Chemistry of Ampakines

Cells of the oligodendroglial lineage express Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-preferring glutamate receptors (AMPA-GluR) during development. Prolonged activation of their AMPA-GluR causes Ca2+ overload, resulting in excitotoxic death. Oligodendroglial progenitors and immature oligodendrocytes are susceptible to excitotoxicity, whereas mature oligodendrocytes are resistant. An unresolved issue has been why Ca2+-permeability of AMPA-GluR varies so markedly with oligodendroglial development, although the level of expression of edited GluR2, an AMPA-GluR subunit which blocks Ca2+ entry, is relatively constant. To address this question, we performed Ca2+ imaging, molecular and electrophysiological analyses using purified cultures of the rat oligodendroglial lineage. We demonstrate that transient up-regulation of expression of GluR3 and GluR4 subunits in oligodendroglial progenitors and immature oligodendrocytes results in the assembly by these cells, but not by oligodendroglial pre-progenitors or mature oligodendrocytes, of a population of AMPA-GluR which lack GluR2.

The synaptic targets that the ampakine compounds hit are involved in communication between parts of the brain. They also influence the production of growth factors. This is part of the reason researchers think there are potential therapeutic applications.

This stage-specific up-regulation of edited GluR2-free, and hence Ca2+-permeable, AMPA-GluR explains the selective susceptibility to excitotoxicity of cells at these stages of oligodendroglial differentiation, and is likely to be important to these cells in the trans-synaptic Ca2+-signaling from glutamatergic neurons, which occurs in hippocampus

Ampakines are a structurally diverse family of small molecules that positively modulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, and thereby enhance fast, excitatory transmission throughout the brain. Surprisingly, ampakines have discrete effects on brain activity and behavior. Because their excitatory synaptic targets mediate communication between cortical regions, serve as sites of memory encoding, and regulate the production of growth factors, ampakines have a broad range of potential therapeutic applications. Several of these possibilities have been tested with positive results in preclinical models; preliminary clinical work has also been encouraging.