Administration of Intranasal Insulin During Cardiopulmonary Resuscitation Improves Neurological Outcomes After Cardiac Arrest

INTRODUCTION: Over 325,000 people die from cardiac arrest each year. Prognosis is poor and survivors typically experience persistent neurologic deficits. Currently, neuroprotective treatments to reduce brain injury in cardiac arrest survivors are limited and ineffective. This study evaluates the potential neuroprotection induced by high dose intranasal insulin (HD-IN-I) in a rodent model of asphyxial cardiac arrest. METHODS: Male Long Evans rats were block randomized to sham-operated controls or 8-minute asphyxial cardiac arrest treated with placebo or HD-IN-I at the onset of CPR. To investigate mechanism of action, hippocampi were collected 30 minutes post-ROSC and analyzed by Western blot for phosphorylation of Akt. To assess long-term functional outcomes, neurobehavioral evaluation was conducted using neurologic function scores daily and Barnes maze, Rotarod, and passive avoidance on days 7-10 post-ROSC. Histologic quantification of surviving hippocampal CA1 pyramidal neurons was also conducted. RESULTS: Hippocampal phospho-Akt/total Akt ratio increased 2-fold in the placebo group and 5.7-fold in HD-IN-I group relative to shams (p \u3c 0.05). Rats treated with HD-IN-I had significantly improved performance on Rotarod, Barnes maze, and passive avoidance (p \u3c 0.05). HD-IN-I had no significant effect on ROSC rate, 10-day survival, systemic glycemic response, or on the number of surviving CA1 pyramidal neurons compared to placebo treatment. DISCUSSION: This study is the first to demonstrate that HD-IN-I administered at the onset of CPR, causes phosphorylation of brain Akt and results in significant neuroprotection. This primary work strongly suggests that intranasal insulin could be the first highly effective neuroprotective treatment for cardiac arrest patients

Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury

The current standard of care for acute myocardial infarction or ‘heart attack’ is timely restoration of blood flow to the ischemic region of the heart. While reperfusion is essential for the salvage of ischemic myocardium, re-introduction of blood flow paradoxically kills (rather than rescues) a population of previously ischemic cardiomyocytes—a phenomenon referred to as ‘lethal myocardial ischemia-reperfusion (IR) injury’. There is long-standing and exhaustive evidence that mitochondria are at the nexus of lethal IR injury. However, during the past decade, the paradigm of mitochondria as mediators of IR-induced cardiomyocyte death has been expanded to include the highly orchestrated process of mitochondrial quality control. Our aims in this review are to: (1) briefly summarize the current understanding of the pathogenesis of IR injury, and (2) incorporating landmark data from a broad spectrum of models (including immortalized cells, primary cardiomyocytes and intact hearts), provide a critical discussion of the emerging concept that mitochondrial dynamics and mitophagy (the components of mitochondrial quality control) may contribute to the pathogenesis of cardiomyocyte death in the setting of ischemia-reperfusion

Does Disruption of Optic Atrophy-1 (OPA1) Contribute to Cell Death in HL-1 Cardiomyocytes Subjected to Lethal Ischemia-Reperfusion Injury?

Disruption of mitochondrial structure/function is well-recognized to be a determinant of cell death in cardiomyocytes subjected to lethal episodes of ischemia-reperfusion (IR). However, the precise mitochondrial event(s) that precipitate lethal IR injury remain incompletely resolved. Using the in vitro HL-1 cardiomyocyte model, our aims were to establish whether: (1) proteolytic processing of optic atrophy protein-1 (OPA1), the inner mitochondrial membrane protein responsible for maintaining cristae junction integrity, plays a causal, mechanistic role in determining cardiomyocyte fate in cells subjected to lethal IR injury; and (2) preservation of OPA1 may contribute to the well-documented cardioprotection achieved with ischemic preconditioning (IPC) and remote ischemic conditioning. We report that HL-1 cells subjected to 2.5 h of simulated ischemia displayed increased activity of OMA1 (the metalloprotease responsible for proteolytic processing of OPA1) during the initial 45 min following reoxygenation. This was accompanied by processing of mitochondrial OPA1 (i.e., cleavage to yield short-OPA1 peptides) and release of short-OPA1 into the cytosol. However, siRNA-mediated knockdown of OPA1 content did not exacerbate lethal IR injury, and did not attenuate the cardioprotection seen with IPC and a remote preconditioning stimulus, achieved by transfer of ‘reperfusate’ medium (TRM-IPC) in this cell culture model. Taken together, our results do not support the concept that maintenance of OPA1 integrity plays a mechanistic role in determining cell fate in the HL-1 cardiomyocyte model of lethal IR injury, or that preservation of OPA1 underlies the cardioprotection seen with ischemic conditioning