Ameliorating effect of rovatirelin on the ataxia in rolling mouse Nagoya

Ijiro, Tomoyuki; Yaguchi, Atsushi; Yokoyama, Ayumi; Abe, Yoshikazu; Kiguchi, Sumiyoshi

doi:10.1016/j.ejphar.2020.173271

Cited by 8 publications

(10 citation statements)

References 33 publications

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“…Moreover, the ameliorative effect of rovatirelin on motor dysfunction was ~10‐fold more potent than that of taltirelin. Furthermore, similarly of our previous results using RMN, 10 the rovatirelin‐induced amelioration of the ataxic gait of Ara‐C‐treated rats was not attenuated after 2 weeks of rovatirelin administration, suggesting that the repeated administration of rovatirelin maintains its efficacy without causing TRH receptor desensitization or drug tolerance. Therefore, the ameliorative effect of rovatirelin on motor dysfunction in various SCD model animals suggests the possibility of its therapeutic effect on various types of SCD.…”

Section: Discussionsupporting

confidence: 84%

“…In contrast, the cholinergic nerves in the mPFC and dopaminergic nerves in the striatum and NAc play a role in directly or indirectly controlling motor function. Furthermore, rovatirelin causes an increase in glucose metabolism in the mPFC, striatum and NAc when it improves motor function in the RNM 10 . Therefore, we examined the effects of rovatirelin on ACh levels in the mPFC and DA levels in the dorsal striatum and NAc.…”

Section: Discussionmentioning

confidence: 99%

“…Locomotor activity was measured for 3 minutes as the number of squares crossed in the open‐field test apparatus. The number of falls was counted for 3 minutes, as described in our previous report 10 …”

Section: Methodsmentioning

confidence: 99%

“…Rovatirelin activates noradrenergic neurons in the locus coeruleus (LC) and increases noradrenalin (NA) levels in the medial prefrontal cortex (mPFC) projecting from the LC 8 . Furthermore, rovatirelin improves motor function in rolling mouse Nagoya (RMN), a mouse model of spinocerebellar ataxia type 6 (SCA6), a hereditary SCD, by enhancing glucose metabolism in various brain regions, including the cerebellum, striatum, nucleus accumbens (NAc) and prefrontal cortex 10 . However, the mechanisms of action of rovatirelin in ameliorating ataxia are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…Locomotor activity was measured for 3 minutes as the number of squares crossed in the openfield test apparatus. The number of falls was counted for 3 minutes, as described in our previous report 10. Behavioural observations before drug administration were conducted to select individuals with severe ataxia symptoms according to the following criteria: fall index ≥0.5, locomotor activity ≥10.…”

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confidence: 99%

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

Ijiro

Yaguchi

Yokoyama

et al. 2022

Clin Exp Pharma Physio

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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.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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