Mechanisms of Brain Damage Following Focal Cerebral Ischemia: Changes in Ion Homeostasis and the Importance of Free Radical Formation

Abstract: In this thesis mechanisms of neuronal damage were investigated in an experimental stroke model i.e focal ischemia. The influence of SD-induced calcium transients on neuronal damage were studied in animals with reduced energy supply. The influence of bioenergetic failure on K+e concentration and Ca2+e homeostasis were also investigated in transient focal ischemia. Moreover, the free radical formation was assessed in focal ischemia/reperfusion, as was the scavenging effect of PBN. Animals with a reduction in energy supply showed prolonged SD-induced calcium transients. These prolonged calcium lead occasionally to mild neuronal damage. Similar SDs are recorded in the ischemic penumbra in focal ischemia, and are probably caused by decreased energy supply. The second bioenrgetic failure in the ischemic focus as recorded in K+e concentration increase occurs at 4-6 h of reperfusion after 2 h MCAO. Treatment with PBN delays or prevent the late increase in K+e level. Recordings of Ca2+e and total calcium content in focal ischemia /reperfusion showed disturbed calcium homeostasis in the cortical core and penumbral zone. Free radical formation were enhanced in the recirculation phase after 2 h MCAO, and treatment with PBN did not reduce these free radical formation. It is concluded that the cellular calcium load in energy compromised brain tissue is tolerated without extensive neuronal damage. This indicates that other mechanisms than only exaggerated calcium transients lead to development of the infarct in focal ischemia. Recordings of Ca2+e and total calcium content in focal ischemia /reperfusion suggest that the tissue is irreversibly damaged after 6 h of recirculation. The lack of an effect of BPN treatment despite its neuroprotective effect may suggest that PBN is effective in small compartments e.g the endothelium.