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Thyrotropin-releasing hormone (TRH) and its analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), were administered intravenously to rats, and the blood level and brain distribution were determined by a specific radioimmunoassay. Degradation half-life of DN-1417 in the brain homogenate and blood was 27.5 min and those of TRH were 5 and 7.5 min, respectively. After the administration of DN-1417 (0.625, 2.5 and 10 mg/kg), the blood levels of immunoreactive-DN-1417 exhibited an apparent two compartment open model. The half-life values of the alpha- and beta-phase were 3 approximately 7 and 15 approximately 22 min, respectively. The half-life of the blood level of immunoreactive-DN-1417 was 2 approximately 3 times longer than that of TRH. As a result, the area under the curve of DN-1417 was 2.5 approximately 6 times larger than that of TRH. Blood level of immunoreactive-2-hydroxy-4-carboxybutyryl-histidyl-prolinamide+ ++ (DN-COOH), a main metabolite of DN-1417, was not more than 1% of the immunoreactive DN-1417 level. The distribution of DN-1417 into whole brain was attained its peak at 1 approximately 2 min after the administration. The percentage of transported DN-1417 into the brain at peak time was 0.062-0.163% of each of the doses administered. After the administration of DN-1417 (2.5 mg/kg), the pituitary, nucleus accumbens and hypothalamus showed higher concentrations, while the striatum showed the lowest concentration in the brain tissue examined.

The effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), on the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the metabolites in the various brain regions of rats were determined by means of high performance liquid chromatography with electrochemical detection. DN-1417 (20 mg/kg, i.p.) produced marked decreases in the levels of NE, DA and 5-HT, especially in the nucleus accumbens, striatum and hypothalamus. The maximum effect was observed at 15 min after the administration. DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased significantly in the nucleus accumbens, striatum and hypothalamus, whereas 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid remained unchanged. 3-Methoxytyramine increased significantly in the nucleus accumbens and striatum. Two week chronic administration of DN-1417 (20 mg/kg, i.p.) increased the levels of DA and NE in the nucleus accumbens and DA in the striatum. These results suggest that DN-1417 stimulates the turnover of the cerebral monoamines, especially the release of DA from the nucleus accumbens and striatum in the mesolimbic and nigro-striatal DAergic systems.

The antagonistic effect of a TRH (Thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate) against reserpine-induced reduction of electroconvulsive threshold (EC50) and the involvement of monoaminergic mechanism were studied in mice. Reserpine (2 mg/kg, i.p.) reduced the EC50 to 55-77% of the control in association with the depletion of brain monoamine. TRH and DN-1417 significantly reversed the EC50 reduced by reserpine. DN-1417 partially recovered 5-HT level and increased in the brain levels of 3-methoxy-4-hydroxyphenylglycol, homovanillic acid and 5-hydroxyindoleacetic acid in reserpinized mice. Monoaminergic receptor blockers attenuated, but muscarinic blockers accelerated the antagonistic effects of DN-1417 on the EC50. Neither alpha-methyl-p-tyrosine nor FLA-63 inhibited the effects of DN-1417, whereas p-chlorophenylalanine not only inhibited the antagonistic effect of DN-1417 on the EC50 but also prevented the stimulation effect on 5-HT turnover. Therefore, the antagonistic effect of DN-1417 against reserpine on the EC50 is most likely mediated by the stimulation of monoamine turnover, especially 5-HT in mice.

We investigated the changes of behavioral, electrophysiological and biochemical parameters during and after global cerebral ischemia in rats. Global cerebral ischemia was produced by the temporary occlusion of both common carotid arteries 24 hr after the permanent electrocauterization of bilateral vertebral arteries. Just before recirculation following 10 or 30 min of cerebral ischemia, loss of righting reflex, flattenning of cortical EEG activity, and detrimental decrease of ATP content and marked increase of lactate content in the cerebrum were observed. The alterations of all parameters completely recovered within 60 min after recirculation in 10-min cerebral ischemic rats. However, the 30-min cerebral ischemic rats showed almost no recovery after recirculation, suggesting that some irreversible damages are produced in the cerebrum of the 30-min ischemic rat. On the other hand, it was found that the auditory brain stem evoked response (ABER) and ATP content in the pons plus medulla were only slightly affected by the ischemic procedure, which indicates that the ischemic damages do not ensue in the lower part of the brain stem.