ERK and p38 inhibitors attenuate memory deficits and increase CREB phosphorylation and PGC-1α levels in Aβ-injected rats

In this study, we investigated the effect of intracerebroventricular administration of ERK and p38 specific inhibitors, U0126 and PD169316, respectively, on learning and memory deficits induced by amyloid beta (A beta) in rats. To investigate the effects of these compounds on learning and memory, we performed Morris water maze (MWM) test. U0126 and/or PD169316 improved spatial learning in MWM in A beta-injected rats, 20 days after A beta-injection. To determine the mechanisms of action of U0126 and PD169316, we studies their effect on some intracellular signaling pathways such as Ca+/cAMP-response element binding protein (CREB), c-fos, and transcription factors that regulate mitochondrial biogenesis. Based on our data, CREB and c-fos levels decreased 7 days after A beta-injection, while U0126 and/or PD169316 pretreatments significantly increased these levels. Moreover, U0126 and PD169316 activated peroxisome proliferator-activated receptor gamma coactivator-1a, nuclear respiratory factor 1, and mitochondrial transcription factor A, 7 days after A beta-injection. Surprisingly, these factors were returned to vehicle level, 20 days after A beta-injection. Our findings reinforce the potential neuroprotective effect of these inhibitors against the A beta toxicity. (C) 2012 Elsevier B.V. All rights reserved.