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PubMedDate not supplied

Effects of YM-14673, a new TRH analogue, on neurological deficits in rats with experimental cerebral hematoma.

Effects of YM-14673, a new thyrotropin-releasing hormone (TRH) analogue, on neurological deficits were observed in comparison with those of TRH and citidine diphosphate choline (CDP-choline) in rats with an experimental hematoma. Unilateral cerebral hematoma was prepared by injection of 0.25 ml of autologous blood into the region around capsula interna, putamen and caudate nucleus of the left cerebral hemisphere of the rats. The drug was administered once or multiple times a day immediately after the surgical operation for 7 days and measurement of neurological deficits was conducted every day for 7 days. Neurological deficits, such as hemiplegia, were observed maximally on the 3rd day after the operation and then gradually recovered in the saline-treated group. YM-14673 (0.1, 0.3 mg/kg i.p.) accelerated the recovery of neurological deficits. Single i.p. administration of TRH did not affect the neurological deficits; however, multiple administration (7 times a day for 7 days) of TRH accelerated the recovery of neurological deficits. CDP-choline, a cerebral metabolic enhancer, even in a dose of 300 mg/kg (i.p.) did not show any influence on neurological deficits. These results suggest that YM-14673 ameliorated neurological deficits in the cerebral hematoma models, presumably due to TRH-like activity. Possible mechanisms of the pharmacological actions of YM-14673 are also discussed.

Animals↗
PubMedDate not supplied

Effects of YM-14673, a new TRH analogue, on responses to morphine in rodents.

The influence of YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide dihydrate), a new thyrotropin releasing hormone (TRH) analogue, on morphine-induced hypothermia, development of cerebral ischemia and analgesia was investigated in rodents. YM-14673, in doses not affecting the normal rectal temperature, antagonized morphine-induced hypothermia in mice. Morphine-induced hypothermia was also antagonized by administration of TRH, in doses increasing normal rectal temperature. Morphine increased the appearance rate of convulsions in rats subjected to bilateral occlusion of the carotid artery. YM-14673, unlike TRH, reduced the appearance rate of convulsions increased by morphine in the ischemic rats. Morphine-induced analgesia measured by the hot plate method was not affected by both YM-14673 and TRH. Naloxone antagonized the effect of morphine in the 3 models. These results suggest that YM-14673 possesses physiological opioid antagonistic properties.

Analgesics↗
PubMedDate not supplied

Effects of a new TRH analogue, YM-14673, on spontaneous motor activity in rats.

The effects of a new TRH analogue, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on spontaneous motor activity (SMA) were compared with those of TRH in rats. Intraperitoneal, oral and intracerebral administrations of YM-14673 caused a significant and dose-dependent increase in SMA. TRH also showed similar actions as YM-14673 did, except after oral dosing. These actions of YM-14673 were about 20-100 times more potent than those of TRH. Pretreatment with haloperidol, alpha-methyl-p-tyrosine (alpha-MT) and amino-oxyacetic acid (AOAA) but not atropine, inhibited the ability of both YM-14673 and TRH to increase SMA. Focal microinjection into the nucleus accumbens of both YM-14673 and TRH induced about 100 times more potent increases in SMA than similar injections into the dorsal striatum. It is suggested that YM-14673 possesses more potent facilitatory effects on SMA than TRH, and that these appear to be mediated mainly by the mesolimbic dopaminergic system rather than by the nigrostriatal one. Other possible mechanisms are also discussed.

Aminooxyacetic Acid↗
PubMed1987

Evidence for the combined involvement of serotonergic and alpha 2 adrenergic mechanisms in the analgesic activity of tazadolene succinate.

The analgesic activity of tazadolene succinate was assessed in mice and rats subsequent to pretreatment with various depletors and antagonists of monoamine neurotransmitters. In the mouse warm plate assay, reserpine was confirmed to cause a profound antagonism of tazadolene analgesia. However, yohimbine, Sch 23390 and haloperidol, antagonists of alpha 2 adrenergic, D1 dopaminergic and D2 dopaminergic receptors respectively, did not block tazadolene, nor did the serotonin depletor, p-chlorophenylalanine. But mice treated with both the depletor and yohimbine were significantly resistant to the analgesic effects of tazadolene. Combined treatments of haloperidol or prazosin (an alpha1 adrenergic antagonist) and p-chlorophenylalanine were not similarly effective. In the rat, reserpine blocked tazadolene analgesia in both the hot plate and air induced writhing assays. Likewise, combined treatment with yohimbine and p-chlorophenylalanine also antagonized the analgesia. These results confirm the monoamine dependence of tazadolene analgesia and indicate that both serotonergic and alpha 2 adrenergic mechanisms are involved. The results further suggest that these systems may be in parallel and integrated such that either one is capable of the primary expression of the analgesic effect of tazadolene. Thus, the unique analgesia properties of tazadolene are apparently due to the ability of this compound to activate both serotonergic and alpha 2 adrenergic antinociceptive systems.

Analgesia↗
PubMed1987

Inactivation of pea seed glutamine synthetase by the toxin, tabtoxinine-beta-lactam.

Glutamine synthetase of plants is the physiological target of tabtoxinine-beta-lactam, a toxin produced by several disease-causing pathovars of Pseudomonas syringae. This toxin, a unique amino acid, is an active site-directed, irreversible inhibitor of glutamine synthetase from pea. ATP is required for inactivation. Neither ADP, AMP, nor adenosine 5'-(beta,gamma-methylene)triphosphate (AMP-PCP) supports inactivation. Adenyl-5'-yl imidophosphate (AMP-PNP) is slowly hydrolyzed by glutamine synthetase to produce adenyl-5'-yl phosphoramidate (AMP-PN) and inorganic phosphate as identified by 31P NMR spectroscopic analysis. AMP-PNP also supports a slow inactivation of glutamine synthetase by tabtoxinine-beta-lactam. These data are consistent with gamma-phosphate transfer being involved in the inactivation. Completely inactivated glutamine synthetase has 0.9 mumol of toxin bound/mumol of subunit. One mumol of ATP is bound per mumol of subunit of glutamine synthetase in the absence of either the toxin or another active site-directed inhibitor, methionine sulfoximine; whereas, a 2nd mumol of either [alpha- or gamma-32P]ATP is bound per mumol of subunit when glutamine synthetase is incubated in the presence of either toxin or methionine sulfoximine until all enzyme activity is lost. These data suggest that the gamma-phosphate hydrolyzed from ATP during inactivation remains with the enzyme-inhibitor complex, as well as the ADP. The open chain form, tabtoxinine, was neither a reversible nor an irreversible inhibitor of glutamine synthetase, suggesting that the beta-lactam ring is necessary for inhibition. The inactivation of glutamine synthetase with tabtoxinine-beta-lactam is pseudo-first-order when done in buffer containing 15% (v/v) ethylene glycol. The rate constant for this reaction is 3 X 10(-2) S-1, and the Ki for the toxin is 1 mM. Removal of the ethylene glycol from the buffer allows the reaction to proceed in a non-first-order manner with the apparent rate constant decreasing with time. As the enzyme is inactivated in these conditions, the binding affinity for the toxin appears to decrease, while the Km observed for glutamate does not change.

Adenosine Diphosphate↗
PubMed1987

The biosynthesis of tabtoxinine-beta-lactam. Use of specifically 13C-labeled glucose and 13C NMR spectroscopy to identify its biosynthetic precursors.

Tabtoxinine-beta-lactam, an irreversible inhibitor of glutamine synthetase is produced by several pathovars of Pseudomonas syringae. We have examined tabtoxinine-beta-lactam biosynthesis, an important and poorly characterized step in pathogenesis caused by this organism. We have identified the biosynthetic precursors of tabtoxinine-beta-lactam by incorporating 13C from specifically 13C-labeled D-glucose precursors and determining the labeling pattern using 13C NMR spectroscopy. Tabtoxinine-beta-lactam is generated by combining a 4-carbon fragment, a 2-carbon fragment, and a single carbon. The 4-carbon fragment arises from aspartic acid, and the 2-carbon unit is donated from carbons 2 and 3 of pyruvate. The 6-carbon backbone of tabtoxinine-beta-lactam arises from the condensation of fragments from aspartate and pyruvate, probably using reactions analogous to the initial steps in the pathway of lysine biosynthesis.

Aspartic Acid↗
PubMed1987

Isolation, identification and synthesis of a metabolite of tazadolene succinate.

Metabolism of tazadolene (1), a novel non-opioid analgesic with antidepressant properties, affords the 4-hydroxy and 3-methoxy-4-hydroxy derivatives (phenyl ring) of the drug, and N-[2-(phenylmethylene)cyclohexyl]-beta-alanine (4). The isolation, identification and synthesis of the latter metabolite is described.

Analgesics↗
PubMed1987

L-azetidine-2-carboxylic acid retards lung growth and surfactant synthesis in fetal rats.

Maturation of the pulmonary epithelium during late fetal development is controlled at least in part by the underlying fibroblasts. To further investigate this cellular interdependence and the role of collagen in type 2 cell differentiation, we studied the effects of inhibiting fibroblast function in vivo by injecting the proline analog L-azetidine-2-carboxylic acid (LACA) to timed pregnant rats, and examining changes in cell proliferation and surfactant synthesis in fetal lungs. LACA (200 mg/kg) was injected twice daily for 2 days and rats were killed 2 days later at days 19, 20, 21, and 22 of gestation. Fetal lung weight and DNA content were about 50% of controls, hydroxyproline per dry weight was reduced and by electron microscopy, there appeared to be less fibrillar collagen in the lung. Autoradiography after [3H]thymidine pulse-labeling showed reduced cell proliferation on days 19 and 20 mainly due to lower fibroblast growth with a smaller reduction in epithelial labeling. Lung development in LACA-treated rats was retarded; air sacs were slow to open, epithelial cells retained glycogen longer and fewer cells developed lamellar bodies compared with age-matched controls. There was a reduction in the incidence of epithelial-interstitial cell contacts at day 20 only. Measurements of disaturated phosphatidylcholine showed a 50% reduction per dry weight and a lower disaturated phosphatidylcholine/lipid ratio after LACA. The results indicate that LACA administration in vivo slows fibroblast growth and greatly reduces fibrillar collagen deposition with an accompanying reduction in pulmonary surfactant. This suggests that secreted matrix influences growth and differentiation of the alveolar epithelium.

Animals↗
PubMed1986

Dysmorphogenesis of the inner ear: disruption of extracellular matrix (ECM) formation by an L-proline analog in otic explants.

L-azetidine-2-carboxylic acid (LACA), a l-proline analog, disrupts collagen secretion by cells and prevents normal morphogenesis of in vitro developing organ rudiments. Otic explants derived from 10.5-through 14-day-old mouse embryos were continuously exposed to LACA in the nutrient medium at concentrations of 75, 150, and 300 micrograms/ml. LACA disrupted normal in vitro otic morphogenesis in inner ears explanted from embryos of 10.5 through 13 days' gestation. Development of 14-day-old otic explants were not affected by LACA at the concentrations tested. There was a direct correlation between the embryonic age of the explant when exposed to LACA, and the severity of otic dysmorphogenesis. The younger explants (10.5-to 12-day-old) developed abnormalities of both vestibular and auditory structures, but with increasing embryonic age of the explants (12-to 13.5-day-old) abnormalities were confined more to the auditory portion of the inner ear. Disruption of collagen secretion of connective tissue cells of the otic explants are a major teratogenic action of LACA on inner ear development. Disrupted collagen secretion alters otic extracellular matrix production, which in turn affects the tissue interactions that regulate the progressive expression of otic morphogenesis and differentiation.

Abnormalities, Drug-Induced↗
PubMed1985

[Effect of an analog of proline (L-azetidine-2-carboxylic acid) on in vitro differentiation of the rat fetal testis].

The initial stages of the development of the seminiferous cords involve the differentiation and the aggregation of primordial Sertoli cells opposite to cells which acquire a mesenchymal-like aspect. The hypothesis that the development of the seminiferous cords depends on epithelial-mesenchymal relations between the two cell types was submitted to experimental test. Male gonadal primordia of rat fetuses were cultured in vitro in a synthetic medium containing the proline competitor, L-Azetidine-2-Carboxylic Acid. This drug is known to disturb the synthesis and secretion of collagen and proline-containing proteins. It prevents testicular organogenesis or destroys it if it has begun. It suppresses the expression of laminin and fibronectin in the gonadal primordium. These observations are taken as evidence that cellular correlations of the epithelial-mesenchymal type play a role in the development of the testis as they do in that of other organs.

Animals↗