Under pathological conditions microglia (resident CNS immune cells) become activated, and produce reactive
oxygen and
nitrogen species and pro-inflammatory
cytokines: molecules that can contribute to axon
demyelination and neuron death. Because some microglia functions can exacerbate CNS disorders, including
stroke,
traumatic brain injury, progressive
neurodegenerative disorders such as
Alzheimer's disease,
Parkinson's disease,
amyotrophic lateral sclerosis, and
multiple sclerosis, and several
retinal diseases, controlling their activation might ameliorate immune-mediated CNS disorders. A growing body of evidence now points to
ion channels on microglia as contributing to the above neuropathologies. For example, the
ATP-gated P2X7
purinergic receptor cation channel is up-regulated around
amyloid β-
peptide plaques in transgenic mouse models of
Alzheimer's disease and co-localizes to microglia and astrocytes. Upregulation of the
P2X7 receptor subtype on microglia occurs also following
spinal cord injury and after
ischemia in the cerebral cortex of rats, while
P2X7 receptor-like immunoreactivity is increased in activated microglial cells of
multiple sclerosis and
amyotrophic lateral sclerosis spinal cord. Utilizing neuron/microglia co-cultures as an in vitro model for
neuroinflammation,
P2X7 receptor activation on microglia appears necessary for microglial cell-mediated injury of neurons. A second example can be found in the
chloride intracellular channel 1 (CLIC1), whose expression is related to macrophage activation, undergoes translocation from the cytosol to the plasma membrane (activation) of microglia exposed to
amyloid β-
peptide, and participates in
amyloid β-
peptide-induced neurotoxicity through the generation of
reactive oxygen species. A final example is the small-conductance Ca2+/
calmodulin-activated K+ channel KCNN4/KCa3.1/SK4/IK1, which is highly expressed in rat microglia.
Lipopolysaccharide-activated microglia are capable of killing adjacent neurons in co-culture, and show markedly reduced toxicity when treated with an inhibitor of KCa3.1 channels. Moreover, blocking KCa3.1 channels mitigated the neurotoxicity of
amyloid β-
peptide-stimulated microglia. Excessive microglial cell activation and production of potentially neurotoxic molecules, mediated by
ion channels, may thus constitute viable targets for the discovery and development of
neurodegenerative disease therapeutics. This chapter will review recent data that reflect the prevailing approaches targeting
neuroinflammation as a pathophysiological process contributing to the onset or progression of
neurodegenerative diseases, with a focus on microglial
ion channels and their neuroprotective potential.