alpha-Fluoromethylhistidine-induced inhibition of brain histidine decarboxylase. Implications for the CO2-trapping enzymatic method.

The actions of S-alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of the histamine biosynthetic enzyme histidine decarboxylase (HD), were studied on rat brain HD, as measured by a recently developed CO2-trapping enzymatic method. As expected, FMH induced a virtually complete inhibition of HD in the hypothalamus both in vivo and in vitro. In the frontal cortex, however, maximal doses of FMH did not maximally inhibit HD, suggesting the existence of an FMH-resistant form of HD. Careful studies of the conditions under which the assays were performed (homogenate dilution, preincubation times, incubation times, temperatures), as well as experiments with inhibitors of other decarboxylases, were unable to provide an explanation for this. When comparable studies of the effects of FMH in these brain regions were performed by alternative methods for measuring HD activity, no evidence for the existence of an FMH-resistant form of HD could be found. Thus, even though the CO2-trapping method appears to be accurate for measuring HD activity in rat hypothalamic homogenates, the present results show that this method may not be specific when studying brain regions other than the hypothalamus.

Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B.

Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.

The N-methyl-D-aspartate (NMDA) receptor antagonist, dextrorphan, prevents the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) in rats.

Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.