Intravenous infusion of bone marrow mononuclear cells promotes functional recovery and improves impaired cognitive funct
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ORIGINAL ARTICLE
Intravenous infusion of bone marrow mononuclear cells promotes functional recovery and improves impaired cognitive function via inhibition of Rho guanine nucleotide triphosphatases and inflammatory signals in a model of chronic epilepsy Zaquer Suzana Munhoz Costa‑Ferro1 · Gutierre Neves de Oliveira1 · Daniele Vieira da Silva1 · Daniel Rodrigo Marinowic1 · Denise Cantarelli Machado1 · Beatriz Monteiro Longo2 · Jaderson Costa da Costa1 Received: 18 September 2019 / Accepted: 15 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Temporal lobe epilepsy is the most common form of intractable epilepsy in adults. More than 30% of individuals with epilepsy have persistent seizures and have drug-resistant epilepsy. Based on our previous findings, treatment with bone marrow mononuclear cells (BMMC) could interfere with early and chronic phase epilepsy in rats and in clinical settings. In this pilocarpine-induced epilepsy model, animals were randomly assigned to two groups: control (Con) and epileptic pre-treatment (Ep-pre-t). The latter had status epilepticus (SE) induced through pilocarpine intraperitoneal injection. Later, seizure frequency was assessed using a video-monitoring system. Ep-pre-t was further divided into epileptic treated with saline (Ep-Veh) and epileptic treated with BMMC (Ep-BMMC) after an intravenous treatment with BMMC was done on day 22 after SE. Analysis of neurobehavioral parameters revealed that Ep-BMMC had significantly lower frequency of spontaneous recurrent seizures (SRS) in comparison to Ep-pre-t and Ep-Veh groups. Hippocampus-dependent spatial and non-spatial learning and memory were markedly impaired in epileptic rats, a deficit that was robustly recovered by treatment with BMMC. Moreover, long-term potentiation-induced synaptic remodeling present in epileptic rats was restored by BMMC. In addition, BMMC was able to reduce abnormal mossy fiber sprouting in the dentate gyrus. Molecular analysis in hippocampal tissue revealed that BMMC treatment down-regulates the release of inflammatory cytokine tumor necrosis factor-α (TNF-α) and Allograft inflammatory factor-1 (AIF-1) as well as the Rho subfamily of small GTPases [Ras homolog gene family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac)]. Collectively, delayed BMMC treatment showed positive effects when intravenously infused into chronic epileptic rats. Keywords Chronic epilepsy · Bone marrow mononuclear cells · Memory · Exploratory behavior · Mossy fiber sprouting · Long‐term potentiation · Inflammatory responses
Introduction
* Jaderson Costa da Costa [email protected] 1
Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
Laboratory of Neurophysiology, Department of Physiology, Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brazil
2
Epilepsy, which is characterized by recurrent seizures, is a common neurological disorder, affecting approximately 50 million people of all a
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