PMID- 16330497
OWN - NLM
STAT- MEDLINE
DCOM- 20060413
LR  - 20131121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 316
IP  - 3
DP  - 2006 Mar
TI  - R(+)-methanandamide and other cannabinoids induce the expression of 
      cyclooxygenase-2 and matrix metalloproteinases in human nonpigmented ciliary 
      epithelial cells.
PG  - 1219-28
AB  - Prostaglandins (PGs) and matrix metalloproteinases (MMP) have been implicated in 
      lowering intraocular pressure (IOP) by facilitating aqueous humor outflow. A 
      possible role of cyclooxygenase-2 (COX-2) in this process was emphasized by 
      findings showing an impaired COX-2 expression in the nonpigmented ciliary 
      epithelium (NPE) of patients with primary open-angle glaucoma. Using human NPE 
      cells, the present study therefore investigated the effect of the IOP-lowering 
      cannabinoid R(+)-methanandamide [R(+)-MA] on the expression of COX-2 and 
      different MMPs and tissue inhibitors of MMPs (TIMPs). R(+)-MA led to a 
      concentration- and time-dependent increase of COX-2 mRNA expression. 
      R(+)-MA-induced COX-2 expression was accompanied by time-dependent 
      phosphorylations of p38 mitogen-activated protein kinase (MAPK) and p42/44 MAPK 
      and was abrogated by inhibitors of both pathways. Moreover, R(+)-MA increased the 
      mRNA and protein expression of MMP-1, MMP-3, MMP-9, and TIMP-1 but not that of 
      MMP-2 and TIMP-2. Inhibition of COX-2 activity with NS-398 
      [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide] was associated with a 
      virtually complete suppression of R(+)-MA-induced MMP-9 and TIMP-1 expression. 
      Consistent with these data, MMP-9 and TIMP-1 expression was also induced by PGE2, 
      a major COX-2 product. Two other COX-2-inducing cannabinoids, anandamide and 
      Delta9-tetrahydrocannabinol, caused the same pattern of MMP and TIMP expression 
      as R(+)-MA both in the absence and presence of NS-398. Altogether, cannabinoids 
      induce the production of several outflow-facilitating mediators in the human NPE. 
      Our results further imply an involvement of COX-2-dependent PGs in MMP-9 and 
      TIMP-1 expression. In conclusion, stimulation of intraocular COX-2 and MMP 
      expression may represent a potential mechanism contributing to the IOP-lowering 
      action of different cannabinoids.
FAU - Rosch, Susanne
AU  - Rosch S
AD  - Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich 
      Alexander University Erlangen-Nurnberg, Fahrstrasse 17, D-91054 Erlangen, 
      Germany.
FAU - Ramer, Robert
AU  - Ramer R
FAU - Brune, Kay
AU  - Brune K
FAU - Hinz, Burkhard
AU  - Hinz B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20051205
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Arachidonic Acids)
RN  - 0 (Cannabinoids)
RN  - 0 (Nitrobenzenes)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sulfonamides)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 123653-11-2 (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide)
RN  - 150314-39-9 (methanandamide)
RN  - 7J8897W37S (Dronabinol)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Arachidonic Acids/*pharmacology
MH  - Cannabinoids/*pharmacology
MH  - Cells, Cultured
MH  - Cilia/*metabolism
MH  - Cyclooxygenase 2/*genetics
MH  - Dinoprostone/biosynthesis
MH  - Dose-Response Relationship, Drug
MH  - Dronabinol/pharmacology
MH  - Epithelial Cells/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Gene Expression Regulation, Enzymologic/*drug effects
MH  - Humans
MH  - Matrix Metalloproteinases/*genetics
MH  - Nitrobenzenes/pharmacology
MH  - Phosphorylation
MH  - RNA, Messenger/analysis
MH  - Sulfonamides/pharmacology
MH  - Tissue Inhibitor of Metalloproteinase-1/genetics
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2005/12/07 09:00
MHDA- 2006/04/14 09:00
CRDT- 2005/12/07 09:00
PHST- 2005/12/07 09:00 [pubmed]
PHST- 2006/04/14 09:00 [medline]
PHST- 2005/12/07 09:00 [entrez]
AID - jpet.105.092858 [pii]
AID - 10.1124/jpet.105.092858 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2006 Mar;316(3):1219-28. doi: 10.1124/jpet.105.092858. Epub 
      2005 Dec 5.