How Do Strokes Cause Brain Damage?

 by Hamish Orr

Scan of brain following a stroke

With stroke being a leading cause of death across the globe, in order to better understand how to treat strokes we need to understand why they are so devastating. In ischemic stroke, a blockage in a blood vessel leads to an area of the brain being deprived of oxygen and other vital molecules such as glucose, which is needed for carrying out energy dependent reactions. We call this area where the cells have died in the brain the infarct area. I will be talking about ischemic stroke, which accounts for ~80% of strokes worldwide. Understanding the cell death mechanisms is vital for finding novel stroke treatments. 

During ischemic stroke, the blood supply to brain tissue is deprived. The result of this is a lack of glucose and oxygen, both of which are needed in the cell mitochondria for the synthesis of ATP. ATP is needed in cells for almost all energy dependent processes, such as ionic pumps in the cell membrane. The result of this is a drop in the transmembrane potassium gradient (which is maintained by ATP reliant ion channels) and causes intracellular sodium and calcium ion levels to rise. This is called spreading depolarisation. This depolarisation causes glutamate transporters to reverse their direction into the extracellular space. This leads to activation of the neuronal postsynaptic ligand-dependent calcium channels such as the NMDA receptor. (A calcium channel that is controlled by the attachment of glutamate). The higher levels of glutamate causes an influx of calcium into the neurons.

High calcium levels in the cell triggers a number of mechanisms leading to cell necrosis through calcium sensing enzymes which are able to digest and breakdown the proteins and lipids of the cell, including the nuclear material. The higher calcium levels also inhibit the mitochondria preventing them from producing any energy themselves and can trigger programmed cell death (apoptosis) through the intrinsic pathway. ( a complicated biochemical pathway leading to cell death). 

Brain Ischemia produces oxygen free radicals which react with a number of cellular and extracellular structures which are vital for the normal functioning of the brain and its surrounding structures. If these free radicals damage blood vessel endothelial tissue they can damage the ability to vasodilate and vasoconstrict. Reducing the control of blood flow in the brain. Free radicals are also able to trigger cell death by redox signalling pathways. 

Many of the treatments for strokes that we have today are based on the principles from understanding how strokes affect brain tissue, further understanding these will increase the potential for treatment in the future.