Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside-induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission.

Abstract

Thyrotropin-releasing hormone (TRH) and the TRH mimetic taltirelin have been used in Japan for the treatment of spinocerebellar degeneration (SCD), a type of progressive ataxia. A TRH mimetic, rovatirelin, ameliorates ataxia symptoms in the rolling mouse Nagoya, a hereditary SCD model. The aim of this study was to verify the effects of oral administration of rovatirelin on a cytosine arabinoside (Ara-C)-induced ataxia rat model, a sporadic SCD model characterized by gait abnormalities and falls because of cerebellar atrophy and investigate the central nervous system mechanism associated with rovatirelin-mediated amelioration of motor dysfunction in these rats. Rovatirelin at ≥3 mg/kg significantly decreased the fall index, which is a primary endpoint of improved motor function calculated by dividing the number of falls by the locomotor activity, in both male and female rats with Ara-C-induced ataxia. Furthermore, rovatirelin caused a significant increase in locomotor activity in a dose-dependent manner. Taltirelin at ≥30 mg/kg ameliorated motor dysfunction in ataxic rats. Moreover, rovatirelin significantly increased acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and dopamine (DA) levels in the nucleus accumbens (NAc) at ≥3 mg/kg and significantly increased DA levels in the dorsal striatum at ≥10 mg/kg in normal rats. In conclusion, oral administration of rovatirelin ameliorates motor dysfunction in rats with Ara-C-induced ataxia, owing to its ACh-increasing effects in the mPFC and DA-increasing effects in the dorsal striatum and NAc. Furthermore, the effects of rovatirelin were more potent than those of taltirelin.

• Authors: Tomoyuki Ijiro, Atsushi Yaguchi, Ayaka Yokoyama, Sumiyoshi Kiguchi
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 49 Issue 9 Pg. 950-958 (09 2022) ISSN: 1440-1681 [Electronic] Australia
• PMID: 35637550 (Publication Type: Journal Article)
• Copyright: © 2022 John Wiley & Sons Australia, Ltd.

Chemical References

• Oxazolidinones
• Pyrrolidines
• Cytarabine
• Thyrotropin-Releasing Hormone
• rovatirelin
• Acetylcholine
• Dopamine

Topics

• Acetylcholine
• Animals
• Ataxia (chemically induced)
• Cytarabine (adverse effects)
• Dopamine
• Female
• Male
• Mice
• Oxazolidinones
• Pyrrolidines
• Rats
• Spinocerebellar Degenerations
• Synaptic Transmission
• Thyrotropin-Releasing Hormone (adverse effects)