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      Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus

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          Significance

          This study demonstrated that intranasal (IN) administration of A1-exosomes alleviates multiple adverse changes that typically emerge after status epilepticus (SE), a medical crisis that presents a high propensity to evolve into chronic hippocampus dysfunction. Specifically, A1-exosome treatment after SE led to reduced neuron loss and inflammation, maintenance of normal neurogenesis, and preservation of cognitive and memory function. The results have significance for clinical application of A1-exosomes for curbing the evolution of SE-induced injury into chronic hippocampus dysfunction. The results also imply that IN administration of A1-exosomes is therapeutic for other neurological conditions that present with significant neuroinflammation.

          Abstract

          Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrow-derived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          25 April 2017
          10 April 2017
          10 April 2017
          : 114
          : 17
          : E3536-E3545
          Affiliations
          [1] aInstitute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine , Temple, TX 76502;
          [2] bOlin E. Teague Veterans’ Medical Center, Central Texas Veterans Health Care System , Temple, TX 76502;
          [3] cDepartment of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine , College Station, TX 77843;
          [4] dDepartment of Clinical Translational Medicine, Texas A&M Health Science Center College of Medicine , College Station, TX 77843
          Author notes
          5To whom correspondence may be addressed. Email: prockop@ 123456medicine.tamhsc.edu or shetty@ 123456medicine.tamhsc.edu .

          Contributed by Darwin J. Prockop, March 13, 2017 (sent for review December 23, 2016; reviewed by Cesar Borlongan and Daniel A. Peterson)

          Author contributions: Q.L., D.U., B.H., D.J.P., and A.K.S. designed research; Q.L., D.U., B.H., D.-K.K., S.Y.A., and B.S. performed research; D.-K.K. and S.Y.A. contributed new reagents/analytic tools; Q.L., D.U., B.H., D.J.P., and A.K.S. analyzed data; and Q.L., D.U., B.H., D.J.P., and A.K.S. wrote the paper.

          Reviewers: C.B., Center of Excellence for Aging and Brain Repair University of South Florida; and D.A.P., Rosalind Franklin University of Medicine and Science.

          1Present address: Department of Neurosurgery, Xi’an Central Hospital, School of Medicine, Xi’an Jiao Tong University, Xi’an 710003, P.R. China.

          2Q.L. and D.U. contributed equally to this work.

          3Present address: Center for Molecular Neurosciences, Manipal University, Manipal 576104, Karnataka, India.

          4D.J.P. and A.K.S. contributed equally to this work.

          Article
          PMC5410779 PMC5410779 5410779 201703920
          10.1073/pnas.1703920114
          5410779
          28396435
          58a7199f-772e-45aa-9a96-e5df88c24965

          Freely available online through the PNAS open access option.

          History
          Page count
          Pages: 10
          Funding
          Funded by: Texas Emerging Technology Fund (Emerging Technology Fund) 100006945
          Award ID: ETF to A.K.S.
          Funded by: U.S. Department of Veterans Affairs (VA) 100000738
          Award ID: I01 BX002351
          Funded by: HHS | National Institutes of Health (NIH) 100000002
          Award ID: P40OD011050
          Funded by: U.S. Department of Veterans Affairs (VA) 100000738
          Award ID: 1IK6BX003612 (BLRamp;D Research Career Scientist Award)
          Categories
          PNAS Plus
          Biological Sciences
          Neuroscience
          PNAS Plus

          status epilepticus,memory dysfunction,neuroinflammation,exosomes,adult neurogenesis

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