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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperammonemia is mainly found in hepatic encephalopathy and in genetic defects of the urea cycle or other pathways of the intermediary metabolism. Clinically a difference has to be made between chronic moderate hyperammonemia and acutely increased concentrations. Pathogenetic mechanisms of ammonia toxicity to the brain are partly unraveled. In some animal models confounding variables, such as the reduced intake of food and amino acid imbalance due to liver insufficiency, do not allow to establish unequivocal causal relationships between the ammonia concentration and measured effects. In chronic moderate hyperammonemia an increased flux through the serotonin pathway is a key factor. It is caused by an increased transport of large neutral amino acids (including tryptophan) through the blood-brain barrier, accentuated by the imbalance of plasma amino acids in hepatic insufficiency. It is stimulated by D- or L-glutamine. Evidence is presented showing that a functioning gamma-glutamyl cycle (glutathione formation) is a prerequisite. In acute hyperammonemia involvement of NMDA receptors, glutamate, NO and cGMP plays an additional role. In hyperammonemic crises the increased cerebral blood flow leads to brain edema; factors discussed here are increased osmolytes in astrocytes and serotoninergic activity. Recent data indicate that axonal development is affected by ammonia and can be normalized in vitro by creatine supplementation in developing mixed brain cell aggregate cultures, thus reviving the old hypothesis of the impact of hyperammonemia on energy metabolism in the developing brain that could cause mental retardation.
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PMID:Mechanisms of hyperammonemia. 1224 Oct 9

Fetal alcohol syndrome (FAS) stems from maternal alcohol abuse during pregnancy and is an important cause of mental retardation and hyperactivity in children. In the developing brain, alcohol can kill neurons, leading to microencephaly. However, due to their genetic makeup, some individuals are less vulnerable than others to alcohol's neurotoxic effects. Animal studies have demonstrated that one particular gene, neuronal nitric oxide synthase (nNOS), protects developing neurons in vivo against alcohol-induced death. We utilized pharmacologic techniques to demonstrate that nNOS protects neurons against alcohol toxicity by activating the NO-cGMP-PKG signaling pathway. Cerebellar granule cell cultures derived from mice carrying a null mutation for nNOS (nNOS-/- mice) were substantially more vulnerable than cultures from wild-type mice to alcohol-induced cell death. However, activation of the pathway at sites downstream of nNOS protected the cultures against alcohol toxicity. Conversely, blockade of the pathway rendered wild-type cultures vulnerable to alcohol-induced death. We further identified NF-kappaB as the downstream effector through which nNOS and the NO-cGMP-PKG pathway signal their neuroprotective effects. Tumor necrosis factor-alpha (TNF-alpha), which activates NF-kappaB, ameliorated alcohol-induced cell death in nNOS-/- and wild-type cultures, while an NF-kappaB inhibitor (NFi) blocked the protective effects of TNF-alpha and worsened alcohol-induced cell death. Furthermore, NFi blocked the protective effects of NO-cGMP-PKG pathway activators, demonstrating that NF-kappaB is downstream of the NO-cGMP-PKG pathway. As wild-type neurons matured in culture, they became resistant to alcohol toxicity. However, this maturation-dependent alcohol resistance did not occur in nNOS-/- mice and could be reversed in wild-type mice with NFi, demonstrating that nitric oxide and NF-kappaB are crucial for the development of alcohol resistance with age. Thus, nNOS protects developing neurons against alcohol toxicity by activating the NO-cGMP-PKG-NF-kappaB pathway and is crucial for the acquisition of maturation-dependent alcohol resistance.
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PMID:The protective effect of neuronal nitric oxide synthase (nNOS) against alcohol toxicity depends upon the NO-cGMP-PKG pathway and NF-kappaB. 1882 32

When a mother abuses alcohol during pregnancy, the offspring can suffer a myriad of abnormalities, collectively known as fetal alcohol spectrum disorder (FASD). Foremost among these abnormalities is central nervous system dysfunction, which commonly manifests itself as mental retardation, clumsiness, hyperactivity, and poor attention span. These behavior problems are due, in large part, to alcohol-induced neuronal losses in the developing fetal brain. However, not all fetuses are equally affected by maternal alcohol consumption during pregnancy. While some fetuses are severely affected and develop hallmarks of FASD later in life, others exhibit no evident neuropathology or behavioral abnormalities. This variation is likely due, at least in part, to differences in fetal genetics. This review focuses on one particular gene, neuronal nitric oxide synthase, whose mutation worsens alcohol-induced neuronal death, both in vitro and in vivo. In addition, ectopic expression of the neuronal nitric oxide synthase gene protects neurons against alcohol toxicity. The gene encodes an enzyme that produces nitric oxide (NO), which facilitates the protective effects of neuronal growth factors and which underlies the ability of neurons to resist alcohol toxicity as they mature. Nitric oxide exerts its protective effects against alcohol via a specific signaling pathway, the NO-cGMP-PKG pathway. Pharmacologic manipulation of this pathway could be of therapeutic use in preventing or ameliorating FASD.
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PMID:The neuronal nitric oxide synthase (nNOS) gene and neuroprotection against alcohol toxicity. 2567 65