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 dosedependent 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.

Receptor modulators associated with the hypothalamus -pituitary-thyroid axis

“…Further, Ijiro et al ( Ijiro et al, 2020 ) found that in spinocerebellar ataxia (SCA) model animals, rovatirelin, which activates the cerebellum and other parts of the central nervous system to improve motor function, is more effective than taltirelin. Rovatirelin also improve motor dysfunction in a cytarabine-induced rat model of spinocerebellar degeneration (SCD) via acetylcholine and dopamine neurotransmitters ( Ijiro et al, 2022 ). It follows that rovatirelin may have orally effective therapeutic potential for patients with SCD and SCA ( Table 3 ).…”

Biochemical and physiological insights into TRH receptor-mediated signaling

“…TRH mimetics have been shown to be useful in the treatment of spinocerebellar degeneration ( Shimizu et al, 2020 ; Ijiro et al, 2022 ), amyotrophic lateral sclerosis ( Hawley et al, 1987 ), spinal muscular atrophy ( Kat o et al, 2009 ), prolonged disturbance of consciousness due to aneurysmal subarachnoid hemorrhage ( Shibata et al, 2019 ), Parkinson’s disease ( Zheng et al, 2018a ; Zheng et al, 2018b ), epilepsy ( Rajput et al, 2009 ; Sah et al, 2011 ), psychiatric disorders with underlying inflammatory processes ( Kamath, 2012 ), and possibly depression ( Duval et al, 2021 ). The effects of TRH and its analogs on the CNS are usually achieved in cooperation with the modulatory effects of neurotransmitters such as glutamate, dopamine, norepinephrine, acetylcholine, serotonin, or GABA.…”