Biomedical subjects
Publications and source records attributed to A D Sherman.
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Three specific enzymes are involved in the cerebral synthesis of 7,8-dihydrobiopterin from GTP. These were isolated, purified, and characterized. The first enzyme, also catalyzing the rate-limiting step, is GTP-cyclohydrolase A-I or Mg2+-dependent A-II, which hydrolyze the GTP to the specific product 2-amino-6-(5-triphosphoribosyl)-amino-5-or-6-formamido-6-hydroxypyrimidine (FPyd-P3). FPyd-P3 is cyclized by a synthetase to D-erythro-7,8-dihydroneopterintriphosphate (NPTH2-P3). The new enzyme, D-erythro-7,8-dihydroneopterintriphosphate synthetase (enzyme B) is a basic protein of 9177 daltons containing three free SH groups, isoleucyl-seryl- as N- and valyl-glutamyl- as C-terminals. This enzyme of 69 amino acid residues from rat and 68 residues (one less aspartic acid) from guinea pig brain contains no hydroxyproline, methionine, or tryptophan. The enzyme from rat brain will gradually convert its product NPTH2-P3 to BH2, wherease the enzyme from guinea pig brain lacks this property. 2,4-amino-6-hydroxypyrimidine and dFPyd-P3 are effective inhibitors of this enzyme. The synthesis of BH2 from NPTH2-P3, but not from 7,8-dihydroneopterin, is catalyzed by L-erythro-7,8-dihydrobiopterin synthetase (enzyme C), which was purified to electrophoretic purity. This enzyme does not require pyridine nucleotides of Mc2+ for its catalysis.
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Experiments were performed to evaluate the effects on the levels of aspartate, GABA and glutamate in the periaqueductal central gray matter, hypothalamus, midbrain reticular formation and cortex of mouse brain following various treatments. The results indicate that only glutamate among the 3 neurohumors is systematically altered relative to the experimental manipulations. Moreover, among the 4 brain areas examined, the data implicate only the periaqueductal central gray matter as a locus of morphine's antinociceptive action. Morphine also appears to produce a drug-specific effect in hypothalamus which, however, is not analgesia-related. There were no significant pain, stress or drug-related effects on the levels of glutamate in either the midbrain reticular formation or the cortex.
Intraventricularly injected p-chloroamphetamine (p-CA) was actively metabolized to 3,4-dimethoxyamphetamine (3,4-DMA) in the rat brain. Time-course experiments with intraperitoneally injected p-CA confirmed that the presence of cerebral 3,4-DMA was not due to its "one-pass" entry from the peripheral organs. The identity of 3,4-DMA from brain tissue and urine was established by comparison to authentic 3,4-DMA. The synthetic and biological samples were isographic in all analytical systems. 3,4-DMA from biological samples was verified by mass spectrography.
In a comparative study, the effective of intraventricularly or intraperitoneally injected p-chloroamphetamine (p-CA) and some chloroindoles on cerebral levels of serotonin was evaluated. 5-Chloroindole depressed 5-HT levels in the brainstem and telencephalon for three days, 6-chloro-2-methylindole (6-CMI) only during the first day. 5-Chloroindazole had no effect at all. p-CA was more toxic to guinea pigs than to rats. p-CA and 5-chloro-2-methylindole (5-CMI) had no effect on cerebral 5-HT in chicks. Apparently, none of these compounds represented or was converted to a metabolite possibly responsible for the neurotoxic effects of p-CA.
Experiments were performed to determine 1) whether synergism existed between morphine and gamma-hydroxybutyrate in the production of analgesia and 2) the effect of each of these agents on pain-induced changes in brain amino acid content in mice. The analgetic ED50 for both agents was determined using hot plate and tail-flick procedures. The combination of one-half the ED50 of each agent produced an effect equivalent to the ED50 of either agent administered alone in the hot plate but not in the tail-flick test. Although both agents produced an unresponsiveness to noxious stimulation, only morphine prevented pain-induced alterations in brain GABA and glutamate levels.
Whole-brain levels of radioactivity were assessed at 0,2,6,12, or 24 hours, 1 1/2,2,7,10, and 14 days after intraventricular injection of H3 -p-CA. Urinary excretion and peripheral distribution were also followed for one week. The rate of elimination of total radioactivity from brain is biphasic with a T 1/2 of 1.2 hours and 2.5 days after intraventricular and 4.2 hours and 1.9 days after intraperitoneal injection of p-CA. The distribution into cerebellum, neocortex, brainstem, and telencephalon was studied at 1 hour, 2,3,5, and 7 days after injection. At both three and seven days, the radioactivity is still present in all the areas of the brain. The contribution of H3-p-CA to total radioactivity in the toluene extractable fraction was measured. By twelve hours, four chromatographically distinct peaks of radioactivity can be isolated from the toluene extract. The radiolabel in the subcellular fractions was also determined. There is a significant shift of radiolabel from the supernatant to organelle-bound phases between three and seven days.