DEVELOPMENT OF TOLL-LIKE RECEPTOR AGONISTS AS NEUROPROTECTANTS IN BRAIN ISCHEMIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Endogenous mechanisms of ischemic preconditioning-tolerance have reviled the brain's ability to reprogram (precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an antiinflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod -IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential effacy and pharmacokinetic data. Thus our preliminary studies support new robust neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy for TLR9 (K-and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for K-and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and 0 mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K-and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K-and O-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K-and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an INO application for the optimal TLR candidate based on efficacy, pharmacokinetics and tOXicity profiles.