Hidetoshi Asai

Anti-ataxic effects of TRH and its analogue, TA-0910, in Rolling mouse Nagoya by metabolic normalization of the ventral tegmental area.

1 The mechanism of the anti‐ataxic action of thyrotropin‐releasing hormone (TRH) and its analogue, TA‐0910, in the Rolling mouse Nagoya (RMN), an ataxic mutant mouse, has been investigated. 2 TRH (30 mg kg−1, i.p.) and TA‐0910 (3 mg kg−1, i.p.) reduced the fall index (number of falls/spontaneous motor activity), an index of ataxia, 10–30 and 10–60 min after administration, respectively. 3 Relative local cerebral glucose utilization (LCGU) in the cerebellum and ventral tegmental area (VTA) of the rolling mouse was significantly smaller than that in normal animals. TRH (30 mg kg−1, i.p.) and TA‐0910 (3 mg kg−1, i.p.) increased the relative LCGU value of the VTA but not of the cerebellum in rolling mice to the level of normal animals. 4 These results suggest that the ataxia of the rolling mouse may be due to dysfunction of the cerebellum and VTA, and that amelioration by TRH and TA‐0910 could result from metabolic normalization of the VTA.

Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats

In order to determine whether acute tolerance develops by taltirelin hydrate ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-l-histidyl-l-prolinamide tetrahydrate; taltirelin), a thyrotropin-releasing hormone (TRH) analog, we examined the motor behavior, TRH receptors and dopamine D(2) receptors following 2 weeks treatment in rats. Taltirelin selectively bound to TRH receptors and increased the spontaneous motor activity by a single administration, suggesting that the motor effect of taltirelin is mediated by TRH receptors. Following repeated treatment with TRH, there was a significant reduction in the increment of spontaneous motor activity. In contrast, after repeated treatment with taltirelin at a dose that increased the motor activity to a similar extent to TRH by a single administration, there was no apparent change in its motor effect. In accord with the motor activity, we found a significant reduction in the [(3)H]methyl-TRH binding to TRH receptors in the brain following repeated treatment with TRH but not taltirelin. However, the [(3)H]spiperone binding to dopamine D(2) receptors in the corpus striatum did not change by repeated taltirelin and TRH treatments. Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors.

Reversal of hemorrhagic shock in rats using the metabolically stable thyrotropin-releasing hormone analog taltirelin hydrate

We investigated the effect of taltirelin hydrate ((−)-N-[(S)-hexahydro-1-methyl- 2,6-dioxo-4-pyrimidinyl-carbonyl]-L-histidyl-L-prolinamide tetrahydrate; taltirelin), a metabolically stable thyrotropin-releasing hormone (TRH) analog, on circulatory function, respiratory function, and viable time after bleeding in urethane-anesthetized rats. Massive volume-controlled bleeding caused marked reductions in mean arterial pressure (MAP) and respiratory rate (RR). The vital signs of control rats were lost within an average of 23 min after bleeding. Intravenous administration of taltirelin (0.03–0.3 mg/kg) and TRH (1 and 3 mg/kg) immediately after bleeding accelerated recovery of MAP and RR, and prolonged viable time in a dose-dependent manner. The potency of taltirelin in accelerating MAP and RR recovery and prolonging viable time was higher when compared with that of TRH. In addition, recovery of MAP and RR and the extension of viable time by taltirelin were inhibited by preintraperitoneal administration of atropine sulfate, which is a centrally acting muscarinic antagonist, but not by that of atropine methylbromide, which is a peripherally acting muscarinic antagonist. Taltirelin also recovered decreased arterial pH, bicarbonate ions, and base excess, and prevented a decrease in arterial oxygen saturation. In conclusion, the anti-shock effect of taltirelin was more potent than that of TRH. Taltirelin activity was mediated by the central muscarinic cholinergic system. In addition, taltirelin also corrected metabolic acidosis. These results suggest that taltirelin could be useful in the treatment of hypovolemic shock.