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Role of PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries following stroke Zhang, Shu


Stroke is a leading cause of death and disability in developed countries. About 87% of stroke cases results from blood vessel(s) occlusion in the brain, leading to neuronal death and neurological impairment (Lloyd-Jones et al., 2010). The ischemic progression likely involves multiple events, and increasing evidence showed that the ischemic neuronal death is caused, at least in part, by over-activation of N-methyl-Daspartate subtype glutamate receptors (NMDARs) (Rothman, 1983, Rothman, 1984, Simon et al., 1984). A large number of pre-clinical studies showed that NMDAR antagonists have strong neuroprotective effects against ischemic insults (Park et al., 1988b, Bullock et al., 1990). However, none of the following human clinical trials have succeeded yet (Muir, 2006). Several explanations have been suggested (Gladstone et al., 2002), including the following two major reasons that may be overcome by the novel therapeutics proposed here. First, the stroke patient inclusion periods (>6 hours) used by most clinical trials are beyond the therapeutic time window (<1 hour) of NMDAR antagonists. Second, NMDAR antagonists, when used at the concentration required to block excitotoxicity, also abolish the pro-survival downstream cascades of NMDARs, thus leading to intolerable side effects. Therefore, instead of aiming at the receptor per se, my current study turns to focus on identifying NMDAR’s downstream death signals, which may permit a much wider therapeutic time window and are solely involved in pro-death signaling pathways of NMDARs. My results suggest that PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is such a candidate. Both NMDA stimulation on cultured neurons (in vitro) and ischemic insults in rats (in vivo) can trigger ubiquitination-dependent PTEN translocation into the nucleus. Inhibition of PTEN nuclear translocation using an interfering peptide (Tat-K13) can significantly reduce the excitotoxic/ischemic neuronal injuries both in vitro and in vivo. Most excitingly, the intervention time window of PTEN nuclear translocation (6 hours post-ictus) is much wider than that of the only clinically available anti-stroke drug named tissue plasminogen activator (3 hours) (NINDS, 1995). These findings strongly suggest that PTEN nuclear translocation is a critical step leading to excitotoxic/ischemic neuronal injuries, and Tat-K13 represents a potential therapeutic strategy for stroke treatment.

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