Ischemic tolerance and endogenous neuroprotection

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Abstract

Practically any stimulus capable of causing injury to a tissue or organ can, when applied close to (but below) the threshold of damage, activate endogenous protective mechanisms – thus potentially lessening the impact of subsequent, more severe stimuli. A sub-threshold ischemic insult applied to the brain, for example, activates certain cellular pathways that can help to reduce damage caused by subsequent ischemic episodes – a phenomenon known as ‘ischemic preconditioning’ (IP) or ‘ischemic tolerance’ (IT). Although investigated for some time in model organisms, IP/IT has recently been shown in human brain. This opens a window into endogenous neuroprotection and, potentially, a window of opportunity to utilize these mechanisms in the clinic to treat patients with stroke and other CNS disorders.

Section snippets

IP/IT is an archetypal, non-specific stress response

Susceptibility to cell injury from oxygen deprivation is highly variable in the animal kingdom but all animals have developed strategies to cope with restricted substrate delivery. Accordingly, several groups have recently used invertebrates to study IP/IT [6]. Although it is unlikely that inducible protection against stroke is an evolutionary advantage, it is likely that mechanisms that protect against global hypoxia can also protect against stroke.

Because tissue damage in ischemia is the

Learning from Mother Nature: IP/IT as model to study endogenous neuroprotective mechanisms

Incongruity between the striking rate of stroke occurrence (about one every 42 s in the USA alone) and the stumbling pace at which effective stroke therapy is being developed gives impetus to the exploration of novel strategies for neuroprotection. Induction of IP/IT has been suggested as a promising clinical strategy to prepare the brain for situations when ischemia is anticipated (e.g. during surgery of the heart and brain, and in high-risk stroke patients). Here, we propose that possibly an

Mechanisms of IP/IT: complex and redundant signaling cascades

Numerous studies have investigated the signaling cascades of IP/IT in various in vitro and in vivo models. A more detailed review of the many mechanisms investigated so far has recently been published [4]. To facilitate the overview of established mechanisms, the processes of IP/IT induction can be viewed in the temporal order of their involvement and activation: as a sensor of the sub-threshold stimulus, as a transducer of the stimulus, and as effectors of the preconditioning response (Fig. 3).

Open issues and future challenges

There are numerous clinical conditions and procedures in which ischemia of the brain is anticipated (e.g. surgery of the heart and brain). Because IP/IT seems to exist in humans 19, 20, and because there are experimental IP/IT paradigms that involve clinically approved drugs (desferroxamine and erythropoietin [45], isoflurane [29] and KATP openers [46]), IP/IT might be exploited in clinical neurology to protect the brain. To this end, several groups are currently planning clinical trials to

Concluding remarks

We postulate that IP/IT research can guide investigators to targets for acute therapy against the consequences of brain ischemia that would have been difficult to discern by intuition or deduction. Although there are many unresolved issues at the bench, IP/IT strategies could soon be at the bedside in carefully planned clinical trials.

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