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Thiamine as a neuroprotective agent after cardiac arrest

Abstract


Aims


Reduction of pyruvate dehydrogenase (PDH) activity in the brain is associated with neurological deficits in animals resuscitated from cardiac arrest. Thiamine is an essential co-factor of PDH. The objective of this study was to examine whether administration of thiamine improves outcomes after cardiac arrest in mice. Secondarily, we aimed to characterize the impact of cardiac arrest on PDH activity in mice and humans.


Methods


Animal study: Adult mice were subjected to cardiac arrest whereupon cardiopulmonary resuscitation was performed. Thiamine or vehicle was administered 2 min before resuscitation and daily thereafter. Mortality, neurological outcome, and metabolic markers were evaluated.

Human study: In a convenience sample of post-cardiac arrest patients, we measured serial PDH activity from peripheral blood mononuclear cells and compared them to healthy controls.


Results


Animal study: Mice treated with thiamine had increased 10-day survival (48% versus 17%, P < 0.01) and improved neurological function when compared to vehicle-treated mice. In addition, thiamine markedly improved histological brain injury compared to vehicle. The beneficial effects of thiamine were accompanied by improved oxygen consumption in mitochondria, restored thiamine pyrophosphate levels, and increased PDH activity in the brain at 10 days.

Human study: Post-cardiac arrest patients had lower PDH activity in mononuclear cells than did healthy volunteers (estimated difference: ⿿5.8 O.D./min/mg protein, P < 0.001).


Conclusions


The provision of thiamine after cardiac arrest improved neurological outcome and 10-day survival in mice. PDH activity was markedly depressed in post-cardiac arrest patients suggesting that this pathway may represent a therapeutic target.


Introduction


Cardiac arrest occurs in an estimated 400,000 Americans each year (approximately 200,000 treated out-of-hospital cardiac arrest1 and 200,000 treated in-hospital cardiac arrest).2 Although return of spontaneous circulation (ROSC) can often be achieved, only 10â¿¿20% survive,1 with neurological injury being the main cause of death in patients who are initially successfully resuscitated.3, 4 No pharmacological interventions are currently available to provide neuroprotection for patients suffering from cardiac arrest.

Accumulating evidence suggests that mitochondria play a crucial role as effectors and targets of ischemia-reperfusion (I/R) injury after cardiac arrest and cardiopulmonary resuscitation (CPR).5, 6 Impaired aerobic metabolism and aggravation of oxidative stress caused by mitochondrial dysfunction have been implicated as causes of neurological deficits following cardiac arrest.7, 8, 9, 10 Pyruvate dehydrogenase (PDH) is the critical rate-limiting mitochondrial matrix enzyme linking glycolysis to the tricarboxylic acid (TCA) cycle.11, 12 Hyperoxia-induced oxidative inactivation of PDH has been suggested as a culprit in the loss of cerebral aerobic metabolism and neurological deficit after cardiac arrest.7, 11, 12, 13, 14 Activity of PDH and several other key enzymes in the TCA cycle are modulated by the essential co-enzyme thiamine pyrophosphate (TPP). However, whether thiamine (vitamin B1) administration could restore PDH activity and improve outcomes after cardiac arrest remains unknown.

We hypothesized that thiamine would improve survival and neurological outcome in mice after cardiac arrest through stimulation and restoration of PDH activity. We further hypothesized that post-cardiac arrest patients would exhibit PDH activity depression. To address these hypotheses, we simultaneously performed an interventional trial in a mouse model of cardiac arrest and an observational study in post-cardiac arrest patients.



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