Abstract
Cyclooxygenases (COX)-1 and -2 are isoenzymes that catalyze the conversion of arachidonic acid into prostaglandins (PGs). COX-2 and PGs are rapidly increased following seizures and are known to play important roles in the neuroinflammatory process. COX-2 isoform has been predominantly explored as the most suitable target for pharmacological intervention in epilepsy studies, while COX-1 remains poorly investigated. In the present study, we evaluated the effects of selective COX-1 inhibitor or selective COX-2 inhibitor on seizure suppression in the zebrafish pentylenetetrazole (PTZ)-seizure model. Zebrafish larvae were incubated in 5 μM of SC-236 for 24 h or 2.8 μM of SC-560 for 30 min, followed by exposure to 15 mM PTZ for 60 min. Real-time quantitative PCR analysis was carried out to investigate transcription levels of cox1 (ptgs1), as well as to determine cfos levels, used as a marker for neuronal activity. Effects of selective COX-2 or COX-1 inhibitors on locomotor activity response (velocity and distance moved) during PTZ exposure were evaluated using the Danio Vision video-tracking system. Our results showed an inducible expression of the cox1 gene after 60 min of PTZ exposure. Cox1 mRNA levels were upregulated compared with the control group. We found that COX-2 inhibition treatment had no effect on zebrafish PTZ-induced seizures. On the other hand, COX-1 inhibition significantly attenuated PTZ-induced increase of locomotor activity and reduced the c-fos mRNA expression. These findings suggest that COX-1 inhibition rather than COX-2 has positive effects on seizure suppression in the zebrafish PTZ-seizure model.
Highlights
Seizures are conceptually defined as abnormal and hypersynchronous neuronal activity that is caused by an imbalance between excitatory and inhibitory neurotransmission [1]
We previously reported that cox2b mRNA expression was upregulated after PTZ-induced seizures in 7 dpf zebrafish larva [37]
To determine whether the cox1 transcription is affected following PTZ-induced seizure, we used real-time quantitative PCR (qPCR) to measure the relative quantification of the cox1 gene
Summary
Seizures are conceptually defined as abnormal and hypersynchronous neuronal activity that is caused by an imbalance between excitatory and inhibitory neurotransmission [1]. It is not surprising that the mechanisms of action of most antiepileptic drugs (AEDs) target neuronal mechanisms involving in the modulation of voltage-activated ion channels, inhibition of excitatory, or enhancement of inhibitory synaptic neurotransmission [2]. There is accumulated experimental evidence supporting the contribution of non-neuronal cells, astrocytes, and microglia, to the pathophysiology of epilepsy [7,8,9,10,11,12]. It is known that astrocytes and microglia activation promotes the release of proinflammatory mediators, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase (COX)-2, and prostaglandins (PGs) [13, 14]. Inflammatory mediators have been explored as alternative pharmacological targets for therapeutic intervention to treat epilepsy [11, 18, 19]
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