgesic and antiepileptic activity. Flumazenil (GABA antagonist) reduced its analgesic action, although antiseizure activity was changed slightly. As specific propoxazepam actions are anticonvulsant (1 subtype GABAA-R) and analgesic (2 subtype GABAA-R in the spinal cord), it can be suggested that the substance has no abuse-related side-effects.

Material and methods:
The possible involvement of the GABA system in the antinociceptive effect of propoxazepam was examined by administering flumazenil (1 and 10 mg/kg, i.p.), a selective GABA- receptor antagonist, 30 min prior to propoxazepam (1.8 and 10 mg/kg, orally) in rats. Picrotoxin solution (6.5 mg/kg, 95 % of lethality effect in mice) was injected subcutaneously 30 min after propoxazepam administration. Flumazenil was administered intraperitoneally 0.5 hour prior to propoxazepam administration. Time counting was starting from the convulsant injection and during the supervision time, the number of myoclonic convulsions and tonic extensia, time of their onset, as well as time to lethal effect (survival time), were registered.

Results:
Flumazenil and propoxazepam antiseizure effect in the picrotoxin-induced seizures test were estimated as 5.24±2.38 and 0.37±0.07 mg/kg. Antiseizure effect of propoxazepam was reduced with flumazenil administration. Flumazenil (1 mg/kg) had no effect in tail-flick test but abolished the antinociceptive action of propoxazepam (tail flick latency period changes were -1.6% and +55.1, compared to control and propoxazepam alone administration, respectively).

Conclusions:
The mechanism of propoxazepam antiseizure and antinociceptive actions are GABA-R determined. Analgesic action mechanism assumes additional biotargets involvement.

 
REFERENCES (27)
1.
Löscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res. 1988; 2(3): 145 181.
 
2.
Deshmukh R, Thakur A. S, Dewanga D. Mechanism of action of anticonvulsant drugs: a review. Int. J. Pharm. Sci. Res. 2011; 2(2): 225–236.
 
3.
Zeilhofer HU. The glycinergic control of spinal pain processing. Cell Mol Life Sci., 2005; 62: 2027 2035. https://doi.org/ 10.1007/s00018- 005-5107-3.
 
4.
Knabl J, Zeilhofer UB, Crestani F, Rudolph U, Zeilhofer HU. Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain, 2009; 141(3): 233–238. https://doi.org/10.1016/j.pain....
 
5.
Golovenko NYa, Voloshchuk NI, Andronati SA, Taran IV, Reder АS, Pashynska ОS, Larionov VB. Antinociception induced by a novel benzodiazepine receptor agonist and bradykinin receptor antagonist in rodent acute and chronic pain models. European Journal of Biomedical and Pharmaceutical sciences, 2018; 5(12): 79–88.
 
6.
Larionov VB, Reder AS. Рropoxazepam, a novel analgesic with multifunctional mechanism of action: review of preclinical data. International scientific and practical conference «Prospects for the development of medicine in EU countries and Ukraine», Wloclavek, Republic of Poland, December 21–22, 2018. P.111–115.
 
7.
Desai A, Kherallah Y, Szabo C, Marawar R. Gabapentin or pregabalin induced myoclonus: A case series and literature review. J Clin Neurosci. 2019; 61: 225–234.
 
8.
Golovenko NYa, Larionov VB, Andronati SA, Valivodz` IP, Yurpalova T. A. Рharmacodynamic analysis of propoxazepam interaction with GABA-benzodiazepine-receptor-ionophore complex. Neurophysiology. 2018; 50(1): 2–11.
 
9.
Golovenko1 N. Ya. Larionov V. B, Reder A. S, Valivodz I. P. An effector analysis of the interaction of propoxazepam with antagonists of GABA and glycine receptors. Neurochemical Journal, 2017; 11(4): 302–308.
 
10.
Reder A. S. Dispersed substance 7-bromo-5-(o-chlorophenyl)-3- propiloxy-1,2-dihydro-3H-1,4-nebzodiazepine-2-one (I) with at least 50 % volume fraction of particles less than 30 μm for use as anticonvulsive and analgesic drug. Patent UA 118626.
 
11.
Kawakita K, Funakoshi M. A quantitative study on the tail flick test in the rat. Physiol Behav. 1987; 39(2): 235–40.
 
12.
Hunkeler W, Mohler H, Pieri L, et al. Selective antagonists of benzodiazepines. Nature. 1981; 290: 514–516.
 
13.
Klotz U, Ziegler G, Ludwig L, Reimann I. Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in humans. J Clin Pharmncol.1985; 25: 400–406.
 
14.
O’boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M. RO 15– 1788 antagonizes the effects of diazepam in man without affecting its bioavailability. Br J Anaesth. 1983; 55: 349–356.
 
15.
Kauima M, Lasalle G, Rossler I. The partial benzodiazepine agonist properties of RO 15–1788 in pentylenetetrazol-induced seizures in cats. Eur J PharmncoI1983; 93: 113–115.
 
16.
Nutt OJ, Cowen PJ, Litfle HJ. Unusual interactions of benzodiazepine receptor antagonists. Nature 1982; 295: 436–438.
 
17.
Klotz U, Kanto J. Pharmacokinetics and clinical use of flumazenil (Ro 15–1788). Clin Pharmacokinet. 1988; 14(1): 1–12.
 
18.
Golovenko NYa, Larionov VB, Valivodz` I P. Absorption and distribution of 14C-propoxasepam after its intragastral administration. Physiol Zh. 2017; 63(3): 40–48.
 
19.
Takeuchi K. Prostaglandin E prevents indomethacin-induced gastric and intestinal damage through different EP receptor subtypes. J Physiol. Paris, 2001; 95(1–6): 157–163.
 
20.
Voloshchuk NІ, Тaran ІV, Reder АS, Golovenko MYa. Experimental study of ulcerogenic action of propoxazepam. Reports of Vinnytsia National Medical University. 2018; 22(1): 6–9. doi: 10.31393/reports-vnmedical-2018-22(1)-01.
 
21.
Voloshchuk NI, Reder АS, Golovenko MY, Taran IV, Pashinska ОS. Pharmacological analysis of neurochemical antinociceptive mechanisms of propoxazepam action. Pharmacology and drug toxicology. 2017; 1(52): 3–11.
 
22.
Rudolph U, Möhler H, 2014. GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism. Annual Review of Pharmacology and Toxicology 54, 483–507. http://dx.doi.org/10.1146/annu....
 
23.
Ralvenius WT, Benke D, Acuna MA, Rudolph U, Zeilhofer HU, 2015. Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype. Nat Commun 6, 6803. http://dx.doi.org/10.1038/ncom....
 
24.
Ghafari M, Falsafi S. K, Szodorai E, Kim E. J, Li L, Hoger H, Berger J, Fuchs K, Sieghart W, Lubec G. Formation of GABAA receptor complexes containing alpha1 and alpha5 subunits is paralleling a multiple T-maze learning task in mice. Brain Struct Funct. 2016; 222(1): 549–561 http:// dx.doi.org/10.1007/s00429-016-....
 
25.
Rowlett J. K, Platt DM, Lelas S, Atack JR, Dawson GR. [Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. PNAS 2005; 102(3): 915–920.
 
26.
Ralvenius WT, Acuna MA, Benke D, Matthey A, Daali Y, Rudolph U, Desmeules J, Zeilhofer HU, Besson M. The clobazam metabolite N-desmethyl clobazam is an alpha2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia. Neuropharmacology 2016; 109: 366–375. http://dx.doi.org /10.1016/j. neuropharm. 2016.07.004.
 
27.
Bjoern Moosmann, Volker Auwärter. Designer Benzodiazepines: Another Class of New Psychoactive Substances. Springer International Publishing AG, part of Springer Nature 2018. Handbook of Experimental Pharmacology, https://doi.org/10.1007/164. 2018-154.
 
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