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Introduction:

Kisspeptins (Kp) are a family of neuropeptides differing in their length (54, 14, 13 and 10 amino acids in human) but derived from a common precursor. Kp stimulate GnRH secretion through their cognate receptor KISS1R. Kp system has been shown to be implicated in human reproductive disorder and to have an essential role in reproduction control. Hence, Kp system represent an interesting target for the development of new treatment in humans and animals, but the short Kp in vivo half-life hamper at present it use. For exemple a perfusion is necessary to achieve the required LH level to induce ovulation in ewes (Caraty et al., 2007). However, single  injection is required for livestock management.

Our objective was therefore to generate a Kp analogs with improved pharmacokinetics and pharmacodynamics, and to applied it for livestock reproduction control.

Methods:

Kp10 was used as a scaffold. Analogs were generated by combining modifications to improve resistance to degradation and reduce renal clearance. All analogs were screened in vitro to assess potency and efficacy, and the most interesting evaluated for their in vivo activity .Analogs were injected in intact ewes (Ile de France breed) using bolus intramuscular (i.m.) route of administration. Experiments were performed during the breeding season.Artificial luteal phase was simulated by insertion of a vaginal sponge containing fluogestone acetate (FA) (Chronogest, MSD-animal-health) for 14 days.Serial blood samples were collected and plasma stored at -20°C until LH and FSH were measured by RIA. Data are presented by mean ± S.E.M.

Results:

Conclusions:

We generated Kp10 analogs with improved pharmacokinetics and pharmacodynamics that stimulate the reproductive system. A single intramuscular injection of JBM1-153-3 induce synchronized fertile ovulation in ewe pretreated with FA. Further experiments will be focusing on the possibility of inducing ovulation in anestrous ewes.