Effect of social isolation and kisspeptin analogues (KS6 and KS10) on the expression of KISS1, KISS2, and their receptors in danio rerio

Introduction: The kisspeptin system regulates both reproductive and stress-related neuroendocrine functions. In zebrafish (Danio rerio), social isolation disrupts the expression of kiss1, kiss2, and their receptors (kiss1ra, kiss1rb). This study investigates whether kisspeptin analogues KS6 and KS10 can reverse these effects and compares them with the well-known neuropeptide oxytocin. Materials and Methods: Adult zebrafish were exposed to 48-hour social isolation and treated with KS6, KS10 (0.1 mg/L), or oxytocin (0.019 IU/L). Total RNA was extracted from whole brains, followed by cDNA synthesis and quantitative PCR targeting kiss1, kiss2, kiss1ra, and kiss1rb. Gene expression was normalized to gapdh. Statistical significance was assessed using one-way ANOVA and Student’s t-test. Results and Discussion: Social isolation downregulated kiss1, kiss2, and kiss1ra, and upregulated kiss1rb. KS6 significantly increased kiss1 expression and normalized kiss1rb levels. KS10 partially restored kiss1 and kiss2, but reduced kiss1ra and further elevated kiss1rb. Oxytocin reversed all isolation-induced changes. KS6 showed the most consistent restorative effects, whereas KS10 demonstrated a more selective receptor profile, suggesting differential downstream signaling. Conclusion: KS6 effectively reversed social isolation-induced dysregulation of kisspeptin signaling in zebrafish, indicating its potential for modulating neuroendocrine responses to stress. KS10 exhibited selective receptor modulation, which may be valuable for fine-tuned therapeutic strategies. These findings highlight the distinct pharmacological profiles of kisspeptin analogues in stress-related contexts.