Rostral-caudal concentration gradients of histamine metabolites in human cerebrospinal fluid

Abstract

The metabolites of histamine, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), have a large concentration gradient between cisternal and lumbar CSF in the rhesus monkey. The possibility of a t-MH and/or t-MIAA gradient in man was studied in sequential samples of CSF withdrawn from the lumbar space from a healthy male. The mean levels of t-MH and t-MIAA in the 14-16 ml segment of CSF from 6 male volunteers was also measured. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not derived from histamine, was also measured. Levels of t-MH, t-MIAA and p-MIAA were measured by gas chromatography-mass spectrometry. With increasing volumes of CSF removed, t-MH and t-MIAA levels increased linearly (p less than 0.01) when plotted against the midpoints of each volume segment. Levels of t-MH and t-MIAA from the volunteers showed little variation; the means of the levels were within 15% of the respective regression lines of the points from the single subject. In contrast, p-MIAA levels showed no gradient (p greater than 0.6) in serially removed CSF; the individual levels in CSF from the volunteers on unrestricted diets varied widely, suggestive of a dietary influence on p-MIAA levels in the CNS. The concentration gradient of histamine metabolites in CSF confirms the rostral-caudal gradient observed in monkey and argues against plasma or spinal cord as major sources of these metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Presence and Measurement of Imidazoleacetic Acid, a γ‐Aminobutyric Acid Agonist, in Rat Brain and Human Cerebrospinal Fluid

“…The concentrations of IAA in whole rat brain (Table 2) are similar to the concentrations of r-MIAA (Khan-deJwal et aI., 1982a), an unequivocal metabolite ofhistamine in both mammalian brain and peripheral tissues (see Green et al, 1987). In brain, their respective concentrations are -140 and 370 pmol/g; in the first milliliters collected, their levels in lumbar CSF were approximately the same, -3 pmol/ml (Table 2) (Prell et al, 1988). [Levels of t-MIAA in pooled, stored samples of CSF (Khandelwal et al, 19820;Swahn and Sedvall, 1983) have tended to be higher.]…”

Diurnal fluctuation in levels of histamine metabolites in cerebrospinal fluid of rhesus monkey

“…This is not surprising since p-MIAA is not a histamine metabolite; its levels in rat brain have a regional distribution distinct from that of histamine, t-MH and t-MIAA, and were unchanged after histidine loading or selective inhibition of histamine synthesis [34]. Unlike t-MH and t-MIAA, levels ofp-MIAA in CSF do not show a rostro-caudal gradient [42,43] but may be sensitive to changes in diet [43]. The precise source(s) of p-MIAA in the CNS is unknown.…”

“…The levels of histamine metabolites on the CSF grossly reflect the rate of release and metabolism of turnover of histamine in the brain. The rostro-caudal gradients for t-MH and t-MIAA in CSF of monkey [42] and man [43] suggest that these metabolites originate from brain histamine metabolism. Since fluctuations in the levels of histamine metabolites might yield a more direct picture of suggested circadian rhythms of histaminergic activity in mammalian brain, we serially collected CSF from a conscious primate and measured metabolite concentrations as a function of time.…”

Inability to Replicate Cerebrospinal Fluid Histamine Deficits in the Primary Hypersomnias: A Back to the Drawing Board Moment

“…Owing to the fact that histamine is rapidly metabolized to tele-methylhistamine (t-MH) by histamine methyltransferase (t 1/2 of minutes to tens of minutes), probing for alterations in CSF histaminergic activ-ity in human disease conventionally relies upon t-MH assessments by gas chromatographic/mass spectrometric analytical methods. [18][19][20][21] Dauvilliers et al 13 assessed CSF levels of histamine and t-MH employing a sensitive, recently validated liquid chromatographic-tandem mass spectrometric analytical approach. 22 Reliance solely on high-performance liquid chromatography (HPLC) with fluorescence detection of histamine in earlier analyses of primary hypersomnolent CSF is theoretically more liable to false elevations by interference introduced by other biogenic amines, and more prone to false reductions due to delays in sampling and the challenges in rapid aliquoting and snap-freezing of CSF.…”

“…Increasing volumes of CSF collected at the lumbar spine versus a sampling site closer to histamine's cell bodies of origin (e.g., the cerebellomedullary cistern) can also yield elevated t-MH values presumably due to the substantial rostral-caudal CSF gradient of approximately 6:1 that exceeds that observed for other biogenic amines. 23 Additional methodological concerns arise from the fact that histamine and t-MH are also sensitive to dietary factors, 19 stimulant medications expected to excite TMN neurons, 10 diurnal factors, 24 and sleep-wake state, none of which were strictly controlled for in any of the aforementioned studies of primary hypersomnolent CSF. Given this multitude of factors potentially influencing the dependent variables of interest, it is not at all surprising that the lowest versus highest values in both controls and affected subjects were nearly a log-fold apart regardless of the analytical methodology employed.…”