It is established that glutamate exitotoxicity contributes to neurodegeneration in PD and other ND diseases.
I am endeavoring to determine what we can do to minimize or stop this.
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Evidence for Glutamate Dysregulation and Excitotoxicity in Different Neurodegenerative Diseases
Excitotoxicity in Acute Diseases of the CNS
As mentioned above, excitotoxicity was initially defined as an acute insult to nerve cells that leads to cell death by excessive activation of iGluRs. Acute excitotoxicity is known to play an important role in specific CNS disorders including cerebral ischemia, TBI, and status epilepticus. However, the mechanisms underlying acute excitotoxicity differ slightly among these different disorders as described below.
During brain ischemia, the initiation of L-glu- (or L-asp-) mediated excitotoxicity occurs within minutes due to the rapid increase in extracellular cerebral L-glu (and L-asp; reviewed in Dirnagl et al., 1999). The sudden loss of the energy supply due to the shut down of blood flow to the brain leads to a breakdown of the neuronal and astroglial membrane potentials as the maintenance of these is energy-dependent. In neurons, the subsequent membrane depolarization leads to vesicular L-glu release. In addition, energy depletion and disruption of ionic homeostasis inhibits EAAT activity in astrocytes and may even induce a reversal in their action thereby leading to non-vesicular L-glu and L-asp release. The release of L-glu/L-asp (Graham et al., 1990) from these different sources leads to excitotoxicity, mostly by over-activation of iGluRs of the NMDA type as shown by the efficacy of NMDA antagonists in the acute phase in animal models of transient cerebral ischemia (Park et al., 1988; Bielenberg and Beck, 1991; Katsuta et al., 1995).
In TBI, the mechanical tissue damage and disruption of the blood-brain barrier is the initiator of acute secondary neurodegeneration, which, in addition to neuroinflammation and oxidative stress, is mediated by L-glu release from intracellular compartments and thus by acute excitotoxicity (reviewed in Freire, 2012). Accordingly, acute administration of the NMDA antagonist MK801 following TBI ameliorates neuronal loss and long-term behavioral abnormalities (Sönmez et al., 2015).
In status epilepticus, ongoing synchronized activity of excitatory neuronal networks with concurrent breakdown of inhibitory mechanisms is the primary source of increased L-glu (and L-asp) release. As the intensity of synchronous activity is dependent on the integration of a nerve cell into a specific neuronal network and the ability of a nerve cell to withstand excessive glutamatergic input depends, among other properties, on the expression pattern of iGluRs, a rather restricted and maturation-dependent degeneration of neuronal populations is induced by prolonged epileptic seizures (Sankar et al., 1998). The relevance of excitotoxicity in status epilepticus is demonstrated by the fact that NMDA antagonists like ketamine reduce neuronal loss (Loss et al., 2012).
Chronic Excitotoxicity during Progressive Long-Term Neurodegeneration
As compared to acute insults to the CNS, in chronic neurodegenerative diseases the situation is much more complex. First, although compromised mitochondrial function has been repeatedly described in several neurodegenerative diseases (reviewed in Johri and Beal, 2012), the resulting impairments in energy supply are not nearly as severe as the energy failure in ischemic stroke. Thus, if excitotoxicity contributes to neurodegeneration, a very different time course of chronic excitotoxicity has to be assumed. In the following paragraphs, we will summarize what is known about the different pathways that might contribute to excitotoxicity in neurodegenerative diseases. We will focus on amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Huntington's disease (HD) as important examples with sufficiently validated animal models.
The article from which this came:
NAD+, NMN, SARM1 and neuroprotection.
