Abstract
Ischemic stroke is recognized as one of the leading causes of adult disability, morbidity, and death worldwide. Following stroke, acute neuronal excitotoxicity can lead to many deleterious consequences, one of which is the dysregulation of intracellular calcium ultimately culminating in cell death. However, to develop neuroprotective treatments that target neuronal excitotoxicity, it is essential to know the therapeutic time window for intervention following an ischemic event. To address this question, the current study aimed to characterize the magnitude and temporal progression of neuronal intracellular calcium observed following distal middle cerebral artery occlusion (dMCAO) in mice. Using the calcium fluorescence indicator, GCaMP, we tracked neuronal population response in freely moving animals immediately following dMCAO in both the core infarct and peri-infarct regions. Our results demonstrate that calcium excitotoxicity following artery occlusion can be generally characterized by two phases: a transient increase in activity that lasts tens of minutes, followed by a long, slow sustained increase in fluorescence signal. The first phase is primarily thought to represent neuronal hyperexcitability, defining our therapeutic window, while the second may represent gradual cell death. Importantly, we show that the level of intracellular calcium following artery occlusion correlated with the infarct size at 24 h demonstrating a direct connection between excitotoxicity and cell death in our stroke model. In addition, we show that administration of the NMDA antagonist MK-801 resulted in both a decrease in calcium signal and a subsequent reduction in the infarct size. Altogether, this study represents the first demonstration in freely moving animals characterizing the temporal progression of toxic calcium signaling following artery occlusion. In addition, these results define a critical time window for neuroprotective therapeutic intervention in mice.
Highlights
Stroke is both the second leading cause of death globally (Guzik and Bushnell, 2017) and the number one cause of adult long-term disability in the United States
The goal of the current study was to determine the role of intracellular calcium in cell death induced by an ischemic event
The initial recording location was chosen based on calibration experiments in the distal middle cerebral artery occlusion model, demonstrating that this region of the cortex resides in the infarct core
Summary
Stroke is both the second leading cause of death globally (Guzik and Bushnell, 2017) and the number one cause of adult long-term disability in the United States. The World Health Organization estimates that 15 million strokes occur annually, leading to 5 million deaths and 5 million permanently disabled people. While advancements in preventative treatments, such as Excitotoxic Calcium Following dMCAO statins, antihypertensives, and ACE inhibitors, have improved risk management and contributed to the reduction in rates of stroke (Guzik and Bushnell, 2017), they have done little to abate the severity of subsequent impairments. There remains great potential for the development of neuroprotective treatments which target pathological cellular processes initiated by stroke in order to further improve clinical outcomes
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