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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Feb 23

PMID 30794775

Citations 168

Authors

Mary T Joy

Einor Ben Assayag

Dalia Shabashov-Stone

Sigal Liraz-Zaltsman

Jose Mazzitelli

Marcela Arenas

Nora Abduljawad

Efrat Kliper

Amos D Korczyn

Nikita S Thareja

Efrat L Kesner

Miou Zhou

Shan Huang

Tawnie K Silva

Noomi Katz

Natan M Bornstein

Alcino J Silva

Esther Shohami

S Thomas Carmichael

Affiliations

Soon will be listed here.

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.

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References

Fisher M, Holland C, Merzenich M, Vinogradov S . Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry. 2009; 166(7):805-11. PMC: 2720319. DOI: 10.1176/appi.ajp.2009.08050757. View

Brown C, Li P, Boyd J, Delaney K, Murphy T . Extensive turnover of dendritic spines and vascular remodeling in cortical tissues recovering from stroke. J Neurosci. 2007; 27(15):4101-9. PMC: 6672555. DOI: 10.1523/JNEUROSCI.4295-06.2007. View

Wahlund L, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M . A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001; 32(6):1318-22. DOI: 10.1161/01.str.32.6.1318. View

Shin J, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A . Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron. 2012; 74(6):1015-22. PMC: 3383631. DOI: 10.1016/j.neuron.2012.04.028. View

Chollet F, Tardy J, Albucher J, Thalamas C, Berard E, Lamy C . Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011; 10(2):123-30. DOI: 10.1016/S1474-4422(10)70314-8. View

Fu M, Yu X, Lu J, Zuo Y . Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature. 2012; 483(7387):92-5. PMC: 3292711. DOI: 10.1038/nature10844. View

Artzi M, Aizenstein O, Jonas-Kimchi T, Myers V, Hallevi H, Ben Bashat D . FLAIR lesion segmentation: application in patients with brain tumors and acute ischemic stroke. Eur J Radiol. 2013; 82(9):1512-8. DOI: 10.1016/j.ejrad.2013.05.029. View

Watkins T, Wang B, Huntwork-Rodriguez S, Yang J, Jiang Z, Eastham-Anderson J . DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc Natl Acad Sci U S A. 2013; 110(10):4039-44. PMC: 3593899. DOI: 10.1073/pnas.1211074110. View

Paterno R, Folweiler K, Cohen A . Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury. Curr Neurol Neurosci Rep. 2017; 17(7):52. PMC: 5861722. DOI: 10.1007/s11910-017-0762-x. View

10.

Biegon A, Fry P, Paden C, Alexandrovich A, Tsenter J, Shohami E . Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci U S A. 2004; 101(14):5117-22. PMC: 387383. DOI: 10.1073/pnas.0305741101. View

11.

Bigler E . Traumatic brain injury, neuroimaging, and neurodegeneration. Front Hum Neurosci. 2013; 7:395. PMC: 3734373. DOI: 10.3389/fnhum.2013.00395. View

12.

Vilkki J, Lappalainen J, Juvela S, Kanarek K, Hernesniemi J, Siironen J . Relationship of the Met allele of the brain-derived neurotrophic factor Val66Met polymorphism to memory after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2008; 63(2):198-203. DOI: 10.1227/01.NEU.0000320382.21577.8E. View

13.

Huebner E, Strittmatter S . Axon regeneration in the peripheral and central nervous systems. Results Probl Cell Differ. 2009; 48:339-51. PMC: 2846285. DOI: 10.1007/400_2009_19. View

14.

Wang L, Conner J, Nagahara A, Tuszynski M . Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets. Proc Natl Acad Sci U S A. 2016; 113(10):2750-5. PMC: 4790976. DOI: 10.1073/pnas.1514682113. View

15.

Page S, Levine P, Hade E . Psychometric properties and administration of the wrist/hand subscales of the Fugl-Meyer Assessment in minimally impaired upper extremity hemiparesis in stroke. Arch Phys Med Rehabil. 2012; 93(12):2373-6.e5. PMC: 3494780. DOI: 10.1016/j.apmr.2012.06.017. View

16.

Doniger G, Dwolatzky T, Zucker D, Chertkow H, Crystal H, Schweiger A . Computerized cognitive testing battery identifies mild cognitive impairment and mild dementia even in the presence of depressive symptoms. Am J Alzheimers Dis Other Demen. 2006; 21(1):28-36. PMC: 10833222. DOI: 10.1177/153331750602100105. View

17.

Li N, Daie K, Svoboda K, Druckmann S . Robust neuronal dynamics in premotor cortex during motor planning. Nature. 2016; 532(7600):459-64. PMC: 5081260. DOI: 10.1038/nature17643. View

18.

Flierl M, Stahel P, Beauchamp K, Morgan S, Smith W, Shohami E . Mouse closed head injury model induced by a weight-drop device. Nat Protoc. 2009; 4(9):1328-37. DOI: 10.1038/nprot.2009.148. View

19.

Clarkson A, Huang B, MacIsaac S, Mody I, Carmichael S . Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010; 468(7321):305-9. PMC: 3058798. DOI: 10.1038/nature09511. View

20.

Xing S, Lacey E, Skipper-Kallal L, Jiang X, Harris-Love M, Zeng J . Right hemisphere grey matter structure and language outcomes in chronic left hemisphere stroke. Brain. 2015; 139(Pt 1):227-41. PMC: 4990653. DOI: 10.1093/brain/awv323. View