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Abstract

The selective loss of neurones in a range of neurodegenerative diseases is widely thought to involve the process of excitotoxicity, in which glutamate-mediated neuronal killing is elaborated through the excessive stimulation of cell-surface receptors. Every such disease exhibits a distinct regional and subregional pattern of neuronal loss, so processes must be locally triggered to different extents to account for this. We have studied several mechanisms which could lead to excitotoxic glutamate pathophysiology and compared them in different diseases. Our data suggest that glutamate can reach toxic extracellular levels in Alzheimer disease by malfunctions in cellular transporters, and that the toxicity may be exacerbated by continued glutamate release from presynaptic neurones acting on hypersensitive postsynaptic receptors. Thus the excitotoxicity is direct. In contrast, alcoholic brain damage arises in regions where GABA-mediated inhibition is deficient, and fails properly to dampen trans-synaptic excitation. Thus the excitotoxicity is indirect. A variety of such mechanisms is possible, which may combine in different ways.

Anti-inflammatory activity of Wnt signaling in enteric nervous system: in vitro preliminary evidences in rat primary cultures

“…In experimentally LPS-induced colitis, an increased enteric glia activation [ 53 ] and neuronal cell death due to an excessive stimulation of excitatory transmitters [ 54 ] are reported to occur. The endotoxin LPS is an essential membrane component of luminal microflora bacteria that interacts specifically with enteric responsive cells through toll-like receptor 4 (TLR4) [ 55 - 57 ] to regulate intestinal homeostasis.…”

Cortical NMDA Receptor Expression in Human Chronic Alcoholism: Influence of the TaqIA Allele of ANKK1

“…primary motor cortex, PMC) in all but the most severe cases [1]. Neuronal loss may be due to excitotoxicity, an imbalance between excitatory and inhibitory inputs to the cell [2].…”

Sex differences in GABAA receptor subunit transcript expression are mediated by genotype in subjects with alcohol‐related cirrhosis of the liver

“…In contrast, chronic excessive alcohol use decreases the inhibitory effects of GABA A and increases the excitatory effects of glutamate. This can lead to neuronal loss in brain regions such as the DPC, possibly from excitotoxicity, 85 whereas the PMC is less vulnerable to the effects of alcohol misuse. 86 Ethanol is a positive allosteric modulator of GABA A receptors.…”