Mechanisms that Result in Damage During and Following Cerebral Ischemia

Abstract

JUURLINK, B.H.J. AND M.I. SWEENEY. Mechanisms that result in damage during and following cerebral ischemia. NEUROSCI BIOBEHAV REV 21 (2)121–128, 1997.—The destructive mechanisms associated with stroke are initiated by activation of glutamate receptors resulting in elevated intracellular Ca 2+ and reactive oxygen species (ROS) formation. Three major approaches have been investigated to ameliorate ischemia-induced brain damage: (i) interfering with the excitatory action of glutamate; (ii) preventing intracellular accumulation of Ca 2+; and (iii) preventing the destructive actions of reactive oxygen species (ROS). Interference with glutamate action can be achieved by: (i) facilitating mechanisms that maintain membrane potentials; (ii) blocking glutamate receptors; and (iii) inhibiting transmitter glutamate synthesis. Prevention of intracellular Ca 2+ accumulation may be achieved by: (i) blocking Ca 2+ channels; and (ii) facilitating endogenous Ca 2+ homeostatic mechanisms. Destructive actions of ROS can be minimized by: (i) administration of ROS-scavenging drugs; (ii) upregulating endogenous ROS-scavenging mechanisms; and (iii) preventing leukocyte invasion of the affected brain tissue. Current therapies that have arisen out of animal experimentation have not met expectations due, mainly to actions of the drugs outside the lesion site. For future research, we suggest: (i) exploring the ability of compromised blood-brain barrier to specifically target therapeutic drugs to the site of lesion; (ii) preventing inflammation by preventing leukocyte infiltration; (iii) identifying signal transduction mechanisms that upregulate neuronal Ca 2+ homeostatic mechanisms; and (iv) identifying means that will upregulate endogenous ROS-scavenging mechanisms. Past success in reducing the incidence of stroke has been due, to a great extent, to changes to lifestyle behavioural patterns. We predict that future success in decreasing the morbidity associated with stroke will, to a certain extent, also be due to long-term behavioural changes. It seems possible that simple dietary changes may enable the CNS to be better able to cope with ischemic insults by augmenting ROS-scavenging mechanisms, down-regulating pro-inflammatory responses and increasing Ca 2+-homeostatic mechanisms. © 1997 Elsevier Science Ltd. All rights reserved.