Excitotoxic processes contributing to diseases of the central nervous system (CNS)

DiseaseExcitotoxic processReferences
Ischemia

  • Interruption of blood flow leading to energy failure

  • Impairment of glutamate transport and NMDA receptors overactivation

  • Sustained Ca2+ influx

[137, 138]
Epilepsy

  • Dysregulation of EAATs and increase in extracellular Glu levels

[139, 140]
Alzheimer’s disease

  • Amyloid-β1-42 oligomers action on eNMDA receptors, leading to sustained Ca2+ influx, and mitochondrial and synaptic disfunction

[141, 142]

  • Metabolic astrocytic dysfunction and inhibition of lactate production

[143, 144]
Amyotrophic lateral sclerosis

  • Upregulation of AMPA receptors

  • Interneuron alterations and excitation-inhibition imbalance

  • Downregulation of EAAT2 in astrocytes and altered astrocyte metabolism with release of toxic factors

[145, 146]
Parkinson’s disease

  • Loss of dopamine leading to dysregulation of Ca2+ homeostasis

  • Overexpression of mGluR5 receptors

[147, 148]
Huntington’s disease

  • Interaction between mutated HTT protein and the PSD-95 scaffold protein, leading to alteration of the Glu receptors and to impairment of glutamate signaling

[149]

NMDA: N-methyl-D-aspartate; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EAATs: excitatory amino acid transporters