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.

IKK2/NF‐κB signaling protects neurons after traumatic brain injury

“…However, they most likely target the inflammatory phenotype of M1-like microglia and not neurons ( 4 ). Indeed, NF-κB inhibition in microglia and astrocytes has been shown to induce a beneficial outcome from CNS injuries ( 29 , 73 – 77 ).…”

Chronic Hypopituitarism Associated with Increased Postconcussive Symptoms Is Prevalent after Blast-Induced Mild Traumatic Brain Injury

“…Deficiencies in oxytocin appear to be associated with psychiatric conditions involving deficits in social behavior including autism spectrum disorders and schizophrenia ( 84 – 86 ). Although findings in the literature lack consistency, recent research on both central and peripheral actions of oxytocin have identified potential relationships with mood and anxiety ( 87 ), learning and memory ( 88 ), improvement of wound healing ( 89 ), modulation of inflammatory responses ( 90 , 91 ), neuroprotection ( 89 , 91 , 92 ), regulation of food intake and body weight ( 93 ), and reduction of pain sensitivity ( 94 , 95 ).…”

Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now?

“…Studies in murine models have shown that salsalate, a non-steroidal anti-inflammatory drug (NSAID) reduces p-300 mediated acetylation of tau ( 30 ), resulting in improved cognition and reduced atrophy of brain regions such as the hippocampus. Lagraoui et al ( 86 ) reported similar findings in a murine model of traumatic brain injury (TBI) ( 86 ). Salsalate was shown to inhibit inflammatory pathways after TBI proximal to the injury site via reduction in microglia/macrophage activation.…”