The Anti-Inflammatory Drug Carprofen Improves Long-Term Outcome and Induces Gliogenesis after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) initiates acute and chronic inflammatory processes involving cyclooxygenase-2 (COX-2), which may have detrimental effects on outcome and especially on brain regeneration. Therefore we aimed to study whether carprofen, a COX-2 inhibitor, would improve outcome and increase neurogenesis after TBI. TBI was induced in Sabra mice that were then treated with vehicle or carprofen for 7 days. Functional outcome was evaluated with the Neurological Severity Score (NSS).Cytokine levels were assessed 4 h post-TBI and water content was measured 24 h post TBI. Mice were given BrdU to label newborn cells for 10 days. The animals were killed 90 days post-TBI and the lesion size as well as newborn cell fate were assessed. Carprofen significantly reduced lesion size (p=0.002), decreased water content in the lesioned cortex (p=0.03), reduced the number of microglia in the lesioned cortex (p<0.0001), and lowered the levels of proinflammatory cytokines (IL-1β, p=0.03; IL-6, p=0.02). Carprofen led to significantly larger improvements in functional outcome (p≤0.008) which were durable over 90 days. Carprofen also induced a threefold increase in the proliferation of new cells in the peri-lesion area (p≤0.002), but newborn cells differentiated mainly into glia in both groups. Carprofen is neuroprotective and induces cell proliferation and gliogenesis after TBI. Treatment with carprofen is consistently associated with better functional outcome. Our results imply that anti-inflammatory drugs may represent novel therapeutic options for TBI.

The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury

“…The pro-inflammatory mediators, such as COX-2 and iNOS, are inducible and markedly up-regulated after TBI and are believed to play an important role in the secondary process of injury (Khan et al, 2009). We found that PF3845 suppressed the expression of COX-2 and iNOS in brain homogenates and inflammatory cells, consistent with the reports that inhibition of COX-2 and iNOS may improve the functional outcome in rodent models of TBI (Khan et al, 2009; Thau-Zuchman et al, 2012). Despite a significant reduction of iNOS expression in the TBI mouse brain after PF3845 treatment, the density of microglia cells was unaffected.…”

Found in translation: Understanding the biology and behavior of experimental traumatic brain injury

“…For example, spatial memory deficits have been observed following CCI when evaluated using both the MWM and the Barnes maze (Fox et al, 1998, 1999). More recently, dysfunctions in social interaction, such as impaired social investigation, loss of preference for sociability, loss of presence for social novelty, and increased aggression were reported for adult mice who received a pediatric CCI injury (Thau-Zuchman et al, 2012). …”

Administration of TSG-6 improves memory after traumatic brain injury in mice

“…Also, glucocorticoids were shown to aggravate retrograded memory deficits in a TBI model (Chen et al, 2009). Non-steroidal anti-inflammatory drugs produced mixed results in models for TBI with some reports indicating improvements (Kovesdi et al, 2012; Thau Zuchman et al, 2012) but others indicating deleterious effects such as worsened cognitive outcomes (Browne et al, 2006). Strategies to reduce inflammation by targeting toll-like receptor (TLR) ligands, TLR receptors or pro-inflammatory cytokines have also proven ineffective (Rivest, 2011).…”