Combination Treatment with Pulsed Electromagnetic Field and Hypothermia in Global Cerebral Ischemia

Approximately 1,500 people a day succumb to cardiac arrest (CA) in the United States. Unfortunately, despite regular updates of cardiopulmonary resuscitation guidelines, treatment outcomes of CA remain poor. CA and resuscitation induces transient global cerebral ischemia (GCI) and results in delayed loss of vulnerable hippocampal CA1 neurons, and subsequent severe cognitive deficits. This type of neuronal death is well accepted as mitochondria-mediated apoptosis. To date, therapeutic hypothermia (TH) is the only strategy that has been reported to benefit CA patients. However, a recent meta-analysis failed to find a strong beneficial effect upon survival or neurological outcome. In addition, given the multiple adverse effects resulting from HT, application of such a therapy is typically limited. Pulsed Electromagnetic Field (PEMF) is a century-old technology for the treatment by the cosmonauts during space explorations. The underlying mechanisms include PEMF's stimulation on energy metabolism and recovery and the induction of beneficial cellular changes involving circadian rhythm. PEMF therapy has been widely used in clinical studies. The mitochondrial inner membranes are enriched with metals (particularly Cu and Fe within cytochrome c oxidase (CCO)). We hypothesize that mitochondria can be recognized as electromagnetic coil or inductor, wherein the electric current is produced under PEMF to modulate mitochondrial function. This complementary action of PMEF to increase energy production while protect mitochondria, thereby maintaining healthy neuronal function, is of vital importance in adding to the therapeutic action of TH. Our overall hypothesis of this proposal is that PEMF, combined with an improved HT treatment, could synergistically protect against GCI-induced injury and alleviate cognitive impairment. To test these novel hypotheses, the following specific aims are proposed: Aim 1 will determine the effect of PEMF+HT combined treatment on reducing apoptotic neuronal loss and cognitive deficits induced by GCI. Aim 2 will establish the role and therapeutic efficacy of targeting mitochondrial dynamics and function for PEMF+HT neuroprotection. Aim 3 will determine the critical downstream effector mechanism for PEMF+HT neuroprotection involving the suppression of oxidative damage and reductions in reactive gliosis and inflammation. (AHA Program: Innovative Project Award)