MECHANISMS THAT RESULT IN DAMAGE DURING AND FOLLOWING CEREBRAL-ISCHEMIA

The destructive mechanisms associated with stroke are initiated by act ivation of glutamate receptors resulting in elevated intracellular Ca2 + 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 Ca2+; and (iii) preventing the destruct ive actions of reactive oxygen species (ROS). Interference with glutam ate action can be achieved by: (i) facilitating mechanisms that mainta in membrane potentials; (ii) blocking glutamate receptors; and (iii) i nhibiting transmitter glutamate synthesis. Prevention of intracellular Ca2+ accumulation may be achieved by: (i) blocking Ca2+ channels; and (ii) facilitating endogenous Ca2+ homeostatic mechanisms. Destructive actions of ROS can be minimized by: (i) administration of ROS-scaveng ing drugs; (ii) upregulating endogenous ROS-scavenging mechanisms; and (iii) preventing leukocyte invasion of the affected brain tissue. Cur rent therapies that have arisen out of animal experimentation have not met expectations due, mainly to actions of the drugs outside the lesi on site. For future research, we suggest: (i) exploring the ability of compromised blood-brain barrier to specifically target therapeutic dr ugs to the site of lesion; (ii) preventing inflammation by preventing leukocyte infiltration; (iii) identifying signal transduction mechanis ms that upregulate neuronal Ca2+ homeostatic mechanisms; and (iv) iden tifying means that will upregulate endogenous ROS-scavenging mechanism s. Past success in reducing the incidence of stroke has been due, to a great extent, to changes to lifestyle behavioural patterns. We predic t that future success in decreasing the morbidity associated with stro ke will, to a certain extent, also be due to long-term behavioural cha nges. It seems possible that simple dietary changes may enable the CNS to be better able to cope with ischemic insults by augmenting ROS-sca venging mechanisms, down-regulating pro-inflammatory responses and inc reasing Ca2+-homeostatic mechanisms. (C) 1997 Elsevier Science Ltd. Al l rights reserved.