Genetic or Pharmacological Ablation of Acid-Sensing Ion Channel 1a (ASIC1a) Is Not Neuroprotective in a Mouse Model of Spinal Cord Injury

Hi1a Improves Sensorimotor Deficit following Endothelin-1-Induced Stroke in Rats but Does Not Improve Functional Outcomes following Filament-Induced Stroke in Mice

“…In addition, previous studies examining the therapeutic effects of inhibiting ASIC1a have shown promising results in different disease contexts, including myocardial infarction, stroke, spinal cord injury, and renal ischemia-reperfusion injury, in both rats and mice, with Hi1a administered i.v. in myocardial infarction, whereas ASIC1a inhibitors were given intracerebroventricularly or intrathecally when assessing CNS indications. ,,,,, However, not all studies have observed a therapeutic effect with ASIC1a inhibition, since inhibiting ASIC1a using whole PcTx1 venom resulted in decreased infarct volume following stroke when administered intracerebroventricularly but not if administered intravenously, and other studies reported worse disease outcomes with ASIC1a deletion or inhibition in spinal cord injury. , In vitro, ASIC1a KO spinal cord slices displayed greater damage compared to WT mice, and nonselective ASIC1a inhibitors worsened neuronal loss . Similarly, in vivo, ASIC1a KO mice displayed worse functional outcomes and a larger lesion after spinal cord injury, although intravenous treatment with Hi1a did not influence functional outcomes .…”

“…in myocardial infarction, whereas ASIC1a inhibitors were given intracerebroventricularly or intrathecally when assessing CNS indications. ,,,,, However, not all studies have observed a therapeutic effect with ASIC1a inhibition, since inhibiting ASIC1a using whole PcTx1 venom resulted in decreased infarct volume following stroke when administered intracerebroventricularly but not if administered intravenously, and other studies reported worse disease outcomes with ASIC1a deletion or inhibition in spinal cord injury. , In vitro, ASIC1a KO spinal cord slices displayed greater damage compared to WT mice, and nonselective ASIC1a inhibitors worsened neuronal loss . Similarly, in vivo, ASIC1a KO mice displayed worse functional outcomes and a larger lesion after spinal cord injury, although intravenous treatment with Hi1a did not influence functional outcomes . Thus, the results of the current study, where intravenous administration of Hi1a was able to improve some functional outcomes but did not consistently improve all stroke outcomes across both models may be due to a loss of drug efficacy when administered systemically compared to centrally.…”

“…For example, ASIC1a knockout (KO) mice have a marginally worse hindlimb function and marginally increased lesion size compared to wild-type (WT) mice after spinal cord injury, in contrast to the protective effects of ASIC1 KO observed in stroke . Furthermore, treatment with Hi1a intravenously 1 h postspinal cord injury resulted in no change in hindlimb function or neuronal loss . This highlights the fact that further investigation is required to elucidate the mechanistic role of ASIC1a in stroke and whether Hi1a might be a viable therapeutic.…”

“…Furthermore, the protective effects of Hi1a were not blunted when treatment was delayed up to 8 h poststroke, which is a much longer therapeutic window than the current gold-standard treatment for stroke. , Nevertheless, there is some ambiguity in the neuroprotective effect of blunting ASIC1a signaling. For example, ASIC1a knockout (KO) mice have a marginally worse hindlimb function and marginally increased lesion size compared to wild-type (WT) mice after spinal cord injury, in contrast to the protective effects of ASIC1 KO observed in stroke . Furthermore, treatment with Hi1a intravenously 1 h postspinal cord injury resulted in no change in hindlimb function or neuronal loss .…”