Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2α

• Published in: Experimental neurology 2013-11, Vol.249, p.95-103
• Main Authors: Chung, Jee-In, Kim, A Young, Lee, Soo Hwan, Baik, Eun Joo
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Animals, Newborn; Biological and medical sciences; Brain - drug effects; Brain - growth & development; Brain - metabolism; Cells, Cultured; Cyclooxygenase; Cyclooxygenase 2 - biosynthesis; Developing brain; Dinoprost - administration & dosage; Dinoprost - biosynthesis; Disease Susceptibility; Drug toxicity and drugs side effects treatment; Glycosylation; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Medical sciences; Mice; Nervous system (semeiology, syndromes); Neurology; Pharmacology. Drug treatments; Prostaglandin F2α; Seizure; Seizures - metabolism; Toxicity: nervous system and muscle; Up-Regulation - physiology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2013.08.014

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. •Immature mouse brain is highly sensitive to chemically induced seizure, and resistant to NSAIDs.•Developmentally matured neurons are the main source of active COX-2 in the brain.•Little and unglycosylated COX-2 results in aggressive seizure activity in immature brain.•PGF2α, a product of COX-2, rescues KA induced seizure in immature mouse.