Abstract
Acidosis in the brain plays an important role in neuronal injury and is a common feature of several neurological diseases. It has been reported that the sodium–hydrogen exchanger-1 (NHE-1) is a key mediator of acidosis-induced neuronal injury. It modulates the concentration of intra- and extra-cellular sodium and hydrogen ions. During the ischemic state, excessive sodium ions enter neurons and inappropriately activate the sodium–calcium exchanger (NCX). Zinc can also enter neurons through voltage-gated calcium channels and NCX. Here, we tested the hypothesis that zinc enters the intracellular space through NCX and the subsequent zinc accumulation induces neuronal cell death after global cerebral ischemia (GCI). Thus, we conducted the present study to confirm whether inhibition of NHE-1 by amiloride attenuates zinc accumulation and subsequent hippocampus neuronal death following GCI. Mice were subjected to GCI by bilateral common carotid artery (BCCA) occlusion for 30 min, followed by restoration of blood flow and resuscitation. Amiloride (10 mg/kg, intraperitoneally (i.p.)) was immediately injected, which reduced zinc accumulation and neuronal death after GCI. Therefore, the present study demonstrates that amiloride attenuates GCI-induced neuronal injury, likely via the prevention of intracellular zinc accumulation. Consequently, we suggest that amiloride may have a high therapeutic potential for the prevention of GCI-induced neuronal death.
Highlights
Ischemic stroke is one of the most severe cerebral pathological conditions and can manifest via a number of clinical symptoms such as problems in cognition, dizziness, or loss of vision on one side of the visual field [1]
To investigate whether amiloride has neuroprotective effects after global cerebral ischemia (GCI)-induced hippocampus neuronal death, experimental mice were immediately intraperitoneally injected with amiloride (10 mg/kg) after GCI
Amiloride-administered groups displayed a reduction of Fluoro-Jade B (FJB) (+) neurons of approximately 64% in the Sub (GCI-vehicle, 76.9 ± 8.4; GCI-amiloride, 27.2 ± 10.5), 84% in the cornus ammonis 1 (CA1) (GCI-vehicle, 126.2 ± 18.5; GCI-amiloride, 19.5 ± 17.6), 83% in the CA2 (GCI-vehicle, 125.3 ± 22; GCI-amiloride, 20.7 ± 17.9), and 50% in the CA3 (GCI-vehicle, 220.6 ± 30.3; GCI-amiloride, 109.5 ± 29) regions compared with the vehicle-treated groups
Summary
Ischemic stroke is one of the most severe cerebral pathological conditions and can manifest via a number of clinical symptoms such as problems in cognition, dizziness, or loss of vision on one side of the visual field [1]. The development of ischemic conditions in the brain is very dangerous because only a momentary lack of adequate blood flow to the brain can lead to oxygen deprivation, insufficient nutrient provision, and potentially irreversible neural injury [2,3,4]. There are two basic types of ischemic injury: global and focal ischemia. Global ischemia impacts wide areas of brain tissue at once due to the blockage of blood flow to an entire region of the brain, while focal ischemia is limited to a specific region of the brain tissue and is due to the more local disruption of cerebral blood flow. Ischemia-induced brain damage can be recovered by early reperfusion, but this reperfusion process can initiate independent cascades of cell death pathways such as zinc release, microglial activation, and blood–brain barrier (BBB) disruption [5]. If the interruption of blood circulation happens for an extended period prior to the restoration of circulation, brain damage can be permanent
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