Behavioural Brain Research 232 (2012) 165–173 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho mepage: www.elsevier.com/locate/bbr Research report ERK and p38 inhibitors attenuate memory deficits and increase CREB phosphorylation and PGC-1 levels in A-injected rats Ghorbangol Ashabi , Mahmoudreza Ramin , Pegah Azizi , Zahra Taslimi , Shabnam Zeighamy Alamdary , Abbas Haghparast, Niloufar Ansari, Fereshteh Motamedi, Fariba Khodagholi ∗ Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran a r t i c l e i n f o Article history: Received 12 January 2012 Received in revised form 30 March 2012 Accepted 3 April 2012 Available online 9 April 2012 Keywords: Alzheimer’s disease Amyloid beta CREB ERK Hippocampus mitochondrial biogenesis p38 a b s t r a c t 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) 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-injected rats, 20 days after A-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-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-injection. Surprisingly, these factors were returned to vehicle level, 20 days after A-injection. Our findings reinforce the potential neuroprotective effect of these inhibitors against the A toxicity. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Alzheimer’s disease (AD) is a progressive and irreversible loss of neurons and the loss of intellectual abilities, including memory and reasoning. Amyloid  protein (A) is a 40 ± 42 amino acid peptide that is considered to be one of the major contributing factors to the development of AD. Nabeshima and co-workers [1] demonstrated that a continuous infusion of A into the cerebral ventricle in rats results in learning and memory deficits that were accompanied by a reduction of choline acetyltransferase activity, suggesting that accumulation of A is related to cognitive impairments in AD [1,2]. One of the most interesting pathways is mitogen-activated protein kinases (MAPKs) signaling, which is considered as an important regulator of a broad range of genes involved in cellular responses to pro-inflammatory and other stress signals. Three distinct groups of Abbreviations: A, amyloid beta; AD, Alzheimer’s disease; ANOVA, Analysis of Variance; APP, amyloid precursor protein; ARE, antioxidant response element; CREB, Ca + /cAMP-response element binding protein; ECL, electrochemiluminescence; ERK, extracellular signal-regulated protein kinase; i.c.v., intracerebroventricular; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MWM, Morris water maze; NRF-1, nuclear respiratory factor-1; PGC-1, peroxisome proliferator- activated receptor  co-activator 1; TFAM, mitochondrial transcription factor A. ∗ Corresponding author. Tel.: +98 21 22429768; fax: +98 21 22432047. E-mail address: khodagholi@sbmu.ac.ir (F. Khodagholi). well characterized major MAPK subfamily members include extra- cellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK which are serine/threonine protein kinases [3]. A dynamic balance between JNK, ERK and p38-MAPK activation will determine the cellular response, either cell growth or death [4]. Recently, we have reported that inhibition of JNK phos- phorylation reverses memory deficit induced by A [5]. Moreover, several groups using human post-mortem tissues from control and Alzheimer’s cases confirmed the observations that the p38 MAPK activation occurs at the very early stages in human AD brains [6,7]. Accumulating evidence has shown that the ERK signaling path- way has an important role in learning and memory. It has been reported that ERK affects the maintenance of long-term memory, but administration of U0126, had no significant effect on short-term memory in rats [8]. In hippocampus cells oxidative stress reduced ERK expression and ERK suppressed its downstream transcription factor, cAMP-response element binding protein (CREB) [9].CREB is a nuclear transcription factor essential for long-lasting changes in synaptic plasticity that mediates the conversion of short-term memory to long-term memory. Besides this transcription factor is a candidate sensor for energy insufficiency and has been implicated in support of mitochondrial biogenesis [10]. A role of CREB in mito- chondrial biogenesis was highlighted by discovery that the CREB translational complex controls the expression of PGC-1 [11]. In the present study, we investigated the effects of U0126 and PD169316, 0166-4328/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2012.04.006