Excitotoxic hypothesis

To review the neuropathology of Alzheimer s disease, and its relationship to the amyloid cascade hypothesis and the glutamate excitotoxic hypothesis of Alzheimer s disease. 

The development of the excitotoxicity hypothesis of ischemic damage along with the advent of potent glutamate antagonists provided the theoretical basis of what has been named neuroprotection. The failure of more than 40 clinical trials that have applied neuroprotectants to stroke patients, to show a clear clinical benefit has, however, raised concerns about... 

McEntee WJ (1997) Wernicke s encephalopathy an excitotoxicity hypothesis. Metabolic Brain Diseases 12,183-92. 

Although the hypothesis underlying the ability of this moderate affinity open channel blocker to differentiate between phasic physiological and tonic excitotoxic pathological activation of NMDA receptors has gained relatively wide acceptance (Mealing et al. 1997 Kornhuber and Weller 1997 Parsons et al. 1999) it is still unclear how such compounds could differentiate between normal and abnormal synaptic activation of NMDA receptors. 

Danysz W, Parsons CG, Mobius HJ, et al (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer s disease—an unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2 85-97 Davis SM, Lees KR, Albers GW, et al (2000) Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 31 347-354 DeKeyser J (1991) Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 14 562-565 Del Dotto P, Pavese N, Gambaccini G, et al (2001) Intravenous amantadine improves levodopa-induced dyskinesias an acute double-blind placebo-controlled study. Mov Disord 16 515-520... 

Greene JG, Greenamyre JT (1995) Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate. J Neurochem 64 430-436 Gunne LM, Andren PE (1993) An animal model for coexisting tardive dyskinesia and tardive parkinsonism—a glutamate hypothesis for tardive dyskinesia. Clin Neuropharmacol 16 90-95... 

FIGURE 4—17. If too much calcium gets into the neuron and overwhelms any sinks and buffers there, it can destroy the neuron and cause it to degenerate and die. This mechanism of excessive excitation is called excitotoxicity and is a major current hypothesis of the cause of various psychiatric and neurological disorders. This idea postulates that for such diseases, neurons are literally excited to... 

Olney J. W., Wozniak D. F., and Farber N. B. (1997). Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch. Neurol. 54 1234-1240. 

One implication for the excitotoxic cell damage in PD and HD is the binding of 6-hydroxylated L-DOPA on non-NMDA receptors. Thus, the hypothesis arises that an abnormal derivative of the natural DA precursor may be responsible for destroying nigral and striatal cells in these diseases (Hanson et al., 1985 Olney et al., 1990 Cha et al., 1991). 

The research described in this chapter is based on the hypothesis that a causal relationship exists between excitotoxic injury and the generation of ROS, RNS, and lipid peroxidation, Since anticholinesterase agents primarily cause excitotoxicity in brain and skeletal muscle, this chapter describes the correlation between changes in nitric... 

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