Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.

The Journal of Experimental Medicine
Mikko T HuuskonenBerislav V Zlokovic

Abstract

Subcortical white matter (WM) stroke accounts for 25% of all strokes and is the second leading cause of dementia. Despite such clinical importance, we still do not have an effective treatment for ischemic WM stroke, and the mechanisms of WM postischemic neuroprotection remain elusive. 3K3A-activated protein C (APC) is a signaling-selective analogue of endogenous blood protease APC that is currently in development as a neuroprotectant for ischemic stroke patients. Here, we show that 3K3A-APC protects WM tracts and oligodendrocytes from ischemic injury in the corpus callosum in middle-aged mice by activating protease-activated receptor 1 (PAR1) and PAR3. We show that PAR1 and PAR3 were also required for 3K3A-APC's suppression of post-WM stroke microglia and astrocyte responses and overall improvement in neuropathologic and functional outcomes. Our data provide new insights into the neuroprotective APC pathway in the WM and illustrate 3K3A-APC's potential for treating WM stroke in humans, possibly including multiple WM strokes that result in vascular dementia.

References

Mar 29, 2001·Physiological Reviews·N Baumann, D Pham-Dinh
Sep 1, 2005·Annals of Neurology·Berislav V ZlokovicMichael Chopp
Oct 31, 2006·Nature Medicine·Tong ChengBerislav V Zlokovic
Mar 23, 2007·Proceedings of the National Academy of Sciences of the United States of America·Joseph N McLaughlinAsrar B Malik
Jan 27, 2009·Journal of Neurochemistry·Huang GuoBerislav V Zlokovic
Mar 24, 2009·The European Journal of Neuroscience·Huang GuoBerislav V Zlokovic
Apr 1, 2009·Proceedings of the National Academy of Sciences of the United States of America·Angela RussoJoann Trejo
May 15, 2009·Journal of Neuroscience Methods·Elif G SozmenS Thomas Carmichael
May 12, 2010·The Journal of Clinical Investigation·Chunzhang CaoLi Zhang
Jun 4, 2011·Stroke; a Journal of Cerebral Circulation·Jacqueline J J ZhengStephen R Lord
Nov 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Unice J K Soh, JoAnn Trejo
Jun 21, 2012·Journal of Thrombosis and Haemostasis : JTH·R A SchuepbachM Riewald
Dec 6, 2012·Stroke; a Journal of Cerebral Circulation·Carlos MatuteBruce R Ransom
Apr 5, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Huang GuoBerislav V Zlokovic
Jul 23, 2013·Stroke; a Journal of Cerebral Circulation·Shira Rosenzweig, S Thomas Carmichael
Jan 1, 2014·Current Pharmaceutical Design·Patrick LydenBerislav Zlokovic
Mar 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ethan A WinklerBerislav V Zlokovic
Sep 5, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ye ZhangJian Qian Wu
Mar 3, 2015·Nature Neuroscience·Ethan A WinklerBerislav V Zlokovic
Apr 1, 2015·Blood·John H GriffinLaurent O Mosnier
Jun 25, 2015·Journal of the American Heart Association·Joanna M WardlawSusana Muñoz-Maniega
Jul 15, 2015·Developmental Cell·J Bradley ZucheroBen A Barres
Jan 23, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Ranjeet K SinhaJohn H Griffin
Apr 20, 2016·Progress in Neurobiology·Yuan WangGuodong Cao
Jul 13, 2016·Proceedings of the National Academy of Sciences of the United States of America·Joshua Sarfaty SiegelMaurizio Corbetta

❮ Previous
Next ❯

Related Concepts

Related Feeds

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Related Papers

Ageing Research Reviews
Huan LiuXiaoming Hu
The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry
Selva Baltan
Journal of Experimental Psychology. Human Perception and Performance
Jacob A MillerMark D'Esposito
© 2022 Meta ULC. All rights reserved