http://journal.frontiersin.org/article/10.3389/fneur.2015.00115/full?
- 1Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Science, School of Medicine, Federico II University of Naples, Naples, Italy
- 2Fondazione IRCSS SDN, Naples, Italy
Introduction
Cerebral ischemia is a multifactorial and complex disease (1, 2).
Indeed, the intracellular events activated by the loss of perfusion of
the brain and responsible for neuronal damage range from impairment of
intracellular homeostasis to mitochondrial dysfunction and free radical
production (3–5).
The complexity of these events explains the great discrepancy between
the frequency of cerebral ischemic accidents and the lack of effective
treatments able to inhibit or slow neuronal demise following the
ischemic insult. Hence, the urgent need to identify new potential
targets for the development of innovative therapeutic strategies able to
defend the ischemic brain.
On these premises, in the recent years, the attention
of the researchers focused on ischemic tolerance a phenomenon, also
known as ischemic preconditioning (IPC), which consists of a sub-lethal
anoxic insult that makes the tissue in which it occurs more resistant to
a subsequent and potentially lethal ischemia (6–11).
The relevance of this phenomenon is to correlate to the study of the
endogenous mechanisms activated in neurons to allow cell survival after a
sub-lethal ischemic stimulus. By this way, it is possible to identify
new molecular targets useful to develop alternative therapeutic
strategies to treat the ischemic disease. The great interest in the
cerebral IPC and in the tolerance evoked by itself also comes from the
similarity of this phenomenon with those clinical situations occurring
in the human brain. Indeed, it is well known that transient ischemic
attacks (TIAs) do not cause structural damage but appear to protect
brain against a subsequent “stroke” (12, 13).
Therefore, IPC or ischemic tolerance of the brain lie
in a natural adaptive process that can be mimicked by a variety of
sub-lethal insults, such as transient hypoxia, spreading depression,
oxidative stress, hyperthermia, or heat shock, and that increases the
tissue tolerance to a subsequent, potentially lethal ischemia. This
adaptive cytoprotection is a fundamental property of living cells, which
allows them to survive to the exposure to potentially recurrent
stressors. This phenomenon was clearly identified in the heart by Murry
et al. (14) as preconditioning, or subsequently as ischemic tolerance, and in 1990 it was described also in the brain by Kitagawa et al. (15).
Since then, it immediately attracted the interest of clinical and basic
neuroscientists for several reasons. First, this biological process
became widely recognized as a pertinent and effective experimental
instrument to understand how the brain protects itself against ischemia,
thereby providing an innovative approach for the discovery of novel
neuroprotective strategies. Second, retrospective case-control studies
showed a clinical correlate of the phenomenon discovered experimentally.
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