Functional up‐regulation of the M‐current by retigabine contrasts hyperexcitability and excitotoxicity on rat hypoglossal motoneurons

Abstract

Neuronal hyperexcitability is a symptom characterizing several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In the ALS bulbar form, hypoglossal motoneurons (HMs) are an early target for neurodegeneration because of their high vulnerability to metabolic insults. In recent years, our laboratory has developed an in vitro model of a brainstem slice comprising the hypoglossal nucleus in which HM neurodegeneration is achieved by blocking glutamate clearance with dl-threo-β-benzyloxyaspartate (TBOA), thus leading to delayed excitotoxicity. During this process, HMs display a set of hallmarks such as hyperexcitability (and network bursting), reactive oxygen species (ROS) generation and, finally, cell death. The present study aimed to investigate whether blocking early hyperexcitability and bursting with the anti-convulsant drug retigabine was sufficient to achieve neuroprotection against excitotoxicity. Retigabine is a selective positive allosteric modulator of the M-current (I ), an endogenous mechanism that neurons (comprising HMs) express to dampen excitability. Retigabine (10 μm; co-applied with TBOA) contrasted ROS generation, release of endogenous toxic factors into the HM cytoplasm and excitotoxicity-induced HM death. Electrophysiological experiments showed that retigabine readily contrasted and arrested bursting evoked by TBOA administration. Because neuronal I subunits (Kv7.2, Kv7.3 and Kv7.5) were expressed in the hypoglossal nucleus and in functionally connected medullary nuclei, we suggest that they were responsible for the strong reduction in network excitability, a potent phenomenon for achieving neuroprotection against TBOA-induced excitotoxicity. The results of the present study may have translational value for testing novel positive pharmacological modulators of the I under pathological conditions (including neurodegenerative disorders) characterized by excessive neuronal excitability.

Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability

“…In fact, there is accumulating evidence that mutations in the genes encoding KCNQ2/3 subunits or PtdIns(4,5) P 2 -metabolizing enzymes lead to neuropathies similar to those in NPC1 disease. Mutations in KCNQ2/3 cause the hyperexcitability of neurons, leading to epileptic phenotypes in neonatal epilepsy ( Jentsch, 2000 ; Watanabe et al, 2000 ), Huntington disease ( Cao et al, 2015 ), and the bulbar form of amyotrophic lateral sclerosis (ALS) ( Ghezzi et al, 2018 ). Opening KCNQ2/3 channels with retigabine protects motoneurons against the excitotoxicity characteristic of this form of ALS ( Ghezzi et al, 2018 ).…”

“…Mutations in KCNQ2/3 cause the hyperexcitability of neurons, leading to epileptic phenotypes in neonatal epilepsy ( Jentsch, 2000 ; Watanabe et al, 2000 ), Huntington disease ( Cao et al, 2015 ), and the bulbar form of amyotrophic lateral sclerosis (ALS) ( Ghezzi et al, 2018 ). Opening KCNQ2/3 channels with retigabine protects motoneurons against the excitotoxicity characteristic of this form of ALS ( Ghezzi et al, 2018 ). Further, mutations in the enzymes responsible for PtdIns(4,5) P 2 synthesis are associated with Alzheimer disease ( Zhu et al, 2015 ), Parkinson disease ( Cao et al, 2017 ), and Friedreich ataxia ( Bayot et al, 2013 ), another rare neurodegenerative disease.…”

(‐)‐Epicatechin and the Colonic 2,3‐Dihydroxybenzoic Acid Metabolite Regulate Glucose Uptake, Glucose Production, and Improve Insulin Signaling in Renal NRK‐52E Cells

“…[43] In this line, a downregulation of IR and GSK3 has been reported in renal proximal tubules of diabetic rats, [23] and a protective role for GSK3 has been suggested in high glucose-treated renal proximal tubular cells. [44] Moreover, it has been shown that the SGLT-2-mediated transport involved the phosphorylation of SGLT-2 via IR signaling in HEK-293T cells transfected with SGLT-1 and -2, [45] and in diabetic patients the administration of empagliflozin (an SGLT-2 inhibitor) improved insulin secretion and peripheral glucose uptake through poorly defined mechanisms. [46] Indeed, the contribution of the insulinsensitizing effects to the overall beneficial effect of SGLT-2 inhibitory drugs needs to be examined.…”

Lysosomes as a therapeutic target

“…Dysfunction in the activity of KCNQ2/3 or altered levels of PtdIns(4,5)P2, due notably to genetic mutations, might also be involved in other neuropathies (for example, some forms of epilepsy, HD, PD, AD, ALS and Friedrich ataxia). Although further experiments are needed to validate the link discovered between hyperexcitability and cell death in NPC1 disease and other neurodegenerative diseases, small molecules such as retigabine, an anti convulsant drug that keeps KCNQ2/3 channels open, might rep resent important therapeutic tools 324,325 . Other channel opener ligands of KCNQ2/Q3 include ICA069673 and its derivatives.…”