Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice.

Abstract

Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Results: Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45int microglia and CD45hi myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. Conclusion: These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function.

• Authors: Yun Li, Rodney M Ritzel, Niaz Khan, Tuoxin Cao, Junyun He, Zhuofan Lei, Jessica J Matyas, Boris Sabirzhanov, Simon Liu, Hui Li, Bogdan A Stoica, David J Loane, Alan I Faden, Junfang Wu
• Journal: Theranostics (Theranostics) Vol. 10 Issue 25 Pg. 11376-11403 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33052221 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Organic Chemicals
• PLX5622
• Reactive Oxygen Species

Topics

• Administration, Oral
• Animals
• Behavior Observation Techniques
• Behavior, Animal (drug effects, physiology)
• Brain (cytology, drug effects, immunology, pathology)
• Cognitive Dysfunction (immunology, pathology, physiopathology, prevention & control)
• Depression (diagnosis, etiology, prevention & control)
• Disease Models, Animal
• Humans
• Inflammation (drug therapy, pathology, physiopathology)
• Learning (drug effects, physiology)
• Male
• Memory (drug effects, physiology)
• Mice
• Microglia (drug effects, immunology, pathology)
• Motor Activity (drug effects, physiology)
• Organic Chemicals (administration & dosage)
• Reactive Oxygen Species (metabolism)
• Spinal Cord (drug effects, immunology, pathology)
• Spinal Cord Injuries (complications, drug therapy, immunology, pathology)