title: 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.
authors.affiliation: Department of Neurology and the Peritz and Chantal Scheinberg Cerebrovascular Research Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orli
authors.initials: O
authors.lastname: Thau-Zuchman
authors.forename: Esther
authors.initials: E
authors.lastname: Shohami
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Alexandrovich
authors.forename: Victoria
authors.initials: V
authors.lastname: Trembovler
authors.forename: Ronen R
authors.initials: RR
authors.lastname: Leker
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000627:therapeutic use; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D002227:Carbazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D018696:Neuroprotective Agents; C007005:carprofen