Integrative role of cPLA with COX-2 and the effect of non-steriodal anti-inflammatory drugs in a transgenic mouse model of amyotrophic lateral sclerosis.
Cyclooxygenase-2 (COX-2) is a key molecule in the inflammatory pathway in amyotrophic lateral sclerosis (ALS). Cytosolic phospholipase A (cPLA2) is an important enzyme providing substrate for cyclooxygenases. We therefore examined cPLA2 expression in human ALS and mutant Cu/Zn superoxide dismutase (SOD1) transgenic mice and its relation to COX-2. Immunohistochemistry and real-time RT-PCR revealed elevated cPLA2 protein and its mRNA levels in the lumbar spinal cord of mutant SOD1 mice. COX-2 immunoreactivity was increased in lumbar spinal cord sections from both familial ALS (FALS) and sporadic ALS (SALS) as compared to controls, and cPLA2 immunoreactivity was increased in a patient with FALS. Oral administration of the non-selective cyclooxygenase (COX) inhibitor, sulindac, extended the survival (by 10%) of G93A SOD1 mice as compared to littermate controls. Sulindac, as well as the selective COX-2 inhibitors, rofecoxib and celecoxib reduced cPLA2 immunoreactivity in the lumbar spinal cord of G93A transgenic mice. Sulindac treatment preserved motor neurons, and reduced microglial activation and astrocytosis, in the spinal cord of G93A SOD1 transgenic mice. These results suggest that cPLA2 plays an important role in supplying arachidonic acid to the COX-2 driven inflammatory pathway in ALS associated with SOD1 mutations.
Kiaei
Mahmoud
M
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, New York 10021, USA. mak2026@med.cornell.edu
Kipiani
Khatuna
K
Petri
Susanne
S
Choi
Dong-Kug
DK
Chen
Junyu
J
Calingasan
Noel Y
NY
Beal
M Flint
MF
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D003600:Cytosol / Q000201:enzymology; D004195:Disease Models, Animal; D005260:Female; D054513:Group IV Phospholipases A2; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; C516390:Pla2g4a protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human