Encephalopathies neurotransmitters

Schafer DF, Jones EA Hepatic encephalopathy and the gamma-aminobutyric-acid neurotransmitter system. Lancet 1982 ii 18—20. 

Given the high dependency of cerebral energy production and neurotransmitter synthesis on glucose and oxygen, limitations in supply of these substrates results in metabolic encephalopathy. 

There are several theories behind the cause of hepatic encephalopathy. One of these is that the accumulation of toxins in the brain, particularly ammonia, is the cause. Ammonia is produced in the intestine and is usually metabolised in the liver to urea via the urea cycle. As a result of portosystemic shunting and reduced metabolism in the liver, ammonia serum levels rise as the transformation to urea is reduced. However, the validity of this theory is questionable as not all patients with signs of hepatic encephalopathy have raised serum ammonia levels. Another theory is that patients with hepatic encephalopathy have increased permeability of the blood-brain barrier, and hence the increased toxin levels permeate the brain more than usual, leading to altered neuropsychiatric function. There are also theories relating to increased levels of neurotransmitters, short-chain fatty acids, manganese and increased GABA-ergic transmission. 

With respect to the correlation between liver disorders and the functions of the brain, discussion currently focuses on five hypotheses concerning the development of hepatic encephalopathy (7.) intoxication hypothesis, (2.) neurotransmitter hypothesis, (2.) deficiency hypothesis, (4.) synergistic neurotoxicity, and (J.) hypothesis of primary gliopathy. 

L-dopa, a precursor of the neurotransmitters norepinephrine and dopamine, was introduced into HE therapy by J.D. Parkes et al. in 1970. The results were good. As yet, there is still no accepted opinion on the use of this substance. Piracetam, as a nootropic substance, led to a clear improvement in typical electrical brain activities in animals displaying hepatic damage and symptoms of encephalopathy. Similarly, a double-blind randomized cross-over study with the nootropic agent centropheno-xine partly showed positive effects in psychometric testing. Bromocriptine, an agonist of the dopamine receptor, was also used in 1980 for chronic hepatic encephalopathy. (146,163) Application of L-carnitine (6 g/day orally, divided into two doses, for 4 weeks) leads to a marked reduction of hyperammonaemia and a clear improvement in clinical symptoms of HE in cirrhotic patients. (119) (s. p.49)... 

The numerous biochemical substances that may be considered with regard to hepatic encephalopathy or ascites have been outlined in detail, (s. tabs. 15.2 16.5) Similarly, an extensive synopsis of pathogenetically effective biochemical factors can be drawn up for HRS as well. All of them ultimately interfere — directly or indirectly - with the renal retention or excretion of sodium and/ or the balance between vasodilation and vasoconstriction. RAAS is markedly activated. (5, 28, 33, 41, 62, 64, 65) (s. tab. 17.1) Vasodilative factors under discussion include bilirubin, bile acids, nitrogen monoxide (NO), false neurotransmitters, calcitonin peptide (25) as well as platelet-activating factor (RAF). In more recent studies, considerably higher plasma values of the vasoconstrictor leukotrienes (C4 and D4) (41) and endothehn 1 and 3 (42) were detected. 

The pathophysiology of hepatic encephalopathy is not completely understood but includes an increased sensitivity to dietary proteins. Ammonia concentrations are always increased with acute encephalopathy and usually increased with chronic encephalopathy. A reduction of plasma ammonia is often associated with symptomatic improvement. However, since plasma ammonia concentrations do not correlate with the severity of the encephalopathy, it has been suggested that other factors are involved. It is now recognized that a variety of neurotransmitter systems are dysfunctional in hepatic encephalopathy, but the exact cause for the changes is not known. One important contributor is the endogenous benzodiazepine agonist system, but other abnormalities must be invoked to explain all the findings. ... 

Butterworth R. Hepatic encephalopathy A neuropsychiatric disorder involving multiple neurotransmitter systems. Curr Opin Neurol 2000 13 721-7. 

The major controversy in nutritional support of the patient with liver failure has centered around the use of protein products. Modified amino acid solutions for PN (HepatAmine, others) are marketed for patients with liver failure and hepatic encephalopathy. They are enriched with BCAAs and have reduced amounts of AAAs and methionine. The products are formulated on the basis of the false neurotransmitter hypothesis, which concludes that hepatic encephalopathy may be due to increased AAA concentrations in the central nervous system. 

The absolute level of ammonia and its metabolites, such as glutamine, in the blood or cerebrospinal fluid in patients with hepatic encephalopathy correlates only roughly with the presence or severity of the neurologic signs and symptoms. y-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the brain, is also produced in the gut lumen and is shunted into the systemic circulation in increased amounts in patients with hepatic failure. In addition, other compounds (such as aromatic amino acids, false neurotransmitters, and certain short-chain fatty acids) bypass liver metabolism and accumulate in the systemic circulation, adversely affecting central nervous system function. Their relative importance in the pathogenesis of hepatic encephalopathy remains to be determined. 

Jones, E.A., 2002. Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab Brain Dis, 17(4) pp. 275-281... 

Butterworth RF. Neurotransmitter dysfimction in hepatic encephalopathy New approaches and new findings. Metab. Brain Dis., 16, 55-65, 2001... 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

Specialized formulas that are widely used for hepatic failure and hepatic encephalopathy are based on a high content of BCAAs to improve protein malnutrition and restore the amino acid and neurotransmitter balance. Although BCAA-enriched formulas have been proven to improve neurological status in comatose liver patients it is not certain that this is... 

Central nervous system Memory loss and learning difficulties Brain cellular morphology Neurotransmitter release Encephalopathy Cognitive intelligence Brain edema... 

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