# Glutamate Receptor Agonists as Triggers of Neurotoxicity: Decoding Pathways of Five Neurotoxins and Potential Therapeutic Targets

## TL;DR

This paper reviews how certain neurotoxins act like glutamate and cause brain damage, offering insights into treating neurodegenerative diseases.

## Contribution

The paper decodes the mechanisms of five neurotoxins as glutamate receptor agonists and identifies potential therapeutic targets.

## Key findings

- Neurotoxins like BMAA and domoic acid cause excitotoxicity by overactivating glutamate receptors.
- These toxins contribute to diseases like ALS and amnesic shellfish poisoning through oxidative stress and mitochondrial damage.
- Understanding their mechanisms could lead to new treatments for neurodegenerative conditions.

## Abstract

l-Glutamate (l-Glu) is one of the primary
excitatory
neurotransmitters in the nervous system, functioning through both
ionotropic and metabotropic receptors. The release of l-Glu
into the synaptic cleft, its interaction with receptors, and its reuptake
are meticulously regulated by excitatory amino acid transporters.
The structural similarity of various compounds to l-glutamate
is crucial to their ability to interact with NMDA, AMPA, and kainate
receptors. These interactions can significantly influence neural communication
and function. Overstimulation of these receptors, which operate as
ion channels, results in an increased level of calcium ion influx,
a phenomenon known as excitotoxicity, which is often linked to neurodegeneration.
Many neurodegenerative conditions are linked to both acute and chronic
exposures to neurotoxins, whether they originate within the body (endogenous)
or from external sources (exogenous). These neurotoxins often function
as l-glutamate receptor agonists, potentially contributing
to the progression of these diseases. This perspective focuses on
key neurotoxins, including β-N-methylamino-l-alanine (l-BMAA), quinolinic acid (QUIN), domoic
acid, β-N-oxalyl-l-α,β-diaminopropionic
acid (β-ODAP), homocysteine (Hcy), and l-homocysteate, all of which exhibit complementary mechanisms of action. We will
explore their structural characteristics and mechanisms through which
they induce neurotoxicity. Understanding the neurotoxic mechanisms
of these compounds is essential for elucidating the pathology of neurodegenerative
diseases, such as amyotrophic lateral sclerosis, neurolathyrism, and
amnesic shellfish poisoning. This review summarizes the findings of
64 studies to clarify these relationships involving classic events
associated with neurodegeneration such as mitochondrial damage, oxidative
stress, and activation of proapoptotic pathways. In summary, the distinctive
properties of these neurotoxins provide valuable insights that could
help in the development of future therapeutic drugs aimed at treating
and alleviating the effects of neurodegenerative diseases. Understanding
how these neurotoxins interact with neuronal pathways can guide researchers
in designing more effective interventions.