Region selective alterations of soluble guanylate cyclase content and modulation in brain of cirrhotic patients

Abstract

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from experimental animals with hyperammonemia with or without liver failure. The aim of this work was to assess the content and modulation of sGC in brain in chronic liver failure in humans. Expression of the ␣-1, ␣-2, and ␤-1 subunits of sGC was measured by immunoblotting in autopsied frontal cortex and cerebellum from cirrhotic patients and controls. The contents of ␣-1 and ␣-2 subunits of guanylate cyclase was increased both in cortex and cerebellum, whereas the ␤-1 subunit was not affected. Addition of the NO-generating agent S-nitroso-N-acetyl-penicillamine (SNAP) to homogenates of frontal cortex from controls increased the activity of sGC 87-fold, whereas, in homogenates from cirrhotic patients, the increase was significantly higher (183-fold). In contrast, in cerebellum, activation of guanylate cyclase by NO was significantly lower in patients (156-fold) than in controls (248-fold). A similar regional difference was found in rats with portacaval anastomosis. In conclusion, these findings show that the NO-guanylate cyclase signal transduction pathway is strongly altered in brain in patients with chronic liver failure and that the effects are different in different brain areas. Given that activation of sGC by NO in brain is involved in the modulation of important cerebral processes such as intercellular communication, learning and memory, and the sleep-wake cycle, these changes could be implicated in the pathogenesis of hepatic encephalopathy in these patients. (HEPATOLOGY 2002;36:1155-1162 T he pathophysiologic mechanisms responsible for hepatic encephalopathy (HE) in chronic liver failure are incompletely understood. However, disruption of neurotransmitter systems has increasingly been implicated. In particular, selective alterations of glutamatergic and monoaminergic receptor sites have been reported in both experimental animal models of HE 1,2 and the brains of human cirrhotic patients. 3,4 Many of these receptors are functionally coupled to the nitric oxide (NO) cyclic guanosine monophosphate (cGMP) signal transduction pathway, which serves to amplify the postsynaptic response to receptor activation.Previous studies provide evidence for a role for this signal transduction pathway in the mediation of important cerebral functions, including regulation of the sleepwake cycle and some components of learning and memory, abnormalities of which form part of the spectrum of neuropsychiatric symptoms, which characterize HE in chronic liver failure. Furthermore, recent studies in experimental chronic liver failure reveal significant alterations in expression of key components of this signal transduction pathway. Such evidence includes increased expression and activities of neuronal nitric oxide synthase (nNOS) 5 and of the ␣ subunit of soluble guanylate cyclase (sGC). 6 The purpose of the present study was, therefore, to evaluate the NO-cGMP signal transduction pathway in relation to human HE. To accomplish this, the content o...

Role of Bioflavonoid Quercetin on Expression of Urea Cycle Enzymes, Astrocytic and Inflammatory Markers in Hyperammonemic Rats

“…These results corroborate the earlier reports on speeling effects of hyperammonemia or HE on the expression in astrocytic markers [40]. The ammonia concentration in brain (1-5 mM) in the primary cortical astrocytes had lead to a destabilization mRNA expression of GFAP [41][42][43].…”

“…Our administration could also increase the ammonia level in brain to the range 1-5 mM [12]. Liver failure during hyperammonemia is well-known to diminish the level of sGC via NO in (brain) as documented in liver cirrhotic patients [33,40]. The diminished levels of sGC by NO and hence the glutamate-NO-cGMP pathway could be involved in different neurological modifications found in HE.…”

Restoring Soluble Guanylyl Cyclase Expression and Function Blocks the Aggressive Course of Glioma

“…Reduction of sGC expression in human glioma tissues and cell lines. sGC expression in glioma cell lines (U87, U251, U373, A172, LN18, LN229, and D54) was examined by Western blot (A) and real time-Q-PCR (B) and compared with that in BE2 human neuroblastoma cell line, which normally expresses both sGC ␣1 and ␤1 subunits at levels similar to those in normal human cortex (D) (Bonkale et al, 1995;Corbalá n et al, 2002;Sharina et al, 2008). The GEO database analysis of sGC gene expression in human glioma tissues of different grade (C) showed that the expression of sGC ␣1 and ␤1 is markedly decreased in astrocytoma (n ϭ 26), oligodendrocytoma (n ϭ 50), and glioblastoma multiforme (n ϭ 81) compared with normal brain tissues (n ϭ 23).…”

Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts†

“…7,8 This modulation is altered in patients who have died of hepatic encephalopathy, as it is in rats with portacaval anastomosis. 10 Therefore, the function of the glutamate-NO-cGMP pathway also should be altered in the brains of these patients as in rats with portacaval anastomosis and also should be responsible for the impairment of some intellectual functions.…”

“…7,8 Chronic hyperammonemia also impairs the ability of rats to learn a conditional discrimination task. 9 The step of the glutamate-NO-cGMP pathway altered in rat models of hyperammonemia and hepatic encephalopathy is the activation of soluble guanylate cyclase by NO, 8,10 which is also altered in brains of patients who died with hepatic encephalopathy. 10 We hypothesized that the alterations in the function of the glutamate-NO-cGMP pathway in the brain in hyperammonemia and liver disease may be responsible for the impairment in learning ability and intellectual function and that pharmacological modulation of the pathway may restore learning ability in hyperammonemia and hepatic encephalopathy.…”