Stroke is the most common cardiovascular disease which causes neurological impairment. Cardiovascular diseases, such as atherosclerosis and arteriosclerosis, are the most common causes of stroke. Nitric oxide (NO) was discovered to be a signaling molecule in 1998 by Nobel Prize winners Robert F Furchgott, Ferid Murad and Louis J Ignarro. The odorless and colorless gas is considered to be toxic and is a common air pollutant, but further research has proven NO to have an essential role in recovery from and inhibition of stroke. (The Nobel Prize Organization, 1998)
Recognize stroke symptoms and save a life. (Illustration: American Heart Association)
Stroke
100 million people have contracted a stroke during their life, whereas the death rate of the disease is six and a half-million deaths annually: stroke is the leading cause of disability and the second leading cause of death in the world. Every year, 12 million new people suffer from strokes and an additional 25% of people above the age of 25 suffer from a stroke. (WSO): Global Stroke Fact Sheet 2022)
Ischemic and hemorrhagic stroke are the two main divisions of strokes. Hemorrhagic stroke has to do with the bursting of blood vessels in the vicinity of the brain whereas ischemic stroke is caused by plaque buildup. Oxford Dictionary’s definition of ischemia is “the situation when the supply of blood to an organ or part of the body, especially the heart muscles, is less than is needed” (Oxford Learner's Dictionaries, 2024). In terms of a stroke, ischemia is caused by a blood clot — a buildup of plaque blocking the blood flow and consequently the transportation of oxygen. Arteriosclerosis is a common precursor to ischemic stroke and is the process in which the blood vessels become stiff or thick. This can impede blood flow through the affected arteries to organs and tissues. Atherosclerosis is a type of arteriosclerosis, where the blood vessels build up plaque on the artery walls. Plaque is typically made up of fats and cholesterol. When an artery is clogged blood flow is impeded and transportation of oxygen, via the affected artery, is restricted. At low oxygen levels neurons cannot function properly and will eventually die, oftentimes leading to irreparable brain damage and a loss of certain physiological functions. Atherosclerosis could be treated through vasodilation induced by nitric oxide.(Strand et al. 2019)
Nitric oxide
Nitric oxide is a diatomic gas molecule whose production in the endothelium is impeded by atherosclerosis. NO produced in the endothelium spreads throughout the membranes of smooth muscle cells, relaxing contractions of the tissue, ultimately resulting in vasodilation. This regulates the blood pressure and prevents the formation of thrombi, blood clots that form in the veins, arteries or the heart. Therefore, impairment of the enzyme: endothelial nitric oxide synthase (eNOS), will result in the respective inverse effects, increasing risks of future strokes. Activation of eNOS increases the concentration of NO that through a chain reaction, decreases the chance of an ischemic stroke, as seen in Figure 1.
Figure 1. eNOS’ prevention of cardiovascular disease and stroke.
‘Ischemic penumbra refers to a rim of tissue lying just outside the core ischemic region (area most severely damaged by stroke or ischemic event)’ (Genova, 2011). Studies have shown that the ischemic penumbra can be decreased by inhibition of neuronal nitric oxide synthases (nNOS) and induced nitric oxide synthases (iNOS) after an ischemic stroke. Hence, research to target these synthases is ongoing. The current obstacle is the structural similarity of the isozymes, as eNOS is essential to assist neuroprotective recovery. Inhibition of iNOS and eNOS has been supported to be beneficial for recovery through animal studies. Though, differences do occur between the synthases which enables the possibility of finding synthase specific inhibitors of nitric oxide synthases. (Chen et al. 2017)
The use of statins, inhibition of phosphodiesterase and rho-kinases all upregulate eNOS, whereas drugs tested to inhibit iNOS and nNOS mainly inhibit those, though not exclusively. The non-specificity of NOS-inhibition alongside the side effects of statins, inhibition of phosphodiesterase and rho-kinases is the main reason as to why they are not used clinically, as these aspects may worsen rather than improve the state of a stroke patient. Furthermore, there is synergistic network pharmacology, which entails the use of multiple drugs that together work to treat a disease. There have been successful trials with the nNOS-inhibitor L-NAME and an NADPH+ oxidase type 4 (NOX4) inhibitor. Together they managed to decrease cell death, infarct size and protect neuromotor function, with more, in vivo and in vitro. Therefore, research is still ongoing and it is through academic and financial support that we can support the saving of many lives. At https://www.hjarnfonden.se/ you can find articles about stroke, neurological impairments and ongoing research. It is also an opportunity to support medical research by donating a sum or supporting them in other ways.
Thank you!
Nikolaj Lopez and Iris Opander