title: Salsalate treatment following traumatic brain injury reduces inflammation and promotes a neuroprotective and neurogenic transcriptional response with concomitant functional recovery.
abstract: Neuroinflammation plays a critical role in the pathogenesis of traumatic brain injury (TBI). TBI induces rapid activation of astrocytes and microglia, infiltration of peripheral leukocytes, and secretion of inflammatory cytokines. In the context of modest or severe TBI, such inflammation contributes to tissue destruction and permanent brain damage. However, it is clear that the inflammatory response is also necessary to promote post-injury healing. To date, anti-inflammatory therapies, including the broad class of non-steroidal anti-inflammatory drugs (NSAIDs), have met with little success in treatment of TBI, perhaps because these drugs have inhibited both the tissue-damaging and repair-promoting aspects of the inflammatory response, or because inhibition of inflammation alone is insufficient to yield therapeutic benefit. Salsalate is an unacetylated salicylate with long history of use in limiting inflammation. This drug is known to block activation of NF-κB, and recent data suggest that salsalate has a number of additional biological activities, which may also contribute to its efficacy in treatment of human disease. Here, we show that salsalate potently blocks pro-inflammatory gene expression and nitrite secretion by microglia in vitro. Using the controlled cortical impact (CCI) model in mice, we find that salsalate has a broad anti-inflammatory effect on in vivo TBI-induced gene expression, when administered post-injury. Interestingly, salsalate also elevates expression of genes associated with neuroprotection and neurogenesis, including the neuropeptides, oxytocin and thyrotropin releasing hormone. Histological analysis reveals salsalate-dependent decreases in numbers and activation-associated morphological changes in microglia/macrophages, proximal to the injury site. Flow cytometry data show that salsalate changes the kinetics of CCI-induced accumulation of various populations of CD11b-positive myeloid cells in the injured brain. Behavioral assays demonstrate that salsalate treatment promotes significant recovery of function following CCI. These pre-clinical data suggest that salsalate may show promise as a TBI therapy with a multifactorial mechanism of action to enhance functional recovery.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Mouna
authors.initials: M
authors.lastname: Lagraoui
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA; Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Gauthaman
authors.initials: G
authors.lastname: Sukumar
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Latoche
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Sean K
authors.initials: SK
authors.lastname: Maynard
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA; Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Bethesda, MD, USA.
authors.forename: Clifton L
authors.initials: CL
authors.lastname: Dalgard
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA; Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA. Electronic address: brian.schaefer@usuhs.edu.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D051456:Gene Flow / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010121:Oxytocin / Q000235:genetics; D020127:Recovery of Function / Q000187:drug effects*; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use*; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics
chemical_list: D018696:Neuroprotective Agents; D012459:Salicylates; D010121:Oxytocin; D013973:Thyrotropin-Releasing Hormone; C014182:salicylsalicylic acid
keywords: Microglia; Motor function; Myeloid cells; NF-kappaB; NSAID; Neuroprotection; Neuroregeneration; Oxytocin; Salicylate; TBI