pros-methylimidazoleacetic-acid and tele-methylhistamine

In mammalian brain, histamine is known to be metabolized solely by histamine methyltransferase (HMT), forming tele-methylhistamine (t-MH), then tele-methylimidazoleacetic acid (t-MIAA). We previously showed that imidazoleacetic acid (IAA), a GABA agonist, and histamine's metabolite in the periphery, is present in brain where its concentration increased after inhibition of HMT. Also, when [3H]histamine was given intracerebro-ventricularly to rats, a portion was converted to IAA, a process increased by inhibition of HMT. These results indicated that brain has the capacity to oxidize histamine but did not show whether this pathway is operative under physiological conditions. To address this question, rats were infused for > 4 weeks with alpha-fluoromethylhistidine (alpha-FMHis), an irreversible inhibitor of histamine's synthetic enzyme, L-histidine decarboxylase. Compared with controls (untreated and saline-treated rats), brain levels of histamine, t-MH, and t-MIAA in all regions were markedly reduced in treated rats. As a percentage of controls, depletion of t-MIAA > t-MH > histamine in all regions, and regional depletions of histamine co-responded to its turnover rates in regions of rat brain. In contrast, levels of IAA were unchanged as were levels of pros-methylimidazoleacetic acid, an isomer of t-MIAA unrelated to histamine metabolism. Results suggest that in brains of rats, unlike in the periphery, most IAA may not normally derive from histamine. Because histamine in brain can be converted to IAA under certain conditions, direct oxidation of histamine may be a conditional phenomenon. Our results also support the existence of a very slow turnover pool of brain histamine and use of chronic alpha-FMHis infusion as a model to probe the histaminergic system in brain.

Topics: Animals; Brain; Histamine; Histidine Decarboxylase; Imidazoles; Infusion Pumps; Male; Methylhistamines; Methylhistidines; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Time Factors; Tissue Distribution

The metabolites of histamine, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), were measured in lumbar cerebrospinal fluid of healthy, normal volunteers aged 20-31 (n = 4) and 60-72 (n = 8) by gas chromatography-mass spectrometry. Mean levels (pmol/ml) of t-MH, t-MIAA and the sum of t-MH and t-MIAA (2.9, 6.4 and 9.4, respectively) were significantly higher in CSF from older subjects than from younger subjects (1.1, 4.5 and 5.5, respectively). Another older subject had yet higher levels of metabolites (6.7, 15.1 and 21.8, respectively). The sum of the levels of the known metabolites of histamine in brain, i.e. t-MH and t-MIAA, did not overlap between the younger and older subjects. The levels of pros-methylimidazoleacetic acid, an endogenous isomer of t-MIAA that is not derived from metabolism of histamine, did not differ significantly between the two groups. These findings contrast with results of similar studies of metabolites of other aminergic transmitters in showing elevated levels of metabolites of histamine in cerebrospinal fluid with increasing age.

Topics: Adult; Aged; Aging; Female; Humans; Imidazoles; Lumbosacral Region; Male; Methylhistamines; Middle Aged; Neurotransmitter Agents

Similar to metabolites of other aminergic transmitters, histamine metabolites of brain, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), could have a concentration gradient between rostral and caudal sites of CSF. To test this hypothesis, cisternal and lumbar CSF samples were collected in pairs from eight monkeys (Macaca mulatta), and levels of t-MH and t-MIAA were measured by gas chromatography-mass spectrometry. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not a histamine metabolite, was also measured. Cisternal levels (in picomoles per milliliter, mean +/- SEM) of t-MH (9.9 +/- 1.4) and t-MIAA (40.8 +/- 7.6), but not of p-MIAA (9.7 +/- 1.2), exceeded those in lumbar CSF (t-MH, 1.8 +/- 0.3; t-MIAA, 6.8 +/- 0.9; p-MIAA, 8.6 +/- 0.6) in every monkey. The magnitudes of the mean cisternal-lumbar concentration gradients for t-MH (6.6 +/- 1.1) and t-MIAA (6.5 +/- 1.3) were indistinguishable. These gradients exceed those of metabolites of most other transmitters. There was no gradient for the levels of p-MIAA. The cisternal, but not lumbar, levels of t-MH and t-MIAA were correlated. There was no significant difference between the means of the metabolite concentration ratios (t-MIAA/t-MH) in cisternal (4.0 +/- 0.4) and lumbar (4.4 +/- 0.9) CSF. The steepness of these gradients suggests that levels of t-MH and t-MIAA in lumbar CSF might be useful probes of histaminergic metabolism in brain.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cisterna Magna; Hemoglobins; Histamine; Imidazoles; Lumbosacral Region; Macaca mulatta; Methylhistamines; Pyridines