Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats

Abstract

Abstract:Objective: To 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. Methods: Celecoxib (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 α-subunit of γ-amino butyric acid (GABA A ) receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activity were detected by Western blotting. Results: Pretreatment 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. Conclusion: The 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.

Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment

“…The higher dose, i.e., 10 mg/kg, has also been used in an earlier study evaluating the interaction potential of etoricoxib [20]. In different studies of COX inhibitors and seizures, the drug was administered (1) before single seizure (PTZ 60 mg/kg), which shows dosedependent effect [22]; (2) after seizures, which shows an increase in inflammation consequences; (3) prior to seizures, i.e., during the kindling, which shows protection [6][7][8]23], proconvulsant effect, or no effect [13]; and (4) prior to kindling as prophylaxis [24] resulting in increased seizure severity and mortality [10,25,26]. We used a different protocol where etoricoxib treatment was started once the kindling had been established and continued for nine days before PTZ rechallenge (subanticonvulsant dose).…”

Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: Uncontrolled inflammation drives disease progression?

“…Accumulating evidence supports the role of IL-1 in reducing seizure threshold and epileptogenesis in the pilocarpine SE model of epilepsy [44]. Inflammatory mediators that are released from astrocytes, such as COX-2, may directly affect epileptogenesis [74,75]. TNF-α has been identified as a prominent glutamate release modulator in cultured astrocytes; [76] complex cross-talk between microglia and astrocyte during neuroinflammatory insults can influence glutamatedependent responses [77].…”

Ablation of Cyclooxygenase-2 in Forebrain Neurons is Neuroprotective and Dampens Brain Inflammation after Status Epilepticus

“…However, the role of COX-2 expressed by neurons has remained elusive because COX-2 is expressed in many nonneuronal cells, and the only tools available have been pharmacologic inhibitors and global knock-outs. Inhibition of COX-2 can either exacerbate (Baik et al, 1999; Kim et al, 2008; Toscano et al, 2008) or attenuate (Baran et al, 1994; Kunz and Oliw, 2001; Jung et al, 2006; Takemiya et al, 2006; Zhang et al, 2008) the neurodegeneration observed after SE depending on the strategies used to delete or inhibit COX-2. The global COX-2 knock-out mouse is more susceptible to SE (Toscano et al, 2008), preventing conclusions on the role of postseizure COX-2 induction.…”