**2. Pathophysiology of ischemic stroke**

There is a decrease in blood supply which causes a reduction in the amount of ATP in acute ischemic stroke. This condition leads to anaerobic metabolism with the result of lactic acid. The decrease in blood flow also causes an imbalance in ion homeostasis in neuronal cells and leads ischemic cascade that will be followed by multimodal and multicellular mechanisms that cause neuronal cell death [6, 21].

Severe cerebral ischemia also causes loss of energy stores, ion imbalance, the release of excitatory neurotransmitters, and inhibition of glutamate re-uptake [6, 38]. In addition, glutamate will bind to NMDA and AMPA receptors which will cause calcium influx [1, 39]. This calcium overload will cause the stimulation of phospholipases and proteases that will degrade membranes and proteins [38]. Glutamate receptors also cause sodium and water influx and cause cell swelling, edema, and shrinkage of the extracellular space [6, 40]. In addition, the influx of excessive calcium causes the activation of catabolic processes that will activate proteases, lipases, and nucleases [1, 6, 39].

High calcium, sodium, and ADP levels in ischemic cells will stimulate the production of oxygen radicals in the mitochondria, accompanied by the production of free radicals from other sources such as prostaglandins and the degradation of hypoxanthine [39, 41]. These reactive oxygen species (ROS) will damage membrane lipids, proteins, nucleic acids, and carbohydrates [23, 42, 43]. Furthermore, these

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**Figure 1.** *Ischemic cascade in stroke [47].*

ROS are toxic because their basal levels are related to the upregulation of antioxidant enzymes such as SOD, catalase, and glutathione and the scavenger mechanism (α-tocopherol, vitamin C), which is too slow to respond to the production of these ROS [6, 39]. Along with the above mechanism, there will also be a process known as Cortical spreading depression (CSD) which is the depolarization of neurons and glial cells that will spread to surrounding cells at a speed of 2−6 mm/minute [44]. CSD is characterized by an almost complete breakdown of the ion gradient associated with volume shrinkage, loss of electrical activity, swelling of neuron cells, and distortion of dendrites [43, 45]. CSD occurs when the extracellular K+ level exceeds a critical threshold [43]. This CSD wave in ischemic conditions will reach the peri-ischemic area and expand the infarct area (**Figure 1**) [6, 46, 47].
