AMPA Receptor Excitotoxicity and neurodegeneration.

Recently NMDA receptor agonists have been discussed as a means of reducing excitoxicity. I just learned of AMPA receptor Excitotoxicity. Below are quotes from a paper I will link.

Excitotoxicity is one of the primary mechanisms of cell death in a variety of diseases of the central and peripheral nervous systems

The activity of AMPARs is not only crucial to neuronal development and synaptic plasticity in physiological conditions, but also critical in the induction of neuronal death in neuropathological states

Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, chronic pain, and glaucoma, are reviewed. Excitotoxicity is recognized as one of the primary pathological alterations in these neurological disorders. Thus, the potential participation of CP-AMPARs in these disorders is discussed.

couple of PD-associated disease models have identified the involvement of CP-AMPARs in pathological alterations. First, CP-AMPARs are involved in the expression of L-DOPA-induced dyskinesia in PD (Kobylecki et al., 2010). Second, the CP-AMPAR-induced loss of dopamine neurons in the midbrain causes PD-related depression (Zhang et al., 2019). A potential mechanism could be that increased expression of CaMKIIβ in the lateral habenula (LHb) was upregulated in the PD models where the mesocortical DA pathway displayed degeneration. Blockade of CP-AMPARs in the LHb prevented DA neuron death, increased DA release in the prefrontal cortex, and produced antidepressant effects. Thus, a role for CP-AMPARs in PD is beginning to be gleaned and more studies are warranted.

CP-AMPAR-mediated excitotoxicity represents a common mechanism in multiple disease model systems. CP-AMPAR-associated pathological alterations could induce neural excitotoxicity in different brain regions, neural circuits, cellular types, as well as various intracellular signaling pathways, all of which may correspondingly lead to some unique manifestations of neurological diseases

frontiersin.org/articles/10...

[SilentEchoes]

NMDA and AMPA are both synthesized chemicals that activate glutamate receptors.

This begs the question - if these are not naturally occurring substances in our body - how the hell did they get into our brains?

NMDA is not an endogenous substance. It's not found in our body tissue but rather synthesized as an excitotoxin for research into NMDA receptors. The natural ligand for NMDARs is Glutamate (and to a lesser extent, Aspartate) but the receptors also require a co-agonist Glycine or D-serine for activation. There are two separate sub-units. NR1 (which binds Glycine) and NR2 (binds Glutamate).

AMPA is not an endogenous compound but a synthetic glutamate analog that specifically binds the AMPA receptor. Glutamate binds to the AMPA receptor as well.

There are a number of reported endogenous Allosteric Modulators of NMDARs which include Magnesium and Zinc.

The only proposed endogenous antagonist for NMDARs (Glycine and Glutamate sites) and AMPARs is Kynurenic Acid (a metabolite of Tryptophan) which also acts at the Kainate receptor.

brain.phgy.queensu.ca/pare/...

L-tryptophan supplementation in Parkinson's Disease

pubmed.ncbi.nlm.nih.gov/274....

SE