Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malari
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RESEARCH
Open Access
Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malaria Maiara N. Lima1, Helena A. Oliveira1, Paula M. Fagundes1, Vanessa Estato1, Adriano Y. O. Silva1, Rodrigo J. R. X. Freitas1, Beatriz A. B. R. Passos1, Karina S. Oliveira1, Camila N. Batista1, Adriana L. Vallochi1, Patricia R. M. Rocco2,3, Hugo C. Castro-Faria-Neto1,4 and Tatiana Maron-Gutierrez1,4*
Abstract Background: Malaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient’s quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression likebehavior in experimental cerebral malaria. Methods: Male C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 106 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 105 cells in 0.05 ml of saline/ mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release. (Continued on next page)
* Correspondence: [email protected]; [email protected] 1 Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Fiocruz, Av. Brasil, 4365, Pavilhão 108, sala 45, Manguinhos, Rio de Janeiro, RJ 21040-360, Brazil 4 National Institute of Science and Technology on Neuroimmunomodulation, Rio de Janeiro, RJ, Brazil Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicat
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