Basic Mechanisms in Cerebral Hypoxia and Stroke: Background, review and conclusions

Abstract

This chapter reviews material presented at the Symposium and also pertinent literature, seeking answers to three sets of problems: 1. the mechanism of the reversible blockade of synapses in the early stages of hypoxia and ischemia of the central nervous system (CNS); 2. the irreversible injury of neurons during more prolonged severe hypoxia or ischemia; and 3. the delayed cell death that occurs after reoxygenation or reperfusion of previously hypoxic or ischemic brain tissue. During the reversible phase pre- and postsynaptic factors interact to block all synapses, excitatory as well as inhibitory. On the presynaptic side voltage-dependent calcium channels appear blocked in hypoxic presynaptic terminals. Postsynaptically many though not all types of neurons become hyperpolarized, which raises their firing threshold. Hyperpolarization is due to increased K+ −conductance. Acidosis may play a part by raising the threshold of postsynaptic neurons. Cells may be irreversibly injured through several different pathologic processes. Elevation of free intracellular calcium ([Ca2+]i) above a critical level for a critical length of time appears to trigger, or at least hasten, some of these injurious processes. The elevation of [Ca2+]i during severe hypoxia is due to the explosive, spreading depression (SD)-like, depolarization of neurons. Factors contributing to the delayed post-hypoxic or post-ischemic cell death may include excitatory amino acid (EAA)-induced firing, reactive hyperemia and/or hypoxic damage to blood vessels resulting in vasogenic edema and secondary vascular failure, aggravated by lactic acidosis. In the striatum dopamine is required for the damage that EAAs cause in the hippocampus. Adenosine and noradrenaline appear to be endogenous prophylactic agents protecting CNS neurons. Opinions are divided concerning the role of free radicals and peroxide in cerebral ischemia.