The relationship of free and conjugated catecholamines in plasma and cerebrospinal fluid in cerebral and meningeal disease

Abstract

The concentration of free and conjugated norepinephrine (NE), epinephrine (E) and dopamine (DA) were measured by a modified radio-enzymatic assay in the plasma and in the cerebrospinal fluid (CSF) of 45 patients with normal and in 21 patients with disturbed blood-CSF barriers. In patients with an undisturbed blood-CSF barrier the free NE and E in CSF were 128 +/- 45 ng/l and 27 +/- 20 ng/l (mean values +/- S.E.), respectively, and represented about 50% of the average plasma values. Mean DA was not different in plasma (47 +/- 22 ng/l) and in CSF (41 +/- 19 ng/l). Both in plasma and in CSF, considerable higher free catecholamine (CA) levels were measured in patients with dysfunction of the blood-CSF barrier. In one patient with bacterial meningitis twofold higher concentrations of free NE and DA in CSF as compared with plasma were detectable. Sulfate conjugates of catecholamines are predominant in plasma and CSF. The contribution of conjugated CA to total CA in plasma from patients with normal blood-CSF barrier averaged 69.7%, 63.1% and 98.1% for NE, E and DA, respectively and was significantly lower in the CSF (p less than 0.001). In patients with disturbed blood-CSF barrier, the increases of conjugated CA were more pronounced in CSF than in plasma. Further, the contribution of conjugated NE and E to total NE and E in CSF was not only increased in patients with bacterial meningitis, but also in patients with renal insufficiency compared to the "control" patients (p less than 0.02 and p less than 0.001 resp.). Free and conjugated NE, E and DA in the plasma and CSF were related significantly (p less than 0.01 resp.) with stronger correlation for conjugated CA (p less than 0.001 resp.). These results together with findings in the literature, suggest that there is little or no rostral-caudal gradient in CSF CA conjugate concentrations and that even in patients with intact blood-CSF barrier plasma conjugated CA concentrations influence those in CSF. Thus only free CA levels in CSF may reflect the central adrenergic activity.

Determination of Serotonin and Dopamine Metabolites in Human Brain Microdialysis and Cerebrospinal Fluid Samples by UPLC-MS/MS: Discovery of Intact Glucuronide and Sulfate Conjugates

“…Earlier studies reported that DOPAC was detected in human brain tissue samples [19], [21], [22], [34], in microdialysis samples [46], [48] and CSF samples [17], [18], [29], but it was not detected in this study. This may be due to insufficient sensitivity of the method or to fast degradation of DA and DOPAC during the sample storage, as reported earlier by several groups [28], [40], [55].…”

“…neurotransmitter glucuronides and sulfates. Therefore, such conjugates in the human cerebrospinal fluid (CSF) or brain samples have mostly been analyzed after acid or enzymatic hydrolysis of the conjugates [24]–[28]. Sulfate conjugates of DA, 5-HT, epinephrine and norepinephrine [27]–[30] and glucuronide conjugates of DA and norepinephrine [27] have been identified after hydrolysis of the conjugates in CSF samples.…”

The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication

“…Altogether, the results indicated that in rat, neurotransmitters are glucuronidated whereas their phase I metabolites are sulfated (Uutela et al, 2009b ). In human, early studies identified sulfate conjugates of DA and 5-HT (Ratge et al, 1985 ; Tyce et al, 1986 ) and glucuronide conjugate of DA in CSF. Glucuronide conjugates of HVA, DOPAC and 5-HIAA and DOPAC sulfate were detected in a caudate nucleus human sample although HVA and 5-HIAA occurred predominantly as free metabolites (Swahn and Wiesel, 1976 ).…”

Effect of Ganglion Blockade on Cerebrospinal Fluid Norepinephrine

“…Trimethaphan does not appear to enter the CNS (Gilman et al, 1985). Several control treatments were Ratge et al (1985) included to ensure the appropriateness of the sampling sites and times and to determine the contnbution of hypotension which usually accompanies ganglion blockade. These controls included: (1) saline;…”