Central Norepinephrine Metabolism Research Articles

Alzheimer's disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms.

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.

The effects of immobilization stress on electrodermal activity and brain catecholamine levels in rats.

The effects of immobilization stress on electrodermal activity (EDA); skin conductance response magnitude and rate, skin conductance level and habituation number, and brain catecholamine levels; norepinephrine (NE) and dopamine (DA) were investigated in rats. Electrodermal activity was recorded using constant current method. Brain catecholamine levels were determined by a spectrophotophlorometric method. Electrodermal activity parameters (except skin conductance level) increased during immobilization. It was observed that, during immobilization stress, the alteration of norepinephrine and dopamine levels in rat brain was related to cerebral region and the duration of immobilization stress. It was concluded that these electrodermal activity alterations can be attributed to the changes in central norepinephrine metabolism induced by immobilization.

Urinary MHPG sulfate as a marker of central norepinephrine metabolism: a commentary

Measurement of total (free + conjugated) 3 methoxy-4-hydroxyphenylglycol (MHPG) in urine has long been used to assess the metabolism of central norepinephrine (NE). However, available data indicate that total MHPG is not a sensitive marker because the portion of urinary MHPG which derives from brain NE is less than was previously assumed. Several arguments support the view that central MHPG excretion is best represented by the urinary MHPG sulfate fraction. Accordingly, a new strategy has been introduced in last years, involving the separate determination of sulfate and glucuronide conjugates of MHPG as respective markers of central and peripheral NE metabolism. Various biochemical and pharmacological data obtained in healthy subjects and in patients with mental diseases support this hypothesis.

The evaluation of 4-hydroxy-3-methoxyphenylglycol sulfate as a possible marker of central norepinephrine turnover. Studies in healthy volunteers and depressed patients

Much evidence indicates that urinary 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG) is an insensitive measure of central norepinephrine metabolism. This conclusion, however, seems to apply mainly to total urinary MHPG, since previous findings point to the possibility that the major proportion of urinary MHPG sulfate originates in the CNS, while most urinary MHPG glucuronide originates in peripheral organs. To examine this hypothesis, experiments were performed by which we altered MHPG turnover in man at two different stages: firstly, strong physical exercise (ergometer) increased the urinary excretion rate of MHPG glucuronide and not that of MHPG-sulfate; secondly, ethanol (1 g/kg), which is known to block the metabolism of MHPG to vanilmandelic acid in the liver, increases the urinary excretion rate of the glucuronide and not that of sulfate. Both experiments indicate that alteration of peripheral norepinephrine turnover changes the urinary excretion of MHPG glucuronide only and not that of sulfate, thus providing strong, albeit indirect, evidence for a primarily central origin of MHPG sulfate. Preliminary experiments in 32 depressed patients showed little difference in both MHPG fractions compared with healthy controls, apart from a slightly reduced excretion rate of glucuronide. These findings fail to provide any evidence of central, and only small changes in peripheral norepinephrine metabolism in depression.

Is 3,4-dihydroxyphenylglycol the major route of central norepinephrine metabolism in rat brain?

Central norepinephrine (NE) metabolism was assessed by measuring 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3,4-dihydroxyphenylethyleneglycol (DHPG) in different rat brain areas after saline or probenecid (300 mg/kg) administration. Under probenecid, results showed an increased accumulation of total MHPG and DHPG, and a clear preponderance of DHPG levels over MHPG in almost all the brain areas examined. Estimation of their formation rates confirmed that in basal conditions DHPG is formed more rapidly. This study supports the notion that, without ruling out the importance of MHPG, brain DHPG may be a useful index of central NE activity.

Chronic autonomic failure: CSF and plasma 3-methoxy-4-hydroxyphenylglycol.

We measured CSF and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with orthostatic hypotension. Total CSF MHPG levels were significantly lower than normal in patients with either multiple system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). Only IOH patients had low plasma levels of MHPG. Correction of CSF MHPG levels for the contribution from plasma free MHPG provides an index of central norepinephrine metabolism. In MSA, abnormal function of central noradrenergic pathways seems to cause the low CSF MHPG levels. In IOH, the decreased CSF MHPG results from the diminished plasma MHPG levels.

Central norepinephrine metabolism during alcohol intoxication in addicts and healthy volunteers.

The concentrations of the major norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), in lumbar cerebrospinal fluid of alcoholic patients were markedly elevated during intoxication and successively declined during 1 and 3 weeks of abstinence. During intoxication the MOPEG concentration in cerebrospinal fluid showed a statistically significant correlation with the blood alcohol concentration. In healthy volunteers who received 80 grams of ethanol, the MOPEG concentration in cerebrospinal fluid increased significantly. Healthy subjects sampled during intoxication had significantly higher concentrations of MOPEG in the cerebrospinal fluid than did subjects sampled after the end of intoxication. The results indicate that alcohol administration markedly stimulates norepinephrine metabolism in the central nervous system in human subjects possibly by increasing unit impulse activity of central noradrenergic neurons.

Presence of free, sulfate and glucuronide conjugated 3-methoxy-4-hydroxyphenylglycol (MHPG) in human brain, cerebrospinal fluid and plasma

The concentration of the free, glucuronide and the sulfate conjugated forms of 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in human plasma, cerebrospinal fluid (CSF) and brain by mass fragmentography. All three forms of MHPG were detected in the media analyzed. Free MHPG was found to be the predominant form in both the brain and the CSF. The sulfate conjugate of MHPG constitutes about 15% of the total MHPG in the CSF while in the brain the percentage varies between 30% in the hypothalamus and cortex and 80% in the substantia nigra. The concentration of the glucuronide conjugate of MHPG measured in the brain and CSF represents about 5% of the total MHPG concentration. In the plasma free MHPG and its glucuronide and sulfate conjugates are present in about equal concentrations. The relative concentrations of the three forms of MHPG measured in plasma, CSF and brain were compared with their concentrations in the urine from previously published results 9. From this comparison the diagnostic significance of each of the three forms of MHPG in the clinical assessment of central norepinephrine metabolism is discussed.

Central norepinephrine metabolism in affective illness: MHPG in the cerebrospinal fluid.

Concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol in cerebrospinal fluid were measured by a gas chromatographic method in 34 patients with affective illness and in 44 controls. Concentrations of this metabolite in spinal fluid were significantly lower in depressed patients than in controls or manic patients. These low values may occur secondary to depressive phenomena such as reduced psychomotor activity, or they may reflect a primary change in norepinephrine metabolism in depressive illness.

Deviation of central norepinephrine metabolism in hypertensive rats.

Deviation of central norepinephrine metabolism in hypertensive rats.

The stress of aircraft carrier landings. II. 3-methoxy-4-hydroxyphenylglycol excretion in naval aviators.

As a possible reflection of central norepinephrine metabolism, urine MHPG excretion was measured in naval aviators during aircraft carrier landing practice, a complex task and a stress of considerable magnitude. Mean urine MHPG was significantly increased after both day and night carrier landings compared to a nonflying control day. These findings suggest that there may be an accelerated metabolism of brain norepinephrine under conditions of heightened arousal and concentration compared to the normal waking state.