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Cell. 2019 Feb 21;176(5):1143-1157.e13. doi: 10.1016/j.cell.2019.01.044.

CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.

Author information

1
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
2
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Department of Pharmacology, The Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.
4
Department of Pharmacology, The Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel; Institute for Health and Medical Professions, Ono Academic College, Kiryat Ono, Israel.
5
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
6
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
7
Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, and Psychology, Integrative Center for Learning and Memory and Brain Research Institute, UCLA, Los Angeles, CA 90095, USA.
8
Institute for Health and Medical Professions, Ono Academic College, Kiryat Ono, Israel.
9
Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. Electronic address: scarmichael@mednet.ucla.edu.

Abstract

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.

KEYWORDS:

MOCA; NIHSS; astrocyte; axon; axonal sprouting; dendritic spine; microglia; motor; premotor

PMID:
30794775
DOI:
10.1016/j.cell.2019.01.044

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