title: Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment. Involvement of cell cycle activation.
abstract: Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be impacted following SCI. Here we examined effects of isolated thoracic SCI in rats on cognition, brain inflammation, and neurodegeneration. We show for the first time that SCI causes widespread microglial activation in the brain, with increased expression of markers for activated microglia/macrophages, including translocator protein and chemokine ligand 21 (C-C motif). Stereological analysis demonstrated significant neuronal loss in the cortex, thalamus, and hippocampus. SCI caused chronic impairment in spatial, retention, contextual, and fear-related emotional memory-evidenced by poor performance in the Morris water maze, novel objective recognition, and passive avoidance tests. Based on our prior work implicating cell cycle activation (CCA) in chronic neuroinflammation after SCI or traumatic brain injury, we evaluated whether CCA contributed to the observed changes. Increased expression of cell cycle-related genes and proteins was found in hippocampus and cortex after SCI. Posttraumatic brain inflammation, neuronal loss, and cognitive changes were attenuated by systemic post-injury administration of a selective cyclin-dependent kinase inhibitor. These studies demonstrate that chronic brain neurodegeneration occurs after isolated SCI, likely related to sustained microglial activation mediated by cell cycle activation.
authors.affiliation: a Department of Anesthesiology & Center for Shock, Trauma, and Anesthesiology Research (STAR); University of Maryland School of Medicine; Baltimore, MD USA.
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Boris
authors.initials: B
authors.lastname: Sabirzhanov
authors.forename: Zaorui
authors.initials: Z
authors.lastname: Zhao
authors.forename: Kelsey
authors.initials: K
authors.lastname: Guanciale
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Nayar
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D002908:Chronic Disease; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000473:pathology / Q000503:physiopathology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D009410:Nerve Degeneration; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; C532131:CR8 compound; D018797:Cell Cycle Proteins; D054421:Chemokine CCL21; D047428:Protein Kinase Inhibitors; D011687:Purines; D011725:Pyridines; D018844:Cyclin-Dependent Kinases
keywords: brain; cell cycle activation; cognitive impairment; inflammation; neurodegeneration; spinal cord injury