Effect of status epilepticus on expression of brain UDP‐glucuronosyltransferase 1a in rats

Abstract

Status epilepticus (SE) involves severe epileptic seizures that cause oxidative stress in the brain. Oxidative stress is known to influence uridine 5'-diposphate-glucuronosyltransferase (UGT) 1A expression. The present study aimed at elucidating the effect of SE on Ugt1a1, Ugt1a6 and Ugt1a7 expression in the rat brain. Kainic acid was used to create an animal model of SE. Sprague-Dawley rats were treated intraperitoneally with 10 mg/kg kainic acid. Ugt1a1 and Ugt1a7 mRNA levels were increased by SE in the cortex and hippocampus (Ugt1a1: 4.0- and 5.3-fold, respectively; Ugt1a7: 2.8- and 2.5-fold, respectively). Moreover, the induction degree of heme oxygenase-1 mRNA, an oxidative stress marker, was high in these regions, suggesting that oxidative stress could be involved in Ugt1a1 and Ugt1a7 induction. Ugt1a6 was elevated by 1.8-fold in the cortex in both SE and non-response (non-epileptic seizure response) rats, implying that Ugt1a6 induction may be independent from SE. An intraperitoneal single administration of 25 mg/kg diazepam (DZP) for the treatment of SE could attenuate heme oxygenase-1 induction in the cortex, whereas Ugt1a1 was decreased in the hippocampus, but not in the cortex, suggesting that there likely exists an alternative mechanism for Ugt1a1 reduction by DZP treatment. Continuous 14-day administration of DZP inhibited Ugt1a1 induction in the cortex, but did not have an effect on Ugt1a7 induction. This study indicated that SE altered the expression of brain Ugt1a1 and Ugt1a7, which could alter glucuronidation in the brain.

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

“…Status epilepticus significantly up-regulated expressions of Ugt1a1 and Ugt1a7 mRNA in cortex and hippocampus of rat but not in liver. The up-regulation of Ugt1a1 and Ugt1a7 in brain was considered to be related to oxidative stress (Asai et al, 2018a). UGT1A4 catalyzes the N-glucuronidation of some antiepileptics (such as lamotrigine and midazolam), tricyclic antidepressants (such as doxepin, imipramine and amitriptyline) and antipsychotics (such as clozapine, olanzapine and trifluoperazine).…”