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Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
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Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
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Journal Article
Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo
2015
Overview
Background
Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS). It is widely accepted that inflammatory cells play major roles in the pathogenesis of MS, possibly through the use of serine protease granzyme B (GrB) secreted from the granules of cytotoxic T cells. We have previously identified GrB as a mediator of axonal injury and neuronal death. In this study, our goal was to evaluate the effect of GrB inhibition in the human system in vitro, and in vivo in EAE using the newly isolated GrB-inhibitor serpina3n.
Methods
We used a well-established in vitro model of neuroinflammation characterized by a co-culture system between human fetal neurons and lymphocytes. In vivo, we induced EAE in 10- to 12-week-old female C57/BL6 mice and treated them intravenously with serpina3n.
Results
In the in vitro co-culture system, pre-treatment of lymphocytes with serpina3n prevented neuronal killing and cleavage of the cytoskeletal protein alpha-tubulin, a known substrate for GrB. Moreover, in EAE, 50 μg serpina3n substantially reduced the severity of the disease. This dose was administered intravenously twice at days 7 and 20 post EAE induction. serpina3n treatment reduced axonal and neuronal injury compared to the vehicle-treated control group and maintained the integrity of myelin. Interestingly, serpina3n treatment did not seem to reduce the infiltration of immune cells (CD4
+
and CD8
+
T cells) into the CNS.
Conclusion
Our data suggest further studies on serpina3n as a potentially novel therapeutic strategy for the treatment of inflammatory-mediated neurodegenerative diseases such as MS.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V
Subject
Acute-Phase Proteins - therapeutic use
/ Analysis
/ Animals
/ Biomedical and Life Sciences
/ Complications and side effects
/ Dose-Response Relationship, Drug
/ Encephalomyelitis, Autoimmune, Experimental - chemically induced
/ Encephalomyelitis, Autoimmune, Experimental - prevention & control
/ Female
/ Fetus
/ Freund's Adjuvant - toxicity
/ Humans
/ Mice
/ Myelin-Oligodendrocyte Glycoprotein - toxicity
/ Neurofilament Proteins - metabolism
/ Neurons
/ Neuroprotective Agents - therapeutic use
/ Peptide Fragments - toxicity
/ T cells
/ T-Lymphocytes - drug effects
/ Thrombin
/ Tubulins
