Targeting Microglial K_ATPChannels to Treat Neurodegenerative Diseases: A Mitochondrial Issue

Abstract

Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATP channel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…In the healthy CNS, microglia present a highly ramified morphology, express receptors for neurotransmitters and neuromodulators [116][117][118], dynamically monitor the neuronal microenvironment and actively respond to neuronal activity as an integrated part of the "quad-partite" synapse [119][120][121]. This non-inflammatory microglial activity has important roles in CNS development eliminating the excess of neurons and controlling synaptic pruning and maturation of excitatory synapses (see [122] for a review).…”

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

“…Therefore, control of microglial activation should bring therapeutic benefit for any central disorder related with neuroinflammation. A growing body of evidence suggests that ion channels expressed by microglia are modulators of cell functions, and highlights their direct involvement in these neuropathologies (Kettenmann et al, 2011;Ortega et al, 2012aOrtega et al, , 2013Rodríguez et al, 2013;Virgili et al, 2011Virgili et al, , 2014.…”

“…We investigated activated microglia in our in vivo experimental model of neurodegeneration and in in vitro cultures of the BV2 microglial cell line. In our rodent model, N-methyl-D-aspartate (NMDA) is stereotaxicaly microinjected into the hippocampal formation to induce a neurodegenerative process involving neuronal necrosis and a potent inflammatory reaction mainly mediated by microglia (Ortega et al, 2012b;Rodríguez et al, 2013). BV2 cell culture allows the determination of the function of the L-type VGCC in microglia activity.…”

Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus

“…Despite these findings, the role of K ATP channel in the neurogenesis associated with inflammatory conditions is still largely unknown. Diazoxide (7-chloro-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide; Dzx) is a wellknown drug that opens K ATP channels showing high affinity for mitochondrial K ATP (mito K ATP ) channels (Ashcroft and Gribble, 2000;Rodríguez et al, 2013). Dzx activates K ATP channels in pancreatic cells and the smooth muscle of blood vessels, which results in the inhibition of insulin secretion and vasorelaxation (Richer et al, 1990;Petit and Loubatières-Mariani, 1992) and a subsequent increase in the plasma glucose concentration.…”

“…Half of the animals (6 rats in each group) were used for biochemical studies and the other half were used for histological investigations (Figure 1). The Dzx and NMDA doses were chosen according to previous studies (Virgili et al, 2011;Rodríguez et al, 2013;Batlle et al, 2015).…”