**3. Ischemic stroke and oxidative stress**

Uncontrolled oxidative stress, an imbalance between pro-oxidant and antioxidant levels that support pro-oxidants, can cause cell, tissue, and organ injury [22]. High Reactive Oxygen Species (ROS) are known to cause direct damage to lipids [43, 48]. The primary sources of endogenous ROS production are mitochondria, plasma membranes, endoplasmic reticulum, and peroxisomes through various mechanisms, including enzymatic reactions and/or autoxidation of several compounds, such as catecholamines and hydroquinones. In addition, different exogenous stimuli, such as ionizing radiation, ultraviolet light, tobacco smoke, pathogenic infections, environmental toxins, and exposure to herbicides/insecticides, are sources of ROS production in vivo [49].

The two most common ROS affecting lipids are hydroxyl radicals (HO) and hydroperoxyl (HO2). The hydroxyl radical (HO) is a small, active, water-soluble, and chemically reactive oxygen species. This short-lived molecule can be produced from O2 in cellular metabolism under various stress conditions [48, 50]. These radicals can be neutralized or even attack other biomolecules in the cell. Hydroxyl radicals cause

oxidative damage to cells because they are not determined by how much they attack biomolecules and are involved in cellular disorders such as neurodegeneration, cardiovascular disease, and cancer. It is generally assumed that HO in biological systems is formed through a redox reaction by the Fenton reaction; in this reaction, iron (Fe2+) reacts with hydrogen peroxide (H2O2), and the Haber−Weiss reaction results in the production of Fe2+ when superoxide reacts with ferrous iron (Fe3+). In addition to the iron redox cycle described above, several other transition metals, including Cu, Ni, and Co, can be responsible for forming HO in living cells [22, 48].

Heme oxygenase (HO) is a crucial enzyme of Heme metabolism. The HO-1 isoform is expressed mainly in vascular structures but is very low in normal CNS and can be induced after brain tissue injury. HO-1 is strongly induced after ischemia and will be overexpressed and play a protective role against ischemia after permanent vascular occlusion [6, 51–55].

An initial study to determine the role of HO-1 in ischemic conditions found that HO-1 will significantly reduce infarct volume. Mice that do not have HO-1 will have a larger infarct volume than the wild type [56–58]. Several materials induce HO-1 with promising results in preclinical studies. Some natural ingredients that activate the Nrf-HO-1 pathway, such as dimethyl fumarate, ginkgo biloba, curcumin, polyphenols, and terpenoids, will increase the neuroprotective effect on stroke models [56, 59, 60].
