About this Research Topic
Glutamate is the primary excitatory neurotransmitter of the Central Nervous System (CNS) affecting all the aspects of cognition. Fifty years ago, the seminal work by John W. Olney revealed that the systemic administration of monosodium glutamate in newborn mice produces widespread neuronal loss, thereby indicating the neurotoxic “dark side” of the transmitter. The discovery prompted the birth of a fascinating new field aimed at exploring the mechanisms involved in excitotoxicity, the glutamate-driven neuronal death.
Studies performed in the following decades have then provided critical insights on the molecular determinants of excitotoxicity, unraveled the ionic dependence of the phenomenon, pinpointed the key role played by the overactivation of the N-methyl-D-aspartate receptors (NMDARs), thereby paving the way for the excitotoxic cascade hypothesis.
Excitotoxicity is now a widely recognized form of neuronal demise that modulates the clinical course of acute conditions, like stroke, traumatic brain and spinal cord injury as well as neurodegenerative disorders like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Parkinson's disease (PD). The excitotoxic cascade has also been proved to be pharmacologically exploitable. In that respect, memantine and riluzole, two FDA-approved drugs targeting the glutamatergic neurotransmission, are now routinely employed for the treatment of AD and ALS, respectively. However, knowledge gaps are still present, and refinements of the hypothesis are needed to allow a more fruitful pharmacological exploitation of the phenomenon. For instance, early trials employing NMDAR antagonists, set to target the upstream mechanisms of the cascade, have produced disappointing results and undesirable levels of side effects.
This Research Topic celebrates the 50th anniversary of the 1969 Olney study. The Research Topic will provide a comprehensive overview and critical reappraisal of the mechanisms involved in the excitotoxic cascade as well as discuss novel glutamate-related targets for therapeutic intervention.
Keywords: N-methyl-D-aspartate receptors, Calcium, Mitochondria, Apoptosis, Oxidative stress
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