Neuropharmacological Responses are Observed in Mice After Systemic Treatment with a Prodrug of Thyrotropin-Releasing Hormone

Short description: Thyrotrophin-releasing hormone (TRH) is a promising agent to treat various brain maladies. However, delivery of this peptide into the brain has been an obstacle. In this exploratory study, a TRH prodrug designed for brain-enhanced delivery was evaluated through the reversal of drug-induced narcosis (analeptic effect) and antidepressant-like effect. Purpose: To show the utility of ketamine/xylazine in a mouse model to evaluate analeptic effect evoked by TRH upon its brain-delivery via a novel prodrug approach, as well as to confirm the antidepressant-like effect of this neuroactive peptide when delivered into the brain. Methods: For the assessment of analeptic effect, CD1 mice were divided into groups of n = 8. Test compounds were dissolved in saline. Mice were treated with a single dose (10 µmol/kg) of prodrug, saline vehicle, TRH, respectively, through the tail vein by i.v. injections. Ten minutes after injection of drug, mice were injected i.p. with either a mixture of ketamine (100 mg/kg) and xylazine (10mg/kg), or sodium pentobarbital (60 mg/kg). Sleeping time was recorded starting from the loss of righting reflex until this reflex was regained. To evaluate antidepressant-like activity using the Porsolt’s swim test, test compounds were administered i.v. through the tail vein at the dose of 3 µmol/kg, in a separate study. For 6 min, the immobility time (the duration of motionless floating after the cessation of struggling and making only movements necessary to keep the head above the water) was recorded. Results: TRH also reduced sleeping times after ketamine/xylazine sedation. Administration of the TRH prodrug also manifested analeptic effect characteristic to the parent peptide. Like after TRH injection, immobility time in Porsolt’s swim test indicative of the peptide’s antidepressant-like activity also shortened after the administration of its prodrug when compared to saline control. Thus, the analeptic and antidepressant-like effects observed after systemic administration of the TRH prodrug has reflected its ability to penetrate the blood-brain barrier followed by the release of the parent peptide at the site of action. Delivery of TRH to the brain by specific prodrug approach would allow for reduction of TRH’s endocrine side effects and for a prolonged duration of action. Conclusions: Treatment by a TRH prodrug reduced the ketamine/xylazine- and sodium pentobarbital-induced sleeping time in mice, as well as shortened the immobility time in Porsolt’s swim test. These observations have indicated a successful delivery of the neuroactive peptide into the brain via its prodrug introduced here.