BACKGROUND: @entity12220 (MAPK) a modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes. OBJECTIVE: To evaluate pre-clinically the pharmacological effects in the brain of @entity12220 MAPKa inhibition with a brain-penetrant specific chemical antagonist. METHODS: @entity68411 , a blood-brain barrier penetrant, highly selective @entity12220 MAPKa inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 @entity19 was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) @entity35 with identified @entity73 ; n=15 per group: vehicle, 0.5, 1.5, and 4.5mg/kg @entity68411 by oral gavage twice daily for 3 weeks. Assessments in aged @entity35 included @entity3426 , @entity29241 , @entity1505 protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance. RESULTS: Drug effect could not be assessed in Tg2576 @entity19 , as @entity32 was evident. In cognitively-impaired aged @entity35 , @entity68411 led to significantly improved performance in the MWM and significant reduction in hippocampal @entity3426 protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower @entity3426 . Drug concentration-effect relationships and predicted @entity1 doses were determined. CONCLUSIONS: Selective inhibition of @entity12220 MAPKa with @entity68411 in aged @entity35 reduces hippocampal @entity3426 levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted @entity1 doses should minimize risks of systemic @entity137 .

Selective Brain-Targeted Antagonism of XXXX MAPKa Reduces Hippocampal @entity3426 Levels and Improves Morris Water Maze Performance in Aged @entity35 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity29241 :: ('29495(Tax:10116)', 'Gene') :: ['PSD-95'] @entity32 :: ('MESH:D007249', 'Disease') :: ['little inflammation'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity73 :: ('MESH:D003072', 'Disease') :: ['cognitive deficits'] @entity1505 :: ('24835(Tax:10116)', 'Gene') :: ['TNFa'] @entity68411 :: ('MESH:C464966', 'Chemical') :: ['VX-745'] @entity3426 :: ('24494(Tax:10116)', 'Gene') :: ['IL-1b'] @entity35 :: ('10116', 'Species') :: ['rats'] @entity12220 :: ('81649(Tax:10116)', 'Gene') :: ['P38 mitogen activated protein kinase', 'p38']
@entity12220 :: (81649(Tax:10116),Gene) :: ['p38']
