Neuroprotection in cerebral ischemia

The brain exhibits, in comparison with other organs, a high sensitivity to a critical reduction in blood flow. A few minutes after cessation of cerebral blood flow the tissue is depleted of primary and secondary energy compounds (glycogen, glucose and high energy phosphates such as adenosine triphosphate and phosphocreatine) due to the low energy reserves of the brain (34, 56). Such a situation occurs during cardiac arrest when blood flow to the brain stops completely. The occlusion of an intracerebral artery, in contrast, may cause a mild or severe reduction or even cessation of cerebral blood flow. The extent of this disturbance depends on the quality of collateral circulation and the local perfusion pressure. Whether these changes are critical for the survival of neurons depends on the duration and density of blood flow reduction. Different functions of neurons are affected at different threshold levels of cerebral blood flow: e.g., spontaneous electrical activity is already impaired when blood flow is reduced to about 60 % of control (26, 42), aerobic glucose metabolism is disturbed when blood flow is reduced to below 35 % of control (50), and at flow levels below about 20% of control the tissue is depleted of ATP (50), the electrolyte homeostasis is disturbed (8–10), and cell death ensues unless blood flow is reestablished. Interestingly, protein synthesis is suppressed already at blood flow levels of about 55 to 60 % of control, i.e., at considerably higher flow levels than those below which disturbances in energy metabolism take place (38).