A role for GABA agonist in controlling the reproduction of female rats via hypothalamic ghrelin, kisspeptin, and RFRP-3 gene expression

Iranian Journal of Veterinary Science and Technology

مقاله 5، دوره 13، شماره 1 - شماره پیاپی 24، شهریور 2021، صفحه 42-47   

نوع مقاله: Research Article

شناسه دیجیتال (DOI): 10.22067/ijvst.2021.64272.0

نویسندگان

Elaheh Rahimi Rick¹؛ Fariba Mahmoudi^{* 1}؛ Homayoun khazali²؛ Asadollah Asadi¹؛ Mahnaz Ghowsi³

¹Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran.

²Department of Animal Science and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.

³Department of Biology, Faculty of sciences, Razi University, Kermanshah. Iran.

چکیده

   Kisspeptin stimulates gonadotropin releasing hormone (GnRH). The GnRH neurons receive inhibitory inputs from ghrelin, RFamide related peptide-3 (RFRP-3), and gamma-aminobutyric acid (GABA) neurons. Polycystic ovary syndrome (PCOS) is associated with increased levels of GnRH/LH and kisspeptin, and decreased release of GABA, ghrelin,  and RFRP-3. In the present study, the effects of GABAB receptor agonist, baclofen, were investigated on GnRH, KiSS1, RFRP-3, and ghrelin gene expression in the hypothalamus of PCOS model rats. For induction of PCOS, female Wistar rats weighing 180-200g received intra-muscular injection of estradiol valerate. Fifteen PCOS rats in three groups received intraperitoneal injections of saline, 5, or 10 mg/kg baclofen for two weeks. The hypothalamic samples were dissected. Gene expression levels of GnRH, KiSS1, RFRP-3, and ghrelin were determined by real time qPCR method. Results revealed that baclofen significantly decreased the mean relative KiSS1 gene expression compared to PCOS group. Also, the mean relative RFRP-3 gene expression significantly increased in the baclofen-receiving rats in comparison to PCOS group. Furthermore, baclofen did not change GnRH or ghrelin mRNA levels in comparison to PCOS group. According to these results it can be concluded that in PCOS condition the GABAergic signaling pathway may suppress GnRH neural activity via down or up regulation of the intra-hypothalamic neuropeptides upstream of GnRH neurons.

کلیدواژه‌ها

Baclofen؛ GnRH؛ kisspeptin؛ ghrelin؛ RFRP-3

سایر فایل های مرتبط با مقاله

IJVST-13-42.xml

IJVST-13-42-g001.jpg

IJVST-13-42-g002.jpg

IJVST-13-42-g003.jpg

مراجع

1.    Polak K, Czyzyk A, Simoncini T, Meczekalski B. New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest. 2017; 40:1-8.
2.    Chaudhari N, Dawalbhakta M, Nampoothiri L. GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile. Reprod Biol Endocrinol. 2018; 16:37.
3.    Di Giorgio NP, Catalano PN, López PV, González B, Semaan SJ, López GC, et al. Lack of functional GABAB receptors alters Kiss1, Gnrh1 and Gad1 mRNA expression in the medial basal hypothalamus at postnatal day 4. Neuroendocrinology. 2013; 98:212-223.
4.    Zhang C, Bosch MA, Rønnekleiv OK, Kelly MJ. Gamma-aminobutyric acid B receptor mediated inhibition of gonadotropin-releasing hormone neurons is suppressed by kisspeptin-G protein-coupled receptor 54 signaling. Endocrinology. 2009; 150: 2388-2394.
5.    Lux-Lantos V, Rey E, Libertun C. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion. Neuroendocrinology. 1992; 56:687-693.
6.    Radwan RA, Abuelezz NZ, Abdelraouf SM, Bakeer EM, Rahman AAAE. Decreased serum level of gamma-amino butyric acid in Egyptian infertile females with polycystic ovary syndrome is correlated with dyslipidemia, total testosterone and 25(OH) vitamin D levels. J Med Biochem. 2019; 38:512-518.
7.    Ullah A, Jahan S, Razak S, Pirzada M, Ullah H, Almajwal A, et al. Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats. J Ovarian Res. 2017; 10:62.
8.    Wahab F, Atika B, Ullah F, Shahab M, Behr R. Metabolic impact on the hypothalamic kisspeptin-Kiss1 signaling pathway. Front Endocrinol (Lausanne). 2018; 9:123.
9.    Mahmoudi F, Khazali H, Janahmadi M. Interactions of morphine and peptide 234 on mean plasma testosterone concentration.  Int J Endocrinol Metab. 2014; 12: 1-5.
10.    Hu KL, Chang HM, Li R, Yu Y, Qiao J. Regulation of LH secretion by RFRP-3 From the hypothalamus to the pituitary. Front Neuroendocrinol. 2019; 52:12-21.
11.    Xiang W, Zhang B, Lv F, Ma Y, Chen H, Chen L, et al. The Inhibitory Effects of RFamide-Related Peptide 3 on Luteinizing Hormone Release Involves an Estradiol-Dependent Manner in Prepubertal but Not in Adult Female Mice. Biol Reprod. 2015; 93:30.
12.    Lv Y, Liang T, Wang G, Li Z. Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism. Biosci Rep. 2018; 38:1-13.
13.    Farkas I, Vastagh C, Sárvári M, Liposits Z. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS One. 2013; 8:1-16.
14.    Mohammadzadeh Sagheb M, Azarpira N, Mokhtary M.  Effect of ghrelin on Kiss-1 and KissR gene transcription and insulin secretion in rat islets of Langerhans and CRI-D2 cell line. Iran J Basic Med Sci. 2017; 20:36-40.
15.    Forbes S, Li XF, Kinsey-Jones J, O'Byrne K. Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neurosci Lett. 2009; 460:143-147.
16.    Tang R, Ding X, Zhu J. Kisspeptin and polycystic ovary syndrome. Front Endocrinol. 2019; 10:1-7.
17.    Di Giorgio NP, Bizzozzero-Hiriart M, Libertun C, Lux-Lantos V. Unraveling the connection between GABA and kisspeptin in the control of reproduction. Reproduction. 2019; 157:225-233.
18.    Zhang C, Tonsfeldt KJ, Qiu J, Bosch MA, Kobayashi K, Steiner RA, et al. Molecular mechanisms that drive estradiol-dependent burst firing of Kiss1 neurons in the rostral periventricular preoptic area. Am J Physiol Endocrinol Metab. 2013; 305:1384-1397.
19.    Farokhnia M, Sheskier MB, Lee MR, Le AN, Singley E, Bouhlal S, et al. Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment. Neuropharmacology. 2018; 137:230-239.
20.    Shaaban Z, Jafarzadeh Shirazi MR, Nooranizadeh MH, Tamadon A, Rahmanifar F, Ahmadloo S, et al. Decreased expression of arginine-phenylalanine-amide-related peptide-3 gene in dorsomedial hypothalamic nucleus of constant light exposure model of polycystic ovarian yyndrome. Int J Fertil Steril. 2018; 12:43-50.
21.    Angelopoulou E, Quignon C, Kriegsfeld LJ, Simonneaux V. Functional implications of RFRP-3 in the central control of daily and seasonal rhythms in reproduction. Front Endocrinol (Lausanne).  2019; 10:183.
22.    Rizwan MZ, Poling MC, Corr M, Cornes PA, Augustine RA, Quennell JH, et al. RFamide-related peptide-3 receptor gene expression in GnRH and kisspeptin neurons and GnRH-dependent mechanism of action. Endocrinology. 2012; 153(8):3770-3779.
23.    Simonneaux V, Ancel C, Poirel VJ, Gauer F. Kisspeptins and RFRP-3 act in concert to synchronize rodent reproduction with seasons. Front Neurosci. 2013; 7:22.
24.    Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego, California, USA: Elsevier Academic Press. 2005.
25.    Khazali H, Mahmoudi F, Janahmadi M. Hypothalamic Kiss1/GPR54 genes expression and plasma LH secretion in morphine treated male rats. Int J fertil steril. 2018; 12: 223-228.