RESEARCH ARTICLE Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle-aged rats Fabrízio dos Santos Cardoso 1 | Erivelton Fernandes França 1 | Fernando Tadeu Serra 1 | Ang  elica Begatti Victorino 2 | Alexandre Aparecido de Almeida 2 | Jansen Fernandes 2 | Francisco Romero Cabral 3 | Daniel Paulino Venancio 4 | Ricardo Mario Arida 2 | S  ergio Gomes da Silva 1,3 1 Universidade de Mogi das Cruzes (UMC). Mogi das Cruzes – SP, Brazil 2 Universidade Federal de S~ao Paulo (UNIFESP), S~ao Paulo – SP, Brazil 3 Hospital Israelita Albert Einstein, S~ao Paulo – SP, Brazil 4 Departamento de Morfologia e Fisiologia, Faculdade de Medicina do ABC, Santo Andr e – SP, Brazil Correspondence S ergio Gomes da Silva, N ucleo de Pesquisas Tecnol  ogicas, Universidade de Mogi das Cruzes, Av. C^andico Xavier de Almeida e Souza, 200., Mogi das Cruzes, S~ao Paulo, Brazil. Email: sgomesilva@hotmail.com Funding information Coordenaç~ao de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnol  ogico (CNPq); Fundaç~ao de Amparo ao Ensino e Pesquisa (FAEP); Fundaç~ao de Amparo a Pesquisa do Estado de S~ao Paulo (FAPESP), Grant/Award Number: #14/00035-1. Abstract Aging is often accompanied by cognitive decline, memory impairment, and an increased suscepti- bility to neurodegenerative disorders. Although the physiological processes of aging are not fully understood, these age-related changes have been interpreted by means of various cellular and molecular theories. Among these theories, alterations in the intracellular signaling pathways associ- ated with cell growth, proliferation, and survival have been highlighted. Based on these observations and on recent evidence showing the beneficial effects of exercise on cognitive func- tion in the elderly, we investigated the cell signaling pathways in the hippocampal formation of middle-aged rats (18 months old) submitted to treadmill exercise over 10 days. To do this, we eval- uated the hippocampal activation of intracellular signaling proteins linked to cell growth, proliferation, and survival, such as Akt, mTOR, p70S6K, ERK, CREB, and p38. We also explored the cognitive performance (inhibitory avoidance) of middle-aged rats. It was found that physical exercise reduces ERK and p38 activation in the hippocampal formation of aged rats, when com- pared to the control group. The hippocampal activation and expression of Akt, mTOR, p70S6K, and CREB were not statistically different between the groups. It was also observed that aged rats from the exercise group exhibited better cognitive performance in the inhibitory avoidance task (aversive memory) than aged rats from the control group. Our results indicate that physical exer- cise reduces intracellular signaling pathways linked to inflammation and cell death (i.e., ERK and p38) and improves memory in middle-aged rats. KEYWORDS aging, brain, hippocampus, p38, physical exercise 1 | INTRODUCTION Exercise is an important means of maintaining health as it improves cardiac, respiratory, and muscular functions (ACSM, 2006). In addition to these beneficial, physical effects, exercise has emerged as an impor- tant “brain stimulator” (Erickson & Kramer, 2009). For instance, an improvement in cognitive performance (in logical memory and Wechs- ler Memory Scale) was found in 87 elderly people subjected to a physi- cal training program (Hill, Storandt, & Malley, 1993). In another study, higher cardiorespiratory fitness (i.e., elevated V_o2max) was associated with better global cognitive function and with better performance in the cognitive domains of memory, executive function, and motor skills in 877 elderlies (Freudenberger et al., 2016). Older women that walked Abbreviations: Akt, protein kinase B; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal protein S6 kinase; ERK, extracellular signal-regulated protein kinase; CREB, cAMP response element-binding protein; p38, p38 mitogen-activated protein kinase. Hippocampus. 2017;1–7. wileyonlinelibrary.com/journal/hipo VC 2017 Wiley Periodicals, Inc. | 1 Received: 18 July 2016 | Revised: 25 April 2017 | Accepted: 2 May 2017 DOI: 10.1002/hipo.22740