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Published on: June 12, 2018
Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2α
Jee-In Chung1, A Young Kim, Soo Hwan Lee
1Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, Republic of Korea.
Insights
Immature brains are more susceptible to seizures due to low cyclooxygenase (COX) activity and prostaglandin (PG) F2α deficiency. Restoring PGF2α levels can reduce seizure severity in young mice.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The immature brain exhibits heightened seizure susceptibility, a mechanism not fully understood.
- Prostaglandin (PG) F2α, produced by cyclooxygenase (COX), acts as an anticonvulsant in adult brains.
- Non-steroidal anti-inflammatory drugs are not recommended for febrile seizures in children.
Purpose of the Study:
- To investigate the role of cyclooxygenase (COX) activity in early-life seizure susceptibility.
- To determine if prostaglandin (PG) F2α deficiency contributes to immature brain vulnerability to seizures.
Main Methods:
- Comparison of kainic acid (KA)-induced seizure activity in immature (postnatal day 9) and mature (postnatal day 35) mice.
- Assessment of COX-2 expression and PGF2α levels in developing mouse brains.
- Evaluation of indomethacin (COX inhibitor) effects on seizure activity.
- Administration of PGF2α to immature mice to assess its anticonvulsant effects.
Main Results:
- Immature mice showed increased severity and duration of KA-induced seizures compared to mature mice.
- Indomethacin did not affect seizures in immature mice but aggravated them in mature mice.
- Immature brains had low basal and KA-induced COX-2 expression and PGF2α release.
- COX expression and activity increased with age during brain development.
- PGF2α administration reduced seizure activity and mortality in immature mice.
Conclusions:
- Low cyclooxygenase (COX) activity and resultant prostaglandin (PG) F2α deficiency are key factors in immature brain seizure susceptibility.
- Age-dependent changes in COX expression and activity are critical for brain maturation and seizure resistance.
- Targeting the COX-PGF2α pathway may offer therapeutic strategies for early-life seizures.
Abstract:
The immature brain is prone to seizure; however, the mechanism underlying this vulnerability has not been clarified. Febrile seizure is common in young children, and the use of non-steroidal anti-inflammatory drugs for febrile seizure is not recommended. In previous studies, we established that prostaglandin (PG) F2α, a product of cyclooxygenase (COX), acts as an endogenous anticonvulsant in the adult mouse. Therefore, we assumed that COX-2 activity was involved with seizure susceptibility in early life. In the present study, immature mice (postnatal day 9) were far more prone to kainic acid (KA)-induced seizures than mature mice (after postnatal day 35). Seizure activity began later in immature mice, but was more severe and was unaffected by a potent COX inhibitor, indomethacin; in contrast, indomethacin aggravated seizure activity in mature mice. Immature mouse brains exhibited little basal COX-2 expression and little KA-induced COX-2 induction, while KA-induced COX-2 expression and PGF2α release were prominent in mature brains. During brain development, COX expression was increased and glycosylated in an age-dependent manner, which was necessary for COX enzyme activity. Intracisternal PGF2α administration also reduced KA-induced seizure activity and mortality. Taken together, low COX activity and the resulting deficiency of PGF2α may be an essential cause of increased seizure susceptibility in the immature brain.
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