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Nonclassical Ion Channels and Ischemia
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
However, ASIC1 has little effect on neural expression in the hypothalamus during ischemia, and ASIC2 performs an up-regulated expression in the anti-apoptotic pathway with Bcl-2 and Bcl-W. So ASIC2 may take part in preventing apoptosis induced by ischemia, and the function of ASICs may vary in different pathologic region [34]. Moreover, the new discovery about potentiation of ASICs by quinine depends on the presence of the ASIC1a and ASIC2a subunits, and the amino acids in ASIC1a are involved in the modulation of ASICs by pHi [35]. In addition to regulation of pH, the antibodies or inhibitors need to block the transport of cations, including calcium, thereby preventing acid-induced cell death [36]. Hi1a, a disulfide-rich spider venom peptide, is a kind of ASIC1a inhibitor and partly inhibits ASIC1a activation in a pH-independent and slowly reversible way, so Hi1a might be a promising neuroprotective agent for the development of therapeutics to protect the brain from ischemic injury in humans [37]. The ASIC2b subunit is expressed in the brain, which overlaps ASIC1a, and its combination with ASIC1a in Xenopus oocytes results in novel proton-gated currents with properties distinct from ASIC1a homomeric channels. ASIC2b/1a heteromeric channels are inhibited by the nonselective potassium channel blockers tetraethylammonium and barium to play a role in acidosis-induced neuronal death [38,39]. Considering the diverse pharmacological profile, it will be still a long process for clinical application, but with the appropriate physical properties, they have the potential to be a suitable treatment for stroke.
Neuroprotective Effects of Psalmotoxin-1, an Acid-Sensing Ion Channel (ASIC) Inhibitor, in Ischemia Reperfusion in Mouse Eyes
Published in Current Eye Research, 2018
Adnan Dibas, Cameron Millar, Abraham Al-Farra, Thomas Yorio
In conclusion, ASIC1a and ASIC2 appear to be involved in I/R-induced RGC death. Our studies demonstrate that ASIC1 inhibition is an important factor in protecting the retina against injury in I/R. Pharmacologic inhibition of ASIC1 could be a therapeutic strategy to protect the retina against oxidative stress in I/R and possibly other conditions. The lack of ASIC2 selective blockers hinders efforts to assess the selective involvement of ASIC2 in I/R pathophysiology. However, it remains to be demonstrated if the selective ASIC1a/2 knockout in RGCs in animals makes them resistant to ischemic injury. This finding would provide strong evidence that ASIC1a and ASIC2 channels are essential players in the pathophysiology of IR injury in RGCs. Also, the underlying mechanisms of protection by psalmotoxin-1, a selective ASIC1a blocker, appear to involve an interaction of calpain and HSP70. This mechanism and additional detailed mechanisms mediating RGCs I/R injury need further elucidation.
Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents
Published in Current Eye Research, 2018
Dorota L. Stankowska, Brett H. Mueller, Hidehiro Oku, Tsunehiko Ikeda, Adnan Dibas
Blockade of ASIC1a channels with amiloride or psalmotoxin-1 reduced primary RGC death induced by hypoxia.30 Although ASIC-2 is expressed in RGCs, its role in RGCs is yet to be characterized.31 ASIC2 was minimally expressed in isolated rat primary RGCs (Dibas et al., unpublished observations). Although ASIC3 is detected in RGCs, it did not significantly contribute to ASIC currents recorded in cultured RGCs32 and therefore was not studied in the current manuscript. Similarly, ASIC4 function in tissues is not known as these channels do not respond to changes in pH.