Effects of Low-dose Lidocaine Administration on Recovery after transient Global Cerebral Ischemia

Abstract

Short periods of ischemia interrupt oxidative metabolism and can lead to irreversible brain damage. Ischemia is often a consequence of cardiac or neurologic surgery; some surgical procedures such as endarterectomies and cardiopulmonary bypass surgery are associated with a greater risk of cerebral ischemia and a large percentage of patients experience cognitive dysfunction after undergoing cardiac surgery. Prophylactic pharmacological neuroprotective interventions would be beneficial for patients undergoing surgery to prevent or minimize brain damage due to ischemia. In my thesis I examined the effects of 2 antiarrhythmic doses of lidocaine on rats in a model of transient global cerebral ischemia. In this model the occlusion of both common carotid arteries combined with hypotension for 10 minutes induced mainly a neuronal loss in the CA1 region of the hippocampus; it did not cause neuronal damage in the CA3 region, the dentate gyrus or the basomedial amygdala. Lidocaine administration given 30 minutes before, during and 60 minutes after 10 minutes of ischemia increased hippocampal CA1 neuronal survival 7 days after global cerebral ischemia and this increased neuronal survival was maintained for 28 days. Lidocaine not only increased hippocampal CA1 neuronal survival, but also preserved behavioral function associated with this region. Rats, which received an antiarrhythmic dose of lidocaine (either 2 mg/kg or 4 mg/kg) demonstrated better cognitive function than rats receiving no lidocaine. There was no significant difference in the learning behavior of rats receiving the two different antiarrhythmic doses of lidocaine. Since brain damage was detected mainly in the CA1 region, I demonstrated that this region is important for learning the active place avoidance task. There was a strong inverse correlation between the number of surviving CA1 neurons and the number of entrances into the shock zone during the last trial of the place avoidance task. Thus, a clinical antiarrhythmic dose of lidocaine increased the number of surviving neurons and preserved their function; this indicates that lidocaine is a good candidate for clinical brain protection.