Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

Frontiers in Neuroscience

Aaron M. Perry¹  Nobel A. Del Mar¹  Chunyan Li¹  Marcia G. Honig¹  Desmond L. Henderson¹  Dylan O’Neal¹  John B. Doty¹  Rachel Cox¹  Anton Reiner²  Bob M. Moore³ 

[1]Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN, United States

[2]Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN, United States

[3]Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, United States

关键词: traumatic brain injury;    visual deficits;    microglia;    CB2 receptors;    neuroinflammation;    inflammatory responses;   

DOI  :  10.3389/fnins.2021.701317

来源: DOAJ

【 摘 要 】

Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades. We previously found that treatment with the CB2 inverse agonist SMM-189 after mild TBI in mice produced by focal cranial blast rescues visual deficits and the optic nerve axon loss that would otherwise result. We have further shown that raloxifene, which is Food and Drug Administration (FDA)-approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields similar benefit in this TBI model through its modulation of microglia. As many different traumatic events produce TBI in humans, it is widely acknowledged that diverse animal models must be used in evaluating possible therapies. Here we examine the consequences of TBI created by blunt impact to the mouse head for visual function and associated pathologies and assess raloxifene benefit. We found that mice subjected to impact TBI exhibited decreases in contrast sensitivity and the B-wave of the electroretinogram, increases in light aversion and resting pupil diameter, and optic nerve axon loss, which were rescued by daily injection of raloxifene at 5 or 10 mg/ml for 2 weeks. Raloxifene treatment was associated with reduced M1 activation and/or enhanced M2 activation in retina, optic nerve, and optic tract after impact TBI. Our results suggest that the higher raloxifene dose, in particular, may be therapeutic for the optic nerve by enhancing the phagocytosis of axonal debris that would otherwise promote inflammation, thereby salvaging less damaged axons. Our current work, together with our prior studies, shows that microglial activation drives secondary injury processes after both impact and cranial blast TBI and raloxifene mitigates microglial activation and visual system injury in both cases. The results thus provide a strong basis for phase 2 human clinical trials evaluating raloxifene as a TBI therapy.

【 授权许可】

Unknown