Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats.
- Author:
Hai-Ju ZHANG
1
;
Ruo-Peng SUN
;
Ge-Fei LEI
;
Lu YANG
;
Chun-Xi LIU
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Blotting, Western; Celecoxib; Cyclooxygenase 2; metabolism; Cyclooxygenase 2 Inhibitors; pharmacology; Disease Models, Animal; Fibrocystic Breast Disease; metabolism; Hippocampus; drug effects; enzymology; pathology; Immunohistochemistry; MAP Kinase Signaling System; drug effects; Male; Mitogen-Activated Protein Kinase Kinases; metabolism; Nitrobenzenes; pharmacology; Pilocarpine; Proto-Oncogene Proteins c-fos; metabolism; Pyrazoles; pharmacology; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; biosynthesis; Status Epilepticus; chemically induced; enzymology; pathology; Sulfonamides; pharmacology; Synapses; drug effects; pathology
- From: Journal of Zhejiang University. Science. B 2008;9(11):903-915
- CountryChina
- Language:English
-
Abstract:
OBJECTIVETo examine modulations caused by cyclooxygenase-2 (COX-2) inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms.
METHODSCelecoxib (a COX-2 inhibitor) was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mIPSCs (miniature GABAergic inhibitory postsynaptic currents) of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis were analyzed by immunohistochemistry, and expressions of alpha-subunit of gamma-amino butyric acid (GABA(A)) receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting.
RESULTSPretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABA(A) receptors. NS-398 (N-2-cyclohexyloxy-4-nitrophenyl-methanesulfonamide), another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs.
CONCLUSIONThe COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.
