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Manuscript ID : JAPAD-2302-1218 (R2) Visit : 186 Page: 19 - 30

Article Type: Original Research

Central Effects of Phoenixin and Muscimol on Pentylenetetrazol-Induced Seizures during Various Stages of the Estrous Cycle among Rats

Subject Areas :

Aliakbar Azadi 1 , Morteza Zendehdel 2 , Jahangir Kaboutari 3 , Negar Panahi 4 , Ahmad Asghari 5

1 - Department of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran.
2 - Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
3 - Department of Basic Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.
4 - Department of Clinical Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran.
5 - Department of Clinical Sciences, Faculty of Specialized Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

Received: 2023-02-16 Accepted : 2023-03-05 Published : 2023-07-23

Keywords: Rat, Pentylenetetrazole, estrus cycle, Phoenixin, Muscimol,

Abstract :

Background & Aim: Catamenial epilepsy is a special form of epilepsy in women whom seizure aggravation is arranged with menstrual cycle that may affect up to 70 % of epileptic women. According to earlier studies, the role of neuropeptide Phoenixin (PNX) in the reproductive system has been observed and its antiepileptic effects have been proven. It also appears that the GABAergic system plays an important role in inhibition of seizures. Therefore, the aim of this study was to investigate the central effects of PNX and muscimol (GABA-A receptor agonist) on Pentylenetetrazol (PNT)-induced seizures during various stages of the estrous cycle among rats.Materials and Methods: In this study, 120 adult female rats were randomly divided into five groups, including intracerebroventricular (ICV) injection of normal saline, PNX (5 μg), PNX (10 μg), muscimol (0.1 μg)+ PNX (5 μg) and muscimol (0.1 μg)+ PNX (10 μg), in proestrus, estrus, metestrus, and diestrus. After ICV injections, acute epilepsy was induced by intraperitoneal (IP) injection of 80 mg/kg of pentylentetrazole. Initiation time of myoclonic seizures (ITMS) and initiation time of tonic–clonic seizures (ITTS) were monitored and recorded for 30 min.Results: The results of the present study showed that PNX alone increased both ITMS and ITTS in all phases of estrus (p<0.05). Furthermore, the injection of PNX with muscimol significantly reinforced the effects of the PNX on ITMS and ITTS in all estrus stages (p<0.05).Conclusion: The results showed that the antiepileptic activity of PNX was probably mediated by GABA-A receptors.

References:


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    28.
  28. Zendehdel M, Kaboutari J, Salimi S, Hassanpour S. The Antiepileptic Effect of Carbamazepine during Estrous Cycle in Pentylenetetrazol-Induced Seizures in Rat. International Journal of Peptide Research and Therapeutics. 2015; 21: 133-138.
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  30. Azadi A, Zendehdel M, Kaboutari J, Panahi N, Asghari A. Central Phoenixin Protective Role on Pentylenetetrazol-Induced Seizures during Various Stages of the Estrous Cycle among Rats. Archives of Razi Institute. 2022; 77(2): 689–695.
    31.
  31. Gonsalves SF, Twitchell B, Harbaugh RE, Krogsgaard-Larsen P, Schousboe A. Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models. Epilepsy research. 1989; 4(1): 34–41.
    32.
  32. Reddy DS. Neuroendocrine aspects of CE. Epilepsy Behav. 2013; 63: 254–266.
    33.
  33. Morrell MJ. Epilepsy in women: the science of why it is special. Neurology1999; 53: 42–48.
    34.
  34. Nicoletti F, Speciale C, Sortino MA, Summa G, Caruso G, Patti F, Canonico PL. Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats. Epilepsia. 1985; 26(3): 252–257.
    35.
  35. Wong M, Moss R. Long-te l seizure activity in adult female rats. Soc Neurosci Abstr. 1998; 24(1): 472–474.
    36.
  36. Cramer JA, Gordon J, Schachter S, Devinsky O. Women with epilepsy: hormonal issues from menarche through menopause. Epilepsy & behavior. 2007; 11(2): 160–178.
    37.
  37. Backstorm T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand. 1976; 54:149–159.
    38.
  38. Khoshnood-Mansoorkhani MJ, Moein MR, Oveisi N. Anticonvulsant activity of Teucrium polium against seizure induced by PTZ and MES in mice. Iran J Pharm Res. 2010; 9(4): 395–401.
    39.
  39. Herzog AG. Hormonal therapies: progesterone. Neurotherapeutics. 2009; 6: 383–391.
    40.
  40. Reddy DS, Rogawski MA. Neurosteroid replacement therapy for CE. Neurotherapeutics. 2009; 6: 392–401.
    41.
  41. Lambert JJ, Cooper MA, Simmons RD, Weir CJ Belelli D. Neurosteroids: endogenous allosteric modulators of GABAAreceptors. Psychoneuroendocrinol. 2009; 34(1): 48–58.
    42.
  42. Lan NC, Chen JS, Belelli D, Pritchett D, Seeburg PH, Gee KW. A steroid recognition site is functionally coupled to an expressed GABAA-benzodiazepine receptor. Eur J Pharmacol Mol Pharmacol Sect. 1990; 188: 403–406.
    43.
  43. Samokhina E, Samokhin A. Neuropathological profile of the pentylenetetrazol (PTZ) kindling model. Int J Neurosci. 2018; 128(11):1086-96.
    44.
  44. Rajeswari JJ, Unniappan S. Phoenixin-20 Stimulates mRNAs Encoding Hypothalamo-Pituitary-Gonadal Hormones, is Pro-Vitellogenic, and Promotes Oocyte Maturation in Zebrafish. Sci Rep. 2020;10(1): 62-64.
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_||_

  1. Luef G, and Rauchenzauner M. Epilepsy and hormones: a critical review. Epilepsy & behavior.2009; 15(1): 73–77.
    2.
  2. Doherty MJ, Rostad SW, Kraemer DL, Vossler DG, Haltiner AM. Neocortical gliosis in temporal lobe epilepsy: gender-based differences. Epilepsia. 2007; 48(8):1455–1459.
    3.
  3. Kaboutari J, Zendehdel M, Habibian S, Azimi M, Shaker M, Karimi B. The antiepileptic effect of sodium valproate during different phases of the estrous cycle in PTZ-induced seizures in rats. Journal of physiology and biochemistry. 2012; 68(2):155–161.
    4.
  4. Frank S, Tyson NA. A Clinical Approach to Catamenial Epilepsy: A Review. The Permanente journal. 2020; 24: 1–3.
    5.
  5. Morris GL, Vanderkolk C. Human sexuality, sex hormones, and epilepsy. Epilepsy & behavior. 2005; 7: S22–S28.
    6.
  6. Harden CL. Sexuality in men and women with epilepsy. CNS spectrums. 2006; 11: 13–18.
    7.
  7. Frye CA. Role of androgens in epilepsy. Expert review of neurotherapeutics. 2006; 6(7): 1061–1075.
    8.
  8. Reddy DS. Role of neurosteroids in catamenial epilepsy. Epilepsy research. 2004; 62(2-3): 99–118.
    9.
  9. Edwards HE, Burnham WM, Mendonca A, Bowlby DA, MacLusky NJ. Steroid hormones affect limbic afterdischarge thresholds and kindling rates in adult female rats. Brain research. 1999; 838(1-2): 136–150.
    10.
  10. Reddy DS, Castaneda DC, O'Malley BW, Rogawski MA. Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. The Journal of pharmacology and experimental therapeutics. 2004; 310(1): 230–239.
    11.
  11. Sherwin BB. Progestogens used in menopause. Side effects, mood and quality of life. The Journal of reproductive medicine. 1999; 44(2): 227–232.
    12.
  12. Borowicz KK, Czuczwar SJ. Aminoglutethimide but not spironolactone enhances the anticonvulsant effect of some antiepileptics against amygdala-kindled seizures in rats. Journal of neural transmission. 2005; 112(7): 891–903.
    13.
  13. Guille C, Spencer S, Cavus I, Epperson CN. The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment. Epilepsy & behavior. 2008; 13(1): 12–24.
    14.
  14. Freeman ME. The neuroendocrine control of the ovarian cycle of the rat. In: Konbil E, Neil J (eds) Physiology of Reproduction, Raven Press, New York. 1975;613–709.
    15.
  15. Rattka M, Brandt C, Bankstahl M, Bröer S, Löscher W. Enhanced susceptibility to the GABA antagonist pentylenetetrazole during the latent period following a pilocarpine-induced status epilepticus in rats. Neuropharmacology. 2011; 60(2-3): 505–512.
    16.
  16. Zendehdel M, Kaboutari J, Ghadimi D, Hassanpour S. The antiepileptic effect of ghrelin during different phases of the estrous cycle in PTZ-induced seizures in rat. Int J Pept Res Ther. 2014; 20: 511–517.
    17.
  17. Krnjevic K. Chemical nature of synaptic transmission in vertebrates, Physiol Rev. 1974; 54: 418-540.
    18.
  18. Wood JD. The role of gamma-aminobutyric acid in the mechanism of seizures. Progress in neurobiology. 1975; 5(1): 77–95.
    19.
  19. Meldrum BS. Epilepsy and gamma-aminobutyric acid-mediated inhibition. International review of neurobiology. 1975; 17: 1–36.
    20.
  20. Haefely W, Polc P, Schaffner R, Keller HH, Pieri L, Mohler H. GABA-Neurotransmitters. Krogsgaard-Larsen et al.(eds), Copenhagen. 1979; 357.
    21.
  21. Yosten GL, Lyu RM, Hsueh AJ, Avsian-Kretchmer O, Chang JK, Tullock CW, Dun SL, Dun N, Samson WK. A novel reproductive peptide, phoenixin. Journal of neuroendocrinology.2013; 25(2): 206–215.
    22.
  22. Billert M, Rak A, Nowak KW, Skrzypski M. Phoenixin: More than Reproductive Peptide. International Journal of Molecular Sciences. 2020; 21(21): 8378.
    23.
  23. Kalamon N, Błaszczyk K, Szlaga A, Billert M, Skrzypski M, Pawlicki P, Górowska-Wójtowicz E, Kotula-Balak M, Błasiak A, Rak A. Levels of the neuropeptide phoenixin-14 and its receptor GRP173 in the hypothalamus, ovary and periovarian adipose tissue in rat model of polycystic ovary syndrome. Biochemical and biophysical research communications. 2020; 528(4): 628–635.
    24.
  24. Pałasz A, Rojczyk E, Bogus K, Worthington JJ, Wiaderkiewicz R. The novel neuropeptide phoenixin is highly co-expressed with nesfatin-1 in the rat hypothalamus, an immunohistochemical study. Neuroscience letters. 2015; 592: 17–21.
    25.
  25. Schalla MA, Stengel A. Phoenixin-A Pleiotropic Gut-Brain Peptide. International journal of molecular sciences. 2018; 19(6): 1726.
    26.
  26. Stein LM, Tullock CW, Mathews SK, Garcia-Galiano D, Elias CF, Samson WK, Yosten GL. Hypothalamic action of phoenixin to control reproductive hormone secretion in females: importance of the orphan G protein-coupled receptor Gpr173. American journal of physiology. Regulatory, integrative and comparative physiology. 2016; 311(3): R489–R496.
    27.
  27. Amado D, Cavalheiro EA. Hormonal and gestational parameters in female rats submitted to the Pilocarpine model of epilepsy. Epilepsy Res. 1998; 32: 266–274.
    28.
  28. Zendehdel M, Kaboutari J, Salimi S, Hassanpour S. The Antiepileptic Effect of Carbamazepine during Estrous Cycle in Pentylenetetrazol-Induced Seizures in Rat. International Journal of Peptide Research and Therapeutics. 2015; 21: 133-138.
    29.
  29. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 6th Edition, Academic Press, San Diego. 2007.
    30.
  30. Azadi A, Zendehdel M, Kaboutari J, Panahi N, Asghari A. Central Phoenixin Protective Role on Pentylenetetrazol-Induced Seizures during Various Stages of the Estrous Cycle among Rats. Archives of Razi Institute. 2022; 77(2): 689–695.
    31.
  31. Gonsalves SF, Twitchell B, Harbaugh RE, Krogsgaard-Larsen P, Schousboe A. Anticonvulsant activity of intracerebroventricularly administered glial GABA uptake inhibitors and other GABAmimetics in chemical seizure models. Epilepsy research. 1989; 4(1): 34–41.
    32.
  32. Reddy DS. Neuroendocrine aspects of CE. Epilepsy Behav. 2013; 63: 254–266.
    33.
  33. Morrell MJ. Epilepsy in women: the science of why it is special. Neurology1999; 53: 42–48.
    34.
  34. Nicoletti F, Speciale C, Sortino MA, Summa G, Caruso G, Patti F, Canonico PL. Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats. Epilepsia. 1985; 26(3): 252–257.
    35.
  35. Wong M, Moss R. Long-te l seizure activity in adult female rats. Soc Neurosci Abstr. 1998; 24(1): 472–474.
    36.
  36. Cramer JA, Gordon J, Schachter S, Devinsky O. Women with epilepsy: hormonal issues from menarche through menopause. Epilepsy & behavior. 2007; 11(2): 160–178.
    37.
  37. Backstorm T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand. 1976; 54:149–159.
    38.
  38. Khoshnood-Mansoorkhani MJ, Moein MR, Oveisi N. Anticonvulsant activity of Teucrium polium against seizure induced by PTZ and MES in mice. Iran J Pharm Res. 2010; 9(4): 395–401.
    39.
  39. Herzog AG. Hormonal therapies: progesterone. Neurotherapeutics. 2009; 6: 383–391.
    40.
  40. Reddy DS, Rogawski MA. Neurosteroid replacement therapy for CE. Neurotherapeutics. 2009; 6: 392–401.
    41.
  41. Lambert JJ, Cooper MA, Simmons RD, Weir CJ Belelli D. Neurosteroids: endogenous allosteric modulators of GABAAreceptors. Psychoneuroendocrinol. 2009; 34(1): 48–58.
    42.
  42. Lan NC, Chen JS, Belelli D, Pritchett D, Seeburg PH, Gee KW. A steroid recognition site is functionally coupled to an expressed GABAA-benzodiazepine receptor. Eur J Pharmacol Mol Pharmacol Sect. 1990; 188: 403–406.
    43.
  43. Samokhina E, Samokhin A. Neuropathological profile of the pentylenetetrazol (PTZ) kindling model. Int J Neurosci. 2018; 128(11):1086-96.
    44.
  44. Rajeswari JJ, Unniappan S. Phoenixin-20 Stimulates mRNAs Encoding Hypothalamo-Pituitary-Gonadal Hormones, is Pro-Vitellogenic, and Promotes Oocyte Maturation in Zebrafish. Sci Rep. 2020;10(1): 62-64.
    45.

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