Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance

Abstract

Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, surgical brain injury, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of "cross-tolerance," in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning.

Keywords: Ischemia; Neuroprotection; Preconditioning; Traumatic brain injury.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Preconditioning paradigms in different animal and cellular models of brain injury

Several kind of preconditioning stimuli, including neurotoxins, thrombin, EPCG, exercise and HSP inducers, have been reported to establish preconditioning against PD or stroke models. Commonly used PD models for preconditioning studies include 6-OHDA or MPTP-lesioned rodents and 6-OHDA-treated dopaminergic cells. Low-dose endotoxin LPS treatment was also applied to establish preconditioning in an in vitro PD model. The major animal models of stroke models used to study preconditioning include focal and global ischemia in adult rodents, and neonatal hypoxia/ischemia.

Figure 2. Ischemic paradigms to induce protection against cerebral ischemia in rodents

Ischemic preconditioning has been effectively used to induce protection against severe cerebral ischemia. Four paradigms have been tested in rodent models: 1. Brief occlusion of the bilateral common carotid arteries combined with either vertebral artery coagulation (4VO, ➀+➁); 2. Brief occlusion of the bilateral common carotid arteries with systemic hypotension (2VO, ➀+systemic hypotension); 3. Brief occlusion of one middle cerebral artery (MCAO, ➂); 4. Occlusion of unilateral femoral artery or the infrarenal abdominal aorta (remote ischemia, ➃ or ➄).

Figure 3. Timeframe for ischemic preconditioning in stroke models

A. There are two time windows of ischemic tolerance that open after a preconditioning stimulus. “Rapid” tolerance develops within minutes and lasts only 1–2 hours after preconditioning. Rapid tolerance typically confers transient and less robust neuroprotection compared to “delayed” tolerance, which develops 1–7 days following preconditioning and requires de novo protein synthesis. If the severe ischemic insult occurs between these two windows, no protection is typically elicited. B. Protection afforded by delayed ischemic preconditioning. Mice were subjected to ischemic preconditioning (IPC, 12 minutes of MCAO) or sham preconditioning (Control), allowed to recover for 48 h, and then subjected to 60 minutes of MCAO. Infarct size was determined by TTC staining. P<0.01.

Figure 4. Predicted pathways underlying remote ischemia-induced protection against cerebral ischemic injury

Remote ischemic preconditioning may induce neuroprotection through neural as well as humoral pathways. Humoral effects would necessitate either a breach in the integrity of the BBB or involve brain permeable factors. Both humoral and neural elements may eventually trigger neuroprotective signaling, such as PPAR and PI3K pathways, in ischemic brain.