Abstract
Acute liver failure (ALF) instantly evokes symptoms of hepatic encephalopathy (HE), mainly attributed to hyperammonemia. Ammonia neurotoxicity is related to disturbances in the nitric oxide (NO)/cGMP pathway. The methylated derivative of L-arginine (MDALs) - asymmetric dimethylarginine (ADMA) but not symmetrically methylated arginine (SDMA) is an endogenous inhibitor of nitric oxide synthase. Elevated blood and brain ADMA was reported in HE patients and experimental animals. The question arose whether ALF evokes changes in the incorporation of the methyl donor S-adenosylmethionine (SAM) to MDALs, and how they affect cGMP accumulation. To this end, we investigated the effect of intracortical perfusion of SAM on the brain extracellular levels of ADMA, SDMA and cGMP in rats with ALF in the thioacetamide (TAA) model. Sprague Dawley rats (250–270 g) received three i.p. injections of TAA (300 mg/kg) at 24 h intervals. Bilateral microdialysis of the prefrontal cortex was carried out 24 h after the last TAA administration. SAM at 2 mM concentration in artificial cerebrospinal fluid was infused for 40 min and then the medium was changed back. The extracellular levels of ADMA and SDMA were analyzed using positive mode electrospray LC–DMS–MS/MS and cGMP was determined with cGMP enzyme immunoassay. ALF resulted in the increased extracellular levels of ADMA (by ~800%) and SDMA (by ~250%). Moreover, in ALF rats infusion of SAM decreased the ADMA and SDMA (~30%) as compared to the basal value. It seems reasonable that an excessive amount of substrate inhibited the enzymes synthesizing MDALs. On the other hand, the cGMP level did not differ between control and TAA rats. SAM increased by ~90% cGMP only in the control group, what indicates affected NO/cGMP pathway in TAA model. The study demonstrates, that ALF modulates methylation of arginine to MDALs in a manner affecting cGMP accumulation.
Highlights
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression
Summary
Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors
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