Cyclooxygenase-2-specific inhibitor improves functional outcomes, provides neuroprotection, and reduces inflammation in a rat model of traumatic brain injury.
OBJECTIVE
Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries.


METHODS
DFU [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2(5)H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model.


RESULTS
DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injury-induced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuroprotective endocannabinoid, in the injured brain.


CONCLUSIONS
These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.
Gopez
Jonas J
JJ
Department of Neurosurgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Yue
Hongfei
H
Vasudevan
Ram
R
Malik
Amir S
AS
Fogelsanger
Lester N
LN
Lewis
Shawn
S
Panikashvili
David
D
Shohami
Esther
E
Jansen
Susan A
SA
Narayan
Raj K
RK
Strauss
Kenneth I
KI
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000032:analysis; D001259:Ataxia / Q000188:drug therapy / Q000209:etiology; D001923:Brain Chemistry; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000032:analysis; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000032:analysis; D063388:Endocannabinoids; D004790:Enzyme Induction; D005106:Exploratory Behavior / Q000187:drug effects; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005989:Glycerides / Q000032:analysis; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011292:Premedication; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012021:Reflex, Abnormal / Q000187:drug effects
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D063388:Endocannabinoids; D005663:Furans; D005989:Glycerides; D018696:Neuroprotective Agents; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat; D015232:Dinoprostone
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