Preconditioning paradigms and pathways in the brain

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Preconditioning is a phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. Preconditioning stimuli include ischemia, low doses of endotoxin, hypoxia, hypothermia and hyperthermia, cortical spreading depression, anesthetics, and 3-nitropropionic acid, among others. Understanding of the mechanisms underlying preconditioning has been elusive, but NMDA receptor activation, nitric oxide, inflammatory cytokines, and suppression of the innate immune system appear to have a role. Elucidation of the endogenous cell survival pathways involved in preconditioning has significant clinical implications for preventing neuronal damage in susceptible patients.



The brain relies upon internal defense mechanisms for protection from injurious stimuli. Preconditioning is a phenomenon whereby low doses of these noxious insults shield the brain from future insults rather than inflicting damage. Preconditioning stimuli include but are not limited to transient global and focal ischemia,1–4 cortical spreading depression,5–7 brief episodes of seizure, exposure to anesthetic inhalants,8–10 low doses of endotoxin (lipopolysaccharide [LPS]),11,12 hypothermia and hyperthermia,13,14 and 3-nitropropionic acid treatment.15,16

Depending on the specific preconditioning stimulus, a state of neuronal tolerance can be established in at least two temporal profiles: one in which the trigger induces protection within minutes (rapid or acute tolerance),17 and one in which the protected state develops after a delay of several hours to days (delayed tolerance).4 Some preconditioning paradigms induce both phases of ischemic tolerance, while others can induce only the acute phase or only the delayed phase.18–21 The acute phase is most likely due to rapid posttranslational modifications of proteins.22,23 In contrast, the delayed phase is dependent on de novo protein synthesis.24,25

Preconditioning by ischemic tolerance was first identified in the heart by Murry et al,26 and was subsequently found to occur in the brain4,27 and a variety of organs including the liver, intestine, kidney, and lung. Preconditioning stimuli can be cross-tolerant, safeguarding against other types of injury. For example, endotoxin preconditioning can protect against subsequent ischemia and vice versa. Thus, there may be some overlapping mechanisms in preconditioning, and unraveling these pathways may uncover an arsenal of neuroprotective therapeutic targets. In this review, we will compare different preconditioning paradigms and discuss potential mechanisms in initiating brain ischemic tolerance.


Refinement of various preconditioning models is of great clinical significance. Cardiovascular or cerebrovascular surgery has a negative impact on brain function due to stoppage of blood flow during surgery. In fact, more than 25% of patients who receive coronary artery bypass surgery suffer from temporary or permanent memory loss.28,29 As a result, it is of premier importance to develop strategies to protect the brain either prior to vascular surgeries or in patients at high risk of stroke. While it would be dangerous and impractical to precondition at-risk patients with ischemia, the identification of underlying preconditioning mechanisms may lead to safer therapeutic factors that can be administered before surgery.


Global ischemic preconditioning in the brain is accomplished by occlusion of the bilateral common carotid arteries. In contrast, in focal ischemic preconditioning, occlusion of one side of the middle cerebral artery is induced for about 1 to 20 minutes, depending on methods and animal species.4,30–32 Twenty-four hours after ischemic preconditioning, stroke is induced in these animals. Preconditioning-induced neuroprotection is observed not only in terms of infarct volume but also in terms of neurological scores and behavior studies.


Tolerance to ischemic injury can also be induced by a small dose of LPS injected into the peritoneal cavity. Dosages vary from 0.05 to 1 mg/kg body weight in small rodents such as mice and rats.11,33–36 This dose of LPS usually does not bring abnormal signs and symptoms to the animals. The ischemic protection yields a reduction of infarct volume of approximately 30%. This tolerant state can be sustained for about 1 week, with maximum protection occurring around 2 to 3 days after injection of LPS.


A relatively convenient method for preconditioning animals is hypoxic exposure. Animals are put in a chamber in which oxygen and nitrogen proportions can be controlled. Oxygen concentration usually ranges from 8% to 13% with normobaric pressure. Exposure time ranges from 1 to 6 hours. Twenty-four to 72 hours later, transient or permanent focal stroke is induced in the animals.37–40 Hypoxia-preconditioned neuroprotection usually starts at 1 to 3 days with a significant reduction of infarct size. Hypoxic preconditioning has also been demonstrated for in vitro neuron culture models using oxygen-glucose deprivation injury.41

3-Nitropropionic acid

3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase, an enzyme required for oxidative phosphorylation and adenosine triphosphate production. When applied at low doses 1 to 4 days before ischemia, 3-NP can lead to ischemic tolerance in the forebrain of gerbils and rats.16,42,43 The dose ranges from 1 to 20 mg/kg body weight.16 Such treatment significantly improves neurological behavior and increases neuronal survival in the CA1 region of hippocampus. In addition, 3-NP preconditioning induces tolerance to hypoxia in hippocampal slice preparations.15,44

Hypothermia and hyperthermia

Hypothermia is a well-characterized protective procedure used during and after cerebral surgery. It is also reported that brief hypothermic or hyperthermic exposure can also lead to ischemic tolerance. The temperatures adopted range from 25°C to 32°C13,45,46 in hypothermia and from 42°C to 43°C in hyperthermia.14

Cortical spreading depression

Cortical spreading depression is defined as the electrophysiologic phenomenon of slowly propagating transient depolarization waves across the cortex. Usually 5 M of potassium chloride is infused into the cortex, or a cotton pad soaked with the solution is put on the surface of dura mater, which results in depolarization, firing of neurons, and cortical spreading depression. Cortical spreading depression induces a prolonged phase of ischemic tolerance that lasts 1 to 7 days.5,6,47,48


Exposure to volatile anesthetics such as isoflurane and halothane within pharmacologic concentration ranges also confers delayed-phase ischemic tolerance of the brain.8–10,49

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