Neuroprotective mechanisms elucidated by molecular biological methods
Background: During the last decades outcome after myocardial infarction has improved tremendously. The same cannot be stated about cardiac arrest. In spite of intense research and training of medical staff only about five percentage of the patients brought in to the emergency rooms after witnessed cardiac arrest survive, and out of those surviving many have neurological deficits. However, not many of the patients survive in neurological vegetative states, the main problem being that those being hurt by a ischaemic cerebral injury die within weeks. When the National Institute of Health some years ago came out with a statement on this problem, it was obvious that no better outcome than in the 1960’s could be expected now unless substantial progress in the field of ischaemic neurological protection could be achieved. After this statement was made public, however, a significant improvement has been published when two different groups independently have found that therapeutic hypothermia in the range 34-32 º C during 24 hours after resuscitation from a cardiac arrest improved survival and neurological outcome. This has changed the chances to find also pharmacological agents that could have the same or even better effects in this situation. In addition it is possible to make valid comparisons between effects of hypothermia and suggested pharmacological agents for screening purposes. A few hundred of such pharmacological compounds have already been tested in different experimental models, and at least one agent has been brought a stage 2 controlled clinical trial, where it unfortunately failed. This knowledge makes it possible both to make comparisons with a successful method as well as with a failing one. All these facts, also including new evidence of why artificial circulation during cardiopulmonary resuscitation (CPR) more or less always is insufficient and that there is no single receptor or molecular mechanism that, when used, elicits efficient neuroprotective mechanisms, has resulted in a knowledge background that seems to indicate that it seems highly probable that efficient neuroprotection after ischaemia and reperfusion is indeed possible.
Action taken: Since a decade we have had an experimental well-functioning model of cardiac arrest in piglets. Gradually the arrest period has been possible to increase. Presently we use a cardiac arrest of 21-23 min including eight minuts CPR, and a follow-up period of at least three hours. After this the animal is sacrificed and the heart and the brain are harvested within a minute. The molecular biology of especially the brain is studied by microarrays, quantitative PCR and protein staining methods.
Considerable evidence has so far been collected implying that different neuroprotective mechanisms and pharmacological agents exhibit both similarities and differences as regards effects in gene activation and proteomics. It seems that block of nitric oxide elicited mechanisms seem essential for successful neuroprotection after long cardiac arrests. During 2010 we have published two major articles on cerebral structural and gene activation changes after cardiac arrest and CPR. In addition we have found that tight management of glucose blood concentrations does not have a major influence on cerebral injury after cardiac arrest and CPR. In contrast, in the same situation the anaesthetic agent propofol seems to decrease cerebral oxidative injury. We have demonstrated experimentally that induced mild hypothermia activates the endothelin system explaining the marked circulatory stability often experienced during mild induced hypothermia after cardiac arrest and CPR. Lately we have established that administration of methylene blue during cardiopulmonary resuscitation markedly potentiates the neuroprotective effects of induced mild hypothermia after cardiac arrest.
Members of the group during 2013
Lars Wiklund, Professor
Cecile Martijn, PhD postdoc
Hari Shanker Sharma, PhD, Associate Professor
Samar Basu, PhD
Fredrik Lennmyr, MD, PhD
Adriana Miclescu, MD, PhD
Egidijus Semenas, MD, PhD student
Maria Molnar, MD, PhD student