Towards a pharmacological neuro-protectant: can anesthesia deliver?

Abstract

Transient global cerebral ischemic injury (tGCI) continues to be a significant cause of death and disability. Global cerebral ischemia usually results from complex medical conditions, including cardiac arrest, circulatory shock, and birth asphyxia or iatrogenic interventions, such as circulatory arrest for cardiovascular surgery. The pathophysiology of global cerebral ischemia is complex. Experimental studies have identified a number of potential therapeutic treatments. Some of these treatments have targeted the initial metabolic events following brain ischemia, including energy failure, calcium ion flux, free radical generation, and the attenuation of excitotoxicity. These harmful mechanisms have been targeted with pharmacological interventions in experimental models. However, none of these promising pharmacological therapies have been successfully translated into clinical use. Such ‘‘easy to administer’’ therapies could be stocked in crash carts for administration to patients once the heart has been restarted. By contrast, physiological therapies, such as therapeutic hypothermia, have gained success in both experimental and clinical settings. This type of therapy is difficult to administer and involves extensive infrastructure, resources, and personnel. However, even therapeutic hypothermia may not be applicable across all human populations. Pre-conditioning is a strategy that involves increasing the brain’s tolerance to ischemia by exposing the brain to minor ischemic insults or pharmacological agents prior to the occurrence of a major ischemic event. While anesthetic preconditioning has shown initial promise in protecting the brain from ischemic events in pre-clinical studies, to date, there is no convincing clinical epidemiology supporting this practice. The pre-clinical science regarding the potential of anesthetic preconditioning is far from clear. This is illustrated in a recent article by Codaccioni et al., who report a transient but non-sustained improvement in neurocognitive testing in a rodent model of focal brain ischemia. In reality, this may simply be reflective of and/or specific to the particular model employed in their experiments. Any potential neuroprotective effects of anesthetic preconditioning depend on the anesthetic agent used to precondition, the species studied, the model of ischemia, the age and sex of the animal, the duration of preconditioning, and the interval between preconditioning and ischemic insult. In other words, it is not clear whether this will translate into a universally applicable therapy for tGCI. Anesthetic preconditioning is one of several strategies that prepare the brain to anticipate or react to the ischemic insult. Examples of other strategies used to precondition the brain include toxins, temperature, pharmaceuticals, and ischemia itself, with the latter showing most promise. The common theme of these strategies is to unbalance several key cell signal transcriptional programs in favour of cell survival, rather than any single metabolic pathway or target protein. Neuronal death after tGCI is complex. Characteristic lesions in vulnerable regions of the brain (such as the hippocampus and the striatum) appear from 12 h to 3 days after resuscitation and continue to evolve in the following weeks to months. Most cells that die do so by programmed cell death (PCD), as opposed to necrosis. This type of neuronal death has several features of apoptosis, with the cysteine-dependent aspartate-directed proteases family (the caspases) featuring strongly as executioners of PCD. Caspases normally exist in an inactivated state (pro-caspases), but under stressful conditions, cleavage (activation) D. R. Doherty, MBBCh (&) Department of Anesthesiology, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada e-mail: ddoherty@cheo.on.ca