RESUMEN
The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms in vitro. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Moléculas de Adhesión de Célula Nerviosa , Péptidos , Recuperación de la Función , Accidente Cerebrovascular , Animales , Masculino , Ratas , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Infarto de la Arteria Cerebral Media/terapia , Infarto de la Arteria Cerebral Media/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/efectos de los fármacos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/metabolismoRESUMEN
The pathogenesis of cerebral atrophy (CA) is not clear. Previous studies show a high incidence of preterm CA in hemodialysis patients. This study aims to investigate the factors influencing CA and to derive a CA prediction nomogram in maintenance-hemodialysis patients. First, brain volumes of hemodialysis patients (≤55 years) were compared against age- and sex-matched healthy controls, and differences were revealed in bilateral insular cisterns width, maximum cerebral sulci width, Evans index, ventricular-brain ratio, frontal atrophy index, and temporal lobe ratio. Then, the patients were divided equally into "no or mild" or "severe" CA groups. Potential factors influencing CA were screened. Kt/V (urea removal index) and hemoglobin levels negatively correlated with CA degree, and were used to establish a nomogram within randomly assigned training and validation patient groups. The areas under the receiver operating characteristic curves (AUROC) for training and validation groups were 0.703 and 0.744, respectively. When potassium and calcium were added to the nomogram, the AUROC for training/validation group increased to 0.748/0.806. The nomogram had optimal AUROC for training (0.759) and validation (0.804) groups when albumin was also included. Hemodialysis patients showed reduced anterior brain volumes and the nomogram established herein may have predictive value for developing CA.
