Diverse roles of cyclooxygenase in the central nervous system and the periphery

Cyclooxygenase (COX) is a rate limiting enzyme for prostaglandin (PG) synthesis. As inflammatory mediator, COX-2 and its product PGs modulate cytokines, chemokines and adhesion molecules in periphery and central nervous system. In the brain, COX-2 is increased by neurodegenerative disease and regulates cell death or seizure activity. In this study, I investigated that differential role of COX-2 in CNS and peripheral disease. In part I, I demonstrated that COX activity was closely involved with neonatal seizure susceptibility, and PGF2α act as anticonvulsant in neonatal brain. In present study, mouse neonate (post-natal day 9; P9) are far more prone to KA-induced seizures than the adult (P35). The seizure activities in the adult, which were aggravated by COX inhibition, showed less than those in the neonate. However, the neonatal seizure was not affected by COX inhibition which caused by little COX activity. Interestingly, in the brain, COXs mRNA and protein were age dependently increased. Neonatal brain mainly expressed unglycosylated COXs and little glycosylated COXs. Because of glycosylation is necessary for COXs enzyme activity, neonate just released little PGF2α and it does not affected by seizure. While in Adult, brain expressed glycosylated COXs and seizure increased COX-2 and PGF2α. Intracisteral PGF2α administration reduced excessive neonatal seizure activity. Taken together, little COX activity is one of the causes which are the susceptibility of neonatal seizure. And PGF2a and COX-2 act as anticonvulsant in neonate. In Part II, I demonstrate role of COX-2 as a therapeutic target in knee arthritis. Arthritis with intra-articular inflammation was accompanied by joint pain, swelling, and stiffness leading to significant functional impairment. Thus, regulation of joint inflammation is a good therapeutic approach for patients with arthritis. COX-2 and prostaglandin is well known inflammatory mediator which regulate cytokine and chemokine with cyclic feedback. In this study, using low intensity ultrasound (LIUS), I demonstrated relevance of COX-2 to arthritis resolution. Complete Freund’s adjuvant (CFA)-induced edema and synovial membrane hyperplasia in the ipsilateral joint were diminished by LIUS. The inflammatory mediators, COX-1/2, IL-1β, iNOS and chemoattractant moleculs but not TNF-α, in the synovial membrane were induced after three days. And they were reduced by LIUS. COX-2 is strongly correlated with the chemoattractant molecules, CCL2, CCR1, CCR5 and CXCR1, and CD11b induction. On immunohistochemical analysis, CFA increased infiltration of CD11b-positive cells in the synovium which was co-localized with COX-2. After three days, neutrophils, myeloperoxidase (MPO)-positive cells filled the inflammatory core; later, monocytes and macrophages, ionized calcium binding adaptor molecule 1 (Iba-1)-positive cells in the periphery infiltrated the core by day five. LIUS markedly reduced CFA-induced inflammatory cells infiltration. These data suggest COX-2 was closely related with edema and immune cell infiltration by pro-inflammatory mediator. And LIUS showed a potent anti-inflammatory effect in this animal arthritis model through COX-2 suppression.

Author dc:creator

• 정, 지인

Contributors dc:contributor

• 백, 은주
• 대학원 의생명과학과
• 200724553

• Cyclooxygenase
• PGF2α
• Seizure
• Neonate
• Arthritis
• NSAID
• Synovium
• Immune cell infiltration

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000013823
000000013823

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/8591