HYPOTHALAMIC-PITUITARY-TESTICULAR-AXIS RESPONSE IN WISTAR RAT TREATED WITH CHLORPROMAZINE, RAUWOLFIA VOMITORIA LEAF AND COMBINATION OF RESERPINE, ASCORBATE AND ZINC
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Date
2021-04
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UNIVERSITY OF ILORIN
Abstract
Synthetic antipsychotic drugs have been reported to induce reproductive toxicity while psychiatric patients treated with traditionally used herb like Rauwolfia vomitoria (RV) showed no traces of reproductive toxicity. Molecular mechanisms underlying control of Hypothalamic-Pituitary-Testicular-Axis (HPTA) by synthetic and traditionally used antipsychotic drugs are poorly understood. Thus, this study aimed to compare the effects of chlorpromazine (CPZ), RV leaf extracts and combination of reserpine, ascorbic acid and zinc (RAZ) on HPT-Axis of Wistar rats. The objectives of the study were to determine: (i) histological changes in the testes and hypothalamus; (ii) gonadotropin releasing hormone (GnRH), cytokeratin-18, Bcl2 and ki-67 protein expression; (iii) expression of Cyclic-adenosine-monophosphate Responsive Element Modulator (CREM), protamine (PRM) genes in the testes (iv) andrological parameters; and (v) antioxidant status.
Seventy-two male Wistar rats (weight: 180.00+4.67g) were assigned into nine groups (A-I) (n=8). Group A (control) was administered physiological saline while rats in Groups B and C received 10 and 20 mg/kg body weight (bwt) of chlorpromazine respectively. Groups D and E received 2.5 and 5 mg/kg bwt of reserpine while Groups F and G received 150 and 300 mg/kg bwt of RV leaf extract respectively. Groups H and I received (2.5:5:100) mg/kg bwt and (5:10:200) mg/kg of combination of RAZ respectively. The administration lasted for 56 days. On the 57th day, the rats were sacrificed, hypothalamus and testes were excised for histological, genes and immunohistochemical examinations while serum was used for hormonal analysis (follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, sperm count, motility and morphology) and biochemical analysis (glutathione peroxidase (Gpx), superoxide dismutase (SOD) and malondialdehyde). Data analyses were done by Analysis of Variance followed by Tukey’s post-hoc test at P<0.05 level of significant.
The findings of the study were that:
i. chlorpromazine and reserpine treated rats showed hypothalamic arcuate neurons and testicular germ cells degeneration;
ii. chlorpromazine and reserpine treated rats showed negative immunoreactivity to GnRH and ki-67 and weak positive immunoreactivity to cytokeratin and Bcl2 proteins while
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RV and combination of RAZ treated rats showed weak positive immunoreactivity to all the proteins;
iii. chlorpromazine and reserpine treated rats when compared with control and RAZ groups showed significant (p<0.001) down regulation of CREM (0.32+0.05), protamine-I (0.14+0.02) and II (0.13+0.02) genes expression;
iv. serum FSH (0.19+0.03 ng/ml), LH (0.33+0.06 ng/ml), testosterone (0.15+0.02 ng/ml), percentage of normal sperm count (17.40+2.59), motility (19.60+2.86) and morphology (16.60+2.91) were significantly (p<0.001) decreased in chlorpromazine and reserpine treated animals while prolactin (0.11+0.03 ng/ml) level was significantly (p<0.01) increased when compared with control and RAZ groups; and
v. serum GPx (21.00+3.50 U/L), SOD (0.54+0.12 u/mL) levels were significantly (p<0.001) reduced in chlorpromazine and reserpine treated rats while malondialdehyde (0.79+0.15) level was significantly (p<0.001) increased compared with control and RAZ groups.
The study concluded that HPT-Axis was impaired by chlorpromazine and reserpine while RV and combination of RAZ (2.5:5:100) mg/kg bwt administration enhanced the axis. The study recommended that combination of RAZ should be prescribed in order to improve reproductive toxicity associated with antipsychotic drugs.
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HYPOTHALAMIC, PITUITARY, TESTICULAR-AXIS, RESPONSE, WISTAR RAT, CHLORPROMAZINE, RAUWOLFIA VOMITORIA LEAF, RESERPINE, ASCORBATE, ZINC, Synthetic antipsychotic drugs, antipsychotic drugs