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.
"Several studies have shown that Aβ increased the K+ currents including fast-inactivating K+ currents (IA) and delayed rectifier K+ currents4546. In fact, blocking specific K+ channels has been proposed as a potential strategy for the treatment of neurodegenerative diseases4447. Here, we found that NTR1 significantly decreased sustained K+ currents in hippocampal neurons from either brain slice or primary cultures. "
[Show abstract][Hide abstract] ABSTRACT: Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Aβ-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K(+) currents. In addition, NTR1 reversed Aβ1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Aβ-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Aβ neurotoxicity.
"Several in vivo studies using the selective KCa3.1 blocker, TRAM-34, show improved outcomes in rodent models of CNS conditions with prominent inflammation; i.e., models of multiple sclerosis (Reich et al., 2005), optic nerve damage (Kaushal et al., 2007), spinal cord injury (Bouhy et al., 2011), and ischemic stroke (Chen et al., 2011). Because KCa3.1 is now considered a therapeutic target for reducing the pro-inflammatory state of the injured CNS (Wulff and Zhorov, 2008; Skaper, 2011; Maezawa et al., 2012), it is essential to determine its roles in other microglial activation states and cell functions. One important microglial function is migration to the damage site. "
[Show abstract][Hide abstract] ABSTRACT: The Ca2+-activated K+ channel, KCa3.1 (KCNN4/IK1/SK4), contributes to ‘classical’, pro-inflammatory activation of microglia, and KCa3.1 blockers have improved the outcome in several rodent models of CNS damage. For instance, blocking KCa3.1 with TRAM-34 rescued retinal ganglion neurons after optic nerve damage in vivo and, reduced p38 MAP kinase activation, production of reactive oxygen and nitrogen species, and neurotoxicity by microglia in vitro. In pursuing the therapeutic potential of KCa3.1 blockers, it is crucial to assess KCa3.1 contributions to other microglial functions and activation states, especially the IL-4-induced ‘alternative’ activation state that can counteract pro-inflammatory states. We recently found that IL-4 increases microglia migration—a crucial function in the healthy and damaged CNS—and that KCa3.1 contributes to P2Y2 receptor-stimulated migration. Here, we discovered that KCa3.1 is greatly increased in alternative-activated rat microglia and then contributes to an enhanced migratory capacity. IL-4 up-regulated KCNN4 mRNA (by 6 hr) and greatly increased the KCa3.1 current by 1 day, and this required de novo protein synthesis. The increase in current was sustained for at least 6 days. IL-4 increased microglial migration and this was reversed by blocking KCa3.1 with TRAM-34. A panel of inhibitors of signal-transduction mediators was used to analyze contributions of IL-4-related signaling pathways. Induction of KCNN4 mRNA and KCa3.1 current was mediated specifically through IL-4 binding to the type I receptor and, surprisingly, it required JAK3, Ras/MEK/ERK signaling and the transcription factor, AP-1, rather than JAK2, STAT6 or PI3K. The same receptor subtype and pathway were required for the enhanced KCa3.1-dependent migration. In providing the first direct signaling link between an IL-4 receptor, expression and roles of an ion channel, this study also highlights the potential importance of KCa3.1 in alternative-activated microglia.
"Potassium channels play an important role in the cardiovascular system and in the CNS. They are critically involved in regulating signaling, proliferation, secretion and migration not only in neurons but also in glial cells such as astrocytes and microglia (Olsen and Sontheimer 2008; Skaper 2011; Steinhauser et al. 2012; Rodriguez et al. 2013). Potassium channels have been also described to modulate the immune response. "
[Show abstract][Hide abstract] ABSTRACT: Activation of mitochondrial ATP-sensitive potassium (KATP) channels is postulated as an effective mechanism to confer cardio and neuroprotection, especially in situations associated to oxidative stress. Pharmacological activation of these channels inhibits glia-mediated neuroinflammation. In this way, diazoxide, an old-known mitochondrial KATP channel opener, has been proposed as an effective and safe treatment for different neurodegenerative diseases, demonstrating efficacy in different animal models, including the experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. Although neuroprotection and modulation of glial reactivity could alone explain the positive effects of diazoxide administration in EAE mice, little is known of its effects on the immune system and the autoimmune reaction that triggers the EAE pathology. The aim of the present work was to study the effects of diazoxide in autoimmune key processes related with EAE, such as antigen presentation and lymphocyte activation and proliferation. Results show that, although diazoxide treatment inhibited in vitro and ex-vivo lymphocyte proliferation from whole splenocytes it had no effect in isolated CD4(+) T cells. In any case, treatment had no impact in lymphocyte activation. Diazoxide can also slightly decrease CD83, CD80, CD86 and major histocompatibility complex class II expression in cultured dendritic cells, demonstrating a possible role in modulating antigen presentation. Taken together, our results indicate that diazoxide treatment attenuates autoimmune encephalomyelitis pathology without immunosuppressive effect.
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