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 preconditioning treatment with a prolyl hydroxylase inhibitor, dimethyloxalylglycine (DMOG), will increase MSC efficacy and paracrine effects in an amyloid-ß (Aß)-injected Alzheimer rat model. MSCs were incubated in different concentrations of DMOG for 24â¯h. Cell viability, migration, and antioxidant capacity was assessed in DMOG-treated and non-treated MSCs before transplantation into Aß-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 Aß-injected rats. Furthermore, we found an increased level of BDNF and total antioxidant capacity in the hippocampus of Aß-injected rats following transplantation of preconditioned relative to untreated MSCs. Our results suggest that preconditioning MSCs with DMOG before transplantation may enhance the efficacy of stem cell based therapy in neurodegenerative disease.
Subject(s)
Alzheimer Disease/therapy , Amino Acids, Dicarboxylic/therapeutic use , Cell Survival/drug effects , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/drug effects , Alzheimer Disease/chemically induced , Amino Acids, Dicarboxylic/pharmacology , Amyloid beta-Peptides , Animals , Disease Models, AnimalABSTRACT
Nicotinic acetylcholine receptors (nAChRs) expressed in the medial prefrontal cortex have critical roles in cognitive function. However, whether nAChRs are required for associative recognition memory and the mechanisms by which nAChRs may contribute to mnemonic processing are not known. We demonstrate that nAChRs in the prefrontal cortex exhibit subtype-specific roles in associative memory encoding and retrieval. We present evidence that these separate roles of nAChRs may rely on bidirectional modulation of plasticity at synaptic inputs to the prefrontal cortex that are essential for associative recognition memory.