Attenuating Proinflammatory Cytokine Upregulation as an AD Therapeutic Strategy

Specific to this proposal, we have developed a new class of orally bioavailable, CNS-penetrant, small molecule compounds that selectively suppress proinflammatory cytokine up-regulation in the CNS, leading to attenuation of AD-relevant pathophysiology progression in a mouse model. Our two lead compounds, termed Minozac and Minokine (see Preliminary Studies and Appendix papers Hu et al., 2007; Munoz et al., 2007), work through different molecular pathways, yet both compounds attenuate proinflammatory cytokine overproduction by activated glia. Minokine is an inhibitor of p38a MAPK, a well-established therapeutic target for peripheral inflammatory diseases such as rheumatoid arthritis. Evidence indicates the importance of p38 MAPK in regulation of proinflammatory cytokine production in activated glia, but there is currently a lack of inhibitor-driven development of a CNS active drug. Our recently published data (Munoz et al., 200"7) show that Minokine is efficacious in suppressing proinflammatory cytokine overproduction from activated glia and can provide protection from tissue injury and disease progression in a mouse model of AD that involves ICV infusion of human oligomeric A(3 (Craft et al., 2004a, 2004b). Specifically, oral administration of Minokine suppressed proinflammatory cytokine up-regulation, attenuated synaptic damage, and prevented hippocampaldependent behavioral deficits. Our data and literatun3 precedents in the field, therefore, make a compelling argument in favor of exploring p38 MAPK as a potential therapeutic target for treatment of neurodegenerative diseases, such as AD, that have elevated levels of proinflammatory cytokines as a component of disease progression. This exploration has been hampered previously by the lack of selective p38a MAPK inhibitors that are CNS-penetrant and non-toxic. The availability of Minokine and testing efficacy in an established AD transgenic mouse model will provide proof-of-copcept that further development of p38 MAPK-targeted compounds may be a useful approach for new AD therapeutics.