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. 2019 Dec;21(4):454-466.
doi: 10.1007/s12017-019-08546-6. Epub 2019 May 27.

Blockade of Acid-Sensing Ion Channels Attenuates Recurrent Hypoglycemia-Induced Potentiation of Ischemic Brain Damage in Treated Diabetic Rats

Ashish K Rehni  1   2 , Vibha Shukla  1   2 , Miguel A Perez-Pinzon  1   2   3 , Kunjan R Dave  4   5   6
Affiliations

Blockade of Acid-Sensing Ion Channels Attenuates Recurrent Hypoglycemia-Induced Potentiation of Ischemic Brain Damage in Treated Diabetic Rats

Ashish K Rehni et al. Neuromolecular Med. 2019 Dec.

Abstract

Diabetes is a chronic metabolic disease and cerebral ischemia is a serious complication of diabetes. Anti-diabetic therapy mitigates this complication but increases the risk of exposure to recurrent hypoglycemia (RH). We showed previously that RH exposure increases ischemic brain damage in insulin-treated diabetic (ITD) rats. The present study evaluated the hypothesis that increased intra-ischemic acidosis in RH-exposed ITD rats leads to pronounced post-ischemic hypoperfusion via activation of acid-sensing (proton-gated) ion channels (ASICs). Streptozotocin-diabetic rats treated with insulin were considered ITD rats. ITD rats were exposed to RH for 5 days and were randomized into Psalmotoxin1 (PcTx1, ASIC1a inhibitor), APETx2 (ASIC3 inhibitor), or vehicle groups. Transient global cerebral ischemia was induced overnight after RH. Cerebral blood flow was measured using laser Doppler flowmetry. Ischemic brain injury in hippocampus was evaluated using histopathology. Post-ischemic hypoperfusion in RH-exposed rats was of greater extent than that in control rats. Inhibition of ASICs prevented RH-induced increase in the extent of post-ischemic hypoperfusion and ischemic brain injury. Since ASIC activation-induced store-operated calcium entry (SOCE) plays a role in vascular tone, next we tested if acidosis activates SOCE via activating ASICs in vascular smooth muscle cells (VSMCs). We observed that SOCE in VSMCs at lower pH is ASIC3 dependent. The results show the role of ASIC in post-ischemic hypoperfusion and increased ischemic damage in RH-exposed ITD rats. Understanding the pathways mediating exacerbated ischemic brain injury in RH-exposed ITD rats may help lower diabetic aggravation of ischemic brain damage.

Keywords: APETx2; Acidosis; Cerebral blood flow; Psalmotoxin1; Store-operated calcium entry; Vascular smooth muscle cells.

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Conflict of interest statement

Conflicts of interest:

The authors declare that they have no conflict of interest.

Figures

Figure 1.
Figure 1.
A) Synopsis of time course and experimental design of the study. All animals were subjected to cerebral ischemia and were euthanized at 7 days of reperfusion for histological analysis. B) Blood glucose levels after diabetes induction and insulin treatment, and C) Blood glucose levels before and during induction of hypoglycemia and after recovery. ITD + vehicle, ITD + RH + vehicle, ITD + RH + PcTx1, and ITD + RH + APETx2. * p<0.05 vs ITD + vehicle, † p<0.05 vs ITD + RH + vehicle and, ‡ p<0.05 ITD + RH + PcTx1.
Figure 2:
Figure 2:
The effect of prior RH exposure to ITD rats on ischemia-induced decrease in percentage change in cerebral blood flow. Percentage change in cerebral blood flow versus time curve of rats belonging to (1) ITD + RH + vehicle and (2) ITD + vehicle. * p<0.05 vs ITD + Vehicle.
Figure 3:
Figure 3:
The effect of PcTx1 and APETx2 on ischemia-induced decrease in percentage change in cerebral blood flow in ITD rats subjected to RH. Percentage change in cerebral blood flow versus time curve of rats belonging to ITD + RH + vehicle, ITD + RH + PcTx1, and ITD + RH + APETx2 groups. ITD + RH + vehicle trace is the same as in Figure 2. † p<0.05, ITD + RH + PcTx1 vs ITD + RH + vehicle and, ‡ p<0.05, ITD + RH + APETx2 vs ITD + RH + vehicle.
Figure 4:
Figure 4:
The effect of PcTx1 and APETx2 on RH-induced increase in ischemic damage in hippocampus of ITD rats. The numbers of normal neurons in CA1 hippocampus of rats belonging to the ITD + vehicle, ITD + RH + vehicle, ITD + RH + PcTx1, and ITD + RH + APETx2 groups are shown. * p<0.05 ITD + vehicle vs ITD + RH + vehicle, † p<0.05 ITD + RH + PcTx1 vs ITD + RH + vehicle, and ‡ p<0.05 ITD + RH + APETx2 vs ITD + RH + vehicle.
Figure 5:
Figure 5:
The role of (A) ASIC3, and (B) ASIC1a in acidosis-induced SOCE in VSMCs. SOCE at pH 7.4, 6.5, and 6.0 in presence of vehicle, APETx2, or PcTx1. *, p<0.05 vs respective vehicle control.
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