Abstract
Cerebral preconditioning (PC) confers endogenous brain protection after stroke. Ischemic stroke patients with a prior transient ischemic attack (TIA) may potentially be in a preconditioned state. Although PC has been associated with the activation of pro-survival signals, the mechanism by which preconditioning confers neuroprotection is not yet fully clarified. Recently, we have described that PC-mediated neuroprotection against ischemic insult is promoted by p53 destabilization, which is mediated by its main regulator MDM2. Moreover, we have previously described that the human Tp53 Arg72Pro single nucleotide polymorphism (SNP) controls susceptibility to ischemia-induced neuronal apoptosis and governs the functional outcome of patients after stroke. Here, we studied the contribution of the human Tp53 Arg72Pro SNP on PC-induced neuroprotection after ischemia. Our results showed that cortical neurons expressing the Pro72-p53 variant exhibited higher PC-mediated neuroprotection as compared with Arg72-p53 neurons. PC prevented ischemia-induced nuclear and cytosolic p53 stabilization in Pro72-p53 neurons. However, PC failed to prevent mitochondrial p53 stabilization, which occurs in Arg72-p53 neurons after ischemia. Furthermore, PC promoted neuroprotection against ischemia by controlling the p53/active caspase-3 pathway in Pro72-p53, but not in Arg72-p53 neurons. Finally, we found that good prognosis associated to TIA within 1 month prior to ischemic stroke was restricted to patients harboring the Pro72 allele. Our findings demonstrate that the Tp53 Arg72Pro SNP controls PC-promoted neuroprotection against a subsequent ischemic insult by modulating mitochondrial p53 stabilization and then modulates TIA-induced ischemic tolerance.
Highlights
The restriction in blood supply to the brain causes a shortage of oxygen and glucose to maintain cellular metabolism, which elicits a pathological response
Since NMDA-PC increased MDM2 levels in neurons (Fig. 1a) and this effect was maintained after oxygen and glucose deprivation (OGD) in both genotypes, we confirmed that only preconditioned Pro72-p53 neurons might display p53 destabilization after ischemia through a MDM2-dependent mechanism
According to our previous results [30], we verified that p53 mRNA remained unaltered during preconditioning (Fig. 1c), which highlights the importance of posttranslational regulation of p53 after ischemic events
Summary
The restriction in blood supply to the brain causes a shortage of oxygen and glucose to maintain cellular metabolism, which elicits a pathological response. Transient brief episodes of controlled ischemia confer protection against a subsequent prolonged ischemia. This phenomenon described as cerebral preconditioning (PC) has been evidenced both in vitro and in vivo models [1,2,3]. The efficacy of PC in reducing brain injury after an ischemic damage has been demonstrated in clinical studies. Transient ischemic attack (TIA) is considered to be the clinical correlate of PC. It provides clear evidence that PC may be effective to reduce brain injury in human against ischemic insult [7,8,9,10]
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