Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations

doi:10.1016/0022-510X(83)90008-4

Journal of the Neurological Sciences

Volume 61, Issue 2, October 1983, Pages 235-248

https://doi.org/10.1016/0022-510X(83)90008-4 Get rights and content

Abstract

The clinical efficacy, dose-response relationship, and safety of TRH-T (thyrotropin releasing hormone tartrate) were assessed in 290 patients with spinocerebellar degeneration (SCD) in a 2-week, double-blind study using placebo as control. 254 patients satisfied the criteria for inclusion in evaluation of the drug efficacy.

The patients were treated with TRH-T in an intramuscular dose of 2 mg, 0.5 mg or 0 mg (placebo) as TRH once a day for 2 weeks. Clinical responses to these treatments were evaluated 3 times: at the end of weeks 1 and 2 of treatment and a week after the end of treatment. The results of “global improvement rating” as well as those of “ataxia improvement rating” showed that both 2 mg and 0.5 mg TRH-T treatments were significantly superior to placebo treatment in patients with predominantly cerebellar form of SCD. The effect was well maintained a week after the end of the 2-week treatment in the patients who were given TRH-T in daily dose of 2 mg and showed improvement at the end of treatment. The results of “improvement rating of each symptom” revealed that 2 mg treatment was significantly more effective than placebo for disorders of standing, gait, speech and writing. In the patients who had no pyramidal involvement or disorder of deep sensation, the drug efficacy and dose-response relationship were evident. Adverse reactions to the drug such as headache, feeling febrile and nausea were observed in 50% of the patients on 2 mg treatment, in 38% of those on 0.5 mg treatment and in 21% of those on placebo patient, however, discontinued treatment because of adverse reactions.

The results suggest that TRH-T improves ataxia in patients with SCD, especially of predominantly cerebellar form.

References (21)

T. Shimamoto
Treatment of senile dementia and cerebellar disorders with phthalazinol — Cyclic AMP-increasing agent, phthalazinol, in therapeutic trial in hitherto incurable morbid conditions, Part 1
Mech. Ageing and Develop.
(1976)
I. Sobue
Effect of thyrotropin-releasing hormone on ataxia of spinocerebellar degeneration
Lancet
(1980)
K. Adachi
Effects of thyrotropin releasing hormone on ataxic gait in Rolling mouse Nagoya
Igaku no Ayumi
(1977)
A. Barbeau
Emerging treatments — Replacement therapy with choline or lecithin in neurological diseases
Can. J. Neurol. Sci.
(1978)
A. Barbeau
Phosphatidylcholine (lecithin) in neurologic disorders
Neurology (Minneap.)
(1978)
S. Chamberlain
Effect of lecithin on disability and plasma free-choline levels in Friedreich's ataxia
J. Neurol. Neurosurg. Psychiat.
(1980)
R.A.P. Kark
Physostigmine in familial ataxias
Neurology (Minneap.)
(1977)
R.A.P. Kark
Double-blind, triple-crossover trial of low doses of oral physostigmine in inherited ataxia
Neurology (Minneap.)
(1981)
S. Kito
Effects of substance P and baclofen on the familial paraplegia
N. Legg
Oral choline in cerebellar ataxia
Brit. Med. J.
(1979)

There are more references available in the full text version of this article.

Cited by (87)

Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration
2020, Journal of the Neurological Sciences
Citation Excerpt :
Impairment of prism adaptation is not always associated with dysmetria, suggesting these two functions are generated by different mechanisms in the cerebellum [4–6]. Thyrotropin releasing hormone (TRH) was reported to improve cerebellar ataxia [12] and has been widely used as a treatment for cerebellar ataxia in SCD patients in Japan. However, effects of TRH on motor adaptation process have not been studied well.
The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task.
Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy.
TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of “Stance” category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252).
TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia).
Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia
2018, Handbook of Clinical Neurology
Citation Excerpt :
These effects have been demonstrated in animals (Muroga et al., 1982). Human studies have confirmed that TRH treatment may improve ataxia in some cases (Sobue et al., 1980, 1983). Congenital hypothyroidism is associated with a growth deficit and mental retardation.
Hormonal disorders are a source of cerebellar ataxia in both children and adults. Normal development of the cerebellum is critically dependent on thyroid hormone, which crosses both the blood–brain barrier and the blood–cerebrospinal fluid barrier thanks to specific transporters, including monocarboxylate transporter 8 and the organic anion-transporting polypeptide 1C1. In particular, growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on thyroid hormone. Disturbances of thyroid hormone may also impact on cerebellar ataxias of other origin, decompensating or aggravating the pre-existing ataxia manifesting with motor ataxia, oculomotor ataxia, and/or Schmahmann syndrome. Parathyroid disorders are associated with a genuine cerebellar syndrome, but symptoms may be subtle. The main conditions combining diabetes and cerebellar ataxia are Friedreich ataxia, ataxia associated with anti-GAD antibodies, autoimmune polyglandular syndromes, aceruloplasminemia, and cerebellar ataxia associated with hypogonadism (especially Holmes ataxia/Boucher–Neuhäuser syndrome). The general workup of cerebellar disorders should include the evaluation of hormonal status, including thyroid-stimulating hormone and free thyroxine levels, and hormonal replacement should be considered depending on the laboratory results. Cerebellar deficits may be reversible in some cases.
Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system
2015, European Journal of Pharmacology
Citation Excerpt :
Several pharmacological studies revealed that TRH improves motor dysfunction of various animal models (Faden et al., 1981, 1984; Kurihara et al., 1985; Horita et al., 1986; Yamamoto and Shimizu, 1989). To date, TRH has been clinically investigated for the treatment of spinocerebellar degeneration (SCD), which is a progressive neurodegenerative disorder causing motor dysfunction (Sobue et al., 1983) and has been approved for use in Japan on patients with SCD. However, TRH has certain limitations as a clinical treatment for SCD due to its short biological half-life (4–5 min) in humans, as well as low intestinal and blood–brain barrier permeability (Bassiri and Utiger, 1973; Griffiths, 1976; Kinoshita et al., 1998; Khomane et al., 2011).
Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (K_i=702 nM) than taltirelin (K_i=3877 nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.
Treatment and management issues in ataxic diseases
2012, Handbook of Clinical Neurology
Citation Excerpt :
Similar small studies with zolpidem have suggested efficacy (Clauss and Nel, 2004; Clauss et al., 2004). Thyrotropin-releasing hormone (TRH) may also modulate GABA receptors and has shown mild efficacy in animal studies and class I trials (Sobue et al., 1983; Filla et al., 1989; Waragai et al., 1997; Shirasaki et al., 2003; Nakamura et al., 2005). Tanabe Seiyaku Co., Ltd., has marketed an oral TRH formulation (Ceredist) since September 2000, approved in Japan as an orphan drug for spinocerebellar ataxia.
Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT
2009, Journal of the Neurological Sciences
Thyrotropin releasing hormone (TRH) therapy improves cerebellar ataxia in patients with spinocerebellar degeneration (SCD). We investigated the effect of TRH on regional cerebral blood flow (rCBF) using the fully automated region of interest (ROI) technique, 3DSRT. Ten patients with SCD received TRH intravenously (2 mg/day) for 14 days and underwent brain perfusion single photon emission computed tomography before and after therapy. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS). The rCBF in each ROI was measured using the noninvasive Patlak plot method and calculated using 3DSRT. TRH significantly improved the ICARS scores and increased rCBF in the callosomarginal segment and cerebellum. Cerebellar rCBF increased in 4 of 5 patients with improved ICARS scores and in 3 of 5 patients without improved ICARS scores after TRH therapy. The correlation between the change in cerebellar rCBF and the improved ICARS score, however, was not significant. These findings indicate that TRH therapy may increase cerebellar rCBF in some patients with cerebellar forms of SCD and that 3DSRT may be useful for evaluating the efficacy of TRH for increasing CBF. The beneficial effects of TRH may be due to increased cerebellar rCBF or the increased rCBF may be a secondary effect of TRH therapy.
Neuropeptides and Their Roles in the Cerebellum
2024, International Journal of Molecular Sciences

View all citing articles on Scopus

^☆: This work was supported by a grant for the new drug development of the Ministry of Health and Welfare of Japan.

^∗: Member of the Drug Evaluation Subcommittee in the Research Committee of Therapeutic Agents for Spinocerebellar Degenerations (Chairman: Prof. I. Sobue).

View full text

Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations☆

Abstract

Mech. Ageing and Develop.

Lancet

Effects of thyrotropin releasing hormone on ataxic gait in Rolling mouse Nagoya

Igaku no Ayumi

Emerging treatments — Replacement therapy with choline or lecithin in neurological diseases

Can. J. Neurol. Sci.

Phosphatidylcholine (lecithin) in neurologic disorders

Neurology (Minneap.)

Effect of lecithin on disability and plasma free-choline levels in Friedreich's ataxia

J. Neurol. Neurosurg. Psychiat.

Physostigmine in familial ataxias

Neurology (Minneap.)

Double-blind, triple-crossover trial of low doses of oral physostigmine in inherited ataxia

Neurology (Minneap.)

Effects of substance P and baclofen on the familial paraplegia

Oral choline in cerebellar ataxia

Brit. Med. J.