Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

Abstract

Progressive neuronal death is the key pathogenic event leading to clinical symptoms in neurodegenerative disorders (NDDs). Neuroprotective treatments are virtually unavailable, partly because of the marked internal heterogeneity of the mechanisms underlying pathology. Targeted neuroprotection would require deep mechanistic knowledge across the entire aetiological spectrum of each NDD and the development of tailored treatments. Although ideal, this strategy appears challenging, as it would require a degree of characterization of both the disease and the patient that is currently unavailable. The alternate strategy is to search for commonalities across molecularly distinct NDD forms and exploit these for the development of drugs with broad-spectrum efficacy. In this view, mounting evidence points to ionic mechanisms (IMs) as targets with potential therapeutic efficacy across distinct NDD subtypes. The scope of this review is to present clinical and preclinical evidence supporting the link between disruption of IMs and neuronal death in specific NDDs and to critically revise past and ongoing attempts of harnessing IMs for the development of neuroprotective treatments.

Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions

“…KATP channels have a well-known physiopathological role in regulating vascular tone, cardiac excitability, and neuronal firing. The insulin release from the pancreas, muscle fatigue and pain, and neurodegeneration [18][19][20][21][22][23][24][25] are also involved in non-familial diseases and in rare KATP channelopathies [21,26] KATP channels are regulated by intracellular nucleotides such as ATP and ADP that finely tune the KATP channel's activity in response to metabolic stress. Interestingly, ZOL is a nitrogen-containing bis-phonate ligand consisting of two phosphate groups and one imidazole group that may overlap with the phosphate group and the purine/ribose ring of these nucleotides.…”

“…KATP channels have a well-known physiopathological role in regulating vascular tone, cardiac excitability, and neuronal firing. The insulin release from the pancreas, muscle fatigue and pain, and neurodegeneration [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] are also involved in non-familial diseases and in rare KATP channelopathies [ 21 , 26 ]…”

The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin

“…Considering that sub-micromolar concentrations of ambient glutamate tonically activate NMDARs in select cell types and/or brain regions, physiologically and pathologically [ 54 , 56 , 57 , 58 , 59 ], our observed QA potentiating effect of sub-saturating L-glutamate concentrations may help explain the quinolinic-induced neurotoxicity by GluN1-GluN2A, GluN1-GluN2B, or GluN1-GluN2D NMDAR subtype hyperactivity ( Figure 2 ). With regard to the GluN1-GluN2D subtypes, potentiation was evident only at 0.04 μM and not at 0.2 μM, suggesting that QA-induced calcium dysregulation at this receptor subtype may be preferentially relevant in the presence of very low ambient glutamate.…”

“…The distribution of NMDAR subtypes is genetically, regionally, and developmentally determined [ 53 ]. Diseases may be triggered, maintained, or worsened by dysregulated calcium currents through NMDARs [ 54 ], including peripheral NMDARs [ 55 ]. The effect of QA on NMDAR in this intracellular FLIPR calcium assay confirms and extends the data obtained by electrophysiological recordings in transduced oocytes expressing heterodimeric NMDARs [ 30 , 31 , 32 , 33 , 34 ].…”

Current clinical application of dantrolene sodium

“…Ca 2+ signaling is crucial for maintaining normal neuronal functions such as membrane excitability, neurotransmitter release, cellular growth, differentiation, and cell death. DS is also an effective drug for disrupting Ca 2+ homeostasis, as reported in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia [ 5 , 79 , 80 ]. Binding of DS to RyRs in the brain may protect neurons from disruptions in Ca 2+ homeostasis [ 79 - 84 ].…”