Methotrexate carried in lipid core nanoparticles reduces microglial activation and is neuroprotective after ischemic cortical stroke
Methotrexate carried in lipid core nanoparticles reduces microglial activation and is neuroprotective after ischemic cortical stroke
Abstract Methotrexate carried in lipid core nanoparticles (LDE-MTX) is a low toxicity compound effective in reducing inflammation and secondary damage in experimental models of arthritis, atherosclerosis, myocardial infarction, cardiac allograft vasculopathy and other pathological conditions. Nevertheless, whether it is neuroprotective after stroke is unknown. Here, we explored whether LDE-MTX could cross blood brain barrier (BBB) to exert anti-inflammatory and neuroprotecive effects after experimental cortical stroke in rats. Tissue uptake was assessed by injecting radioactively labeled-LDE through the caudal vein into both sham (n=18) and adult Wistar rats submitted to endothelin-1 (ET-1)-induced cortical stroke (n=11). To address possible neuroprotective effects of LDE-MTX after stroke, 10 adult male Wistar rats were randomly allocated in two groups: animals treated with LDE-MTX (1 mg/kg, i.v., n=5) or LDE-alone (i.v., n=5) at 4 hours after stroke induction. Animals were perfused with 0.9% saline and 4% paraformaldehyde at 7 days post-injury. Histopathology was assessed by cresyl violet staining. Mature neuronal bodies (anti-NeuN), astrocytes (anti-GFAP) and microglia (anti-Iba1) were immunolabeled by immunohistochemistry. Scintigraphy technique revealed accumulation of tritiated LDE in different brain regions and in non-neural organs without overt toxicity in both sham and ischemic rats. LDE-MTX treatment induced a 10-fold (1000%) reduction in microglial activation in the ischemic cortex and afforded a 319% increase in neuronal preservation in the ischemic periinfarct region compared to LDE-alone group. There was no effect of LDE-MTX treatment on primary infarct area and astrocytosis. The results suggest that LDE-MTX formulation must be considered a very promising neuroprotective agent for ischemic stroke. Future studies using different concentrations and longer survival times are needed before assessing the suitability of LDE-MTX as a neuroprotective agent for human stroke.
Pereira Edmundo L. R.、Dias Michelle N.C.、dos Santos Ijair R.、Gomes-Leal Walace、Feio Danielle Cristine A.、Tavoni Thauany M.、da Silva Priscila Carvalho M.、Hamoy Mois¨|s、Ramos Ana Carolina、Maranh?o Raul
Laboratory of Experimental neuroprotection and neuroregeneration. Institute of Biological Sciences. Federal University of Par¨￠||Neurology Unity, University Hospital Jo?o de Barros Barreto, Federal University of Par¨￠Neurology Unity, University Hospital Jo?o de Barros Barreto, Federal University of Par¨￠Neurology Unity, University Hospital Jo?o de Barros Barreto, Federal University of Par¨￠Laboratory of Experimental neuroprotection and neuroregeneration. Institute of Biological Sciences. Federal University of Par¨￠Laboratory of Molecular Biology. State of Par¨￠ University (UEPA)Heart Institute, Faculty of Medicine, University of S?o PauloHeart Institute, Faculty of Medicine, University of S?o PauloLaboratory of Toxicology and Natural Products. Institute of Biological Sciences. Federal Univesity of Par¨￠Laboratory of Experimental neuroprotection and neuroregeneration. Institute of Biological Sciences. Federal University of Par¨￠Heart Institute, Faculty of Medicine, University of S?o Paulo
医药卫生理论医学研究方法神经病学、精神病学
StrokeNeuroinflammationNeuroprotectionMethotrexateNanotechlogyNanoemulsions
Pereira Edmundo L. R.,Dias Michelle N.C.,dos Santos Ijair R.,Gomes-Leal Walace,Feio Danielle Cristine A.,Tavoni Thauany M.,da Silva Priscila Carvalho M.,Hamoy Mois¨|s,Ramos Ana Carolina,Maranh?o Raul.Methotrexate carried in lipid core nanoparticles reduces microglial activation and is neuroprotective after ischemic cortical stroke[EB/OL].(2025-03-28)[2025-05-21].https://www.biorxiv.org/content/10.1101/2020.06.16.155804.点此复制
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