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Developing novel therapeutics for excitotoxic neuronal death following stroke Lai, Ted


Ischemic stroke is a major cause of death and disability in developed countries, and a major economic burden in the world. The mechanisms mediating stroke damage are likely multifactorial, with N- methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity being an important factor. But NMDAR blockers are not clinically feasible due to their side effects and short therapeutic window. This doctoral dissertation discusses an ongoing effort to develop novel anti-excitotoxic therapeutics that can overcome these limitations. Our strategies are largely based on the premises that NR2A- subunit containing NMDARs (NR2ARs) are pro-survival whereas NR2B-subunit containing NMDARs (NR2BRs) are pro-death, and NR2BRs mediate neuronal death in large by activating a set of neuronal death signaling proteins. Specific Findings: 1, we investigated whether stimulation of NR2ARs by the NMDAR co- agonist glycine rather than blocking NR2BRs would confer a wider therapeutic time window in an in vivo rat model of focal and global ischemia. Because we stimulated neuronal survival rather than blocked neuronal death, our therapeutic remained efficacious up to 6 h post-ictus - a time point when many known death signaling proteins downstream of NR2BRs were already activated. 2, we studied the death-signaling pathway of SREBP1 (sterol response element binding protien 1), a transcription factor downstream of NR2BR, in an in vivo rat model of focal ischemia. In the ischemic brain, we found SREBP1 activation and nuclear translocation due to the ubiquitination and degradation of its inhibitory partner Insig1 (protein encoded by insulin signaling gene1). Notably, the new therapeutic peptide Indip (Insig1 degradation inhibiting peptide) prevented neuronal death when administered 1 h pre- and 2 h post-ictus. Because we targeted a death-signaling protein rather than all signaling proteins downstream of NMDARs, our treatment would have fewer side effects than NMDAR blockers. 3, we developed a novel method to selectively knockdown death-signaling proteins downstream of NR2BRs by means of ubiquitin-tagged peptides. Because interference peptides in the past were limited to disrupting protein-protein interactions and post-translational modifications, this opened a new avenue to develop therapeutics for excitotoxicity following stroke.

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