Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/physbeh Dimethyloxalylglycine preconditioning enhances protective effects of bone marrow-derived mesenchymal stem cells in Aβ- induced Alzheimer disease Banafshe Esmaeilzade a , Tayebe Artimani b,c , Iraj Amiri b,c , Rezvan Najafi d , Siamak Shahidi e , Marie Sabec f , Parviz Farzadinia a , Mohammadali Zare a , Maria Zahiri a , Sara Soleimani Asl b,e, ⁎ a Department of Anatomy, Bushehr University of Medical Sciences, Bushehr, Iran b Endometrium and Endometriosis Research Centre, Hamadan University of Medical Sciences, Iran c Anatomy Department, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran d Research Centre for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran e Neurophysiology Research Centre, Hamadan University of Medical Sciences, Hamadan, Iran f Institut Pasteur, Neurobiologie Intégrative des Systèmes Cholinergiques, Paris, France ARTICLE INFO Keywords: MSCs Dimethyloxalylglycine Cell efficacy Alzheimer disease Spatial memory BDNF ABSTRACT Mesenchymal stem cell (MSC) transplantation therapy has been proposed as a promising approach for the treatment of neurodegenerative disease. Chemical and pharmacological preconditioning before transplantation could optimize the therapeutic properties of transplanted MSCs. In this study, we hypothesized that pre- conditioning treatment with a prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG), will increase MSC efficacy and paracrine effects in an amyloid-β (Aβ)-injected Alzheimer rat model. MSCs were incubated in different concentrations of DMOG for 24 h. Cell viability, migration, and antioxidant capacity was assessed in DMOG-treated and non-treated MSCs before transplantation into Aβ-injected rats. In vitro analysis revealed that DMOG treatment increased cell viability, migration, and expression of CXCR4, CCR2, Nrf2, and HIF-1α in the MSCs. Our in vivo results show that DMOG preconditioning enhances a MSC-mediated rescue of learning and memory function in Aβ-injected rats. Furthermore, we found an increased level of BDNF and total antioxidant capacity in the hippocampus of Aβ-injected rats following transplantation of preconditioned relative to un- treated MSCs. Our results suggest that preconditioning MSCs with DMOG before transplantation may enhance the efficacy of stem cell based therapy in neurodegenerative disease. 1. Introduction Alzheimer's disease (AD) is one of the most common form of neu- rodegenerative disorder and is characterised by cerebral accumulation of amyloid-β (Aβ) peptides and the formation of neurofibrillary tangles. Deposition of Aβ in the hippocampus disrupts synaptic plasticity and impairs learning and memory [1]. In the recent years, techniques for stem cell-based therapy have been developed and show promise as novel therapeutic approach to alleviate Aβ-induced memory impairments [2,3]. However, despite reported success of such approaches there are issues regarding the ef- ficacy of transplanted MSC migrational to target sites [4]. Only a small percentage of cells reach the target tissues and over 90% of trans- planted MSCs die within the first 24 h following transplantation. The MSC niche, the specialised microenvironment in which the cells reside, has been reported to have a critical impact on cell proliferation, differentiation, and survival [5,6]. In brief, the niche includes all of the elements surrounding the stem cells when they are in their naïve state [6] and the strategies that optimize the efficacy of transplanted MSCs are of significant interest [7,8]. Cellular preconditioning by various agents including sublethal exposure to selected stressors, hypoxia, heat shock, cytokines and growth factors have been evidenced to boost the tissue repair capacity of transplanted cells and thus may enhance the potential efficacy of cell therapy [9–11]. Hypoxia-inducible factor 1(HIF-1) as a transcription factor plays an important role in the main- tenance of oxygen homeostasis in the cells. It composed of O2-regulated HIF-1α and constitutively expressed HIF-1β subunits [12]. HIF-1α mediates the adaptive cell response to hypoxia through either deliver O2 to cells or allows cells to survive O2 deprivation [12,13]. Previous studies have shown that increased expression of HIF1α could improve osteogenic and angiogenic capacity in vitro and in vivo [14]. Under hypoxic conditions HIF-1α participates in the promotion of cell survival https://doi.org/10.1016/j.physbeh.2018.11.034 Received 5 July 2018; Received in revised form 21 November 2018; Accepted 26 November 2018 ⁎ Corresponding author. E-mail address: s.soleimaniasl@umsha.ac.ir (S. Soleimani Asl). Physiology & Behavior 199 (2019) 265–272 Available online 27 November 2018 0031-9384/ © 2018 Elsevier Inc. All rights reserved. T