Therapeutic Trial of Intrathecal Thyrotropin-Releasing Hormone (TRH) and a TRH-Analogue in Amyotrophic Lateral Sclerosis (ALS)

Thyrotropin-releasing hormone (TRH) is widely distributed in the central nervous system (CNS) and possibly plays an important role as a facilitatory neuromodulator and/or ergotrophic factor independent of its endocrine action[6,7,9,18]. It has been found in high concentrations in the anterior horns of the spinal cord and in cranial nerve nuclei of the brainstem, it shows excitatory actions on lower motor neurons in laboratory animals, and it has trophic effects on ventral spinal cord cultures[15]. In cats, TRH improved neurologic recovery from experimental spinal injury [5]. Its concentrations in the anterior horn regions of ALS patients on the other hand are decreased, its levels in the cerebrospinal fluid (CSF) seem to be reduced[3,12]. Engel et al.[2] reported for the first time a transient improvement of muscle strength and spasticity in ALS under very high intravenous doses of TRH (2 - 19 mg/min). Further trials with subcutaneous applications were promising and showed some clinical benefit up to 12 days[4]. Other intravenous studies had negative results[13]. Imoto et al.[8] injected TRH intramuscularly (4 mg daily) without unequivocal effects. TRH has a plasma half-life of only 4-5 min because of rapid enzymatic degradation, and its ability to cross the blood brain barrier is only limited. These difficulties might be circumvented by intrathecal application or by the use of TRH-analogues which have a protracted biological stability, therefore enhanced bioavailability to the CNS and enhanced neuro-pharmacological potency[10,11].