Abstract
Objective. To evaluate the effect of CLMD administration on epileptic seizures and brain injury in pentylenetetrazole- (PZT-) kindled mice. Methods. The effect of pretreatment with CLMD (5, 10, and 20 ml/kg (mg/kg) by gavage) for seven days on PTZ-induced kindling, duration and grade of kindling-induced seizures, and pathological injury in the cortex and hippocampus was evaluated. Male BALB/c mice with adenosine A1 receptor knockout were subjected to intraperitoneal injection of PTZ (35 mg/kg) once every day until kindling was successfully induced. Quantitative reverse transcription polymerase chain reaction, immunofluorescence, and western blot were performed to assess the mRNA and protein levels of p-glycoprotein (PGP), multidrug resistance-associated protein 1 (MRP1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and adenylate kinase (ADK) in the cortex and hippocampus. Results. PTZ successfully induced kindling in mice after 21 days, wherein CLMD showed an obvious dose-dependent antiepileptic effect. High-dose CLMD significantly increased the latency of epileptic seizures, decreased the sustained time of epileptic seizures and the seizure grade, and ameliorated the histopathological changes in the cortex and hippocampus. Furthermore, PTZ kindling induced significantly higher levels of PGP, MRP1, COX-2, PGE2, and ADK, but this effect was inhibited by pretreatment with CLMD in a dose-dependent manner. Conclusion. Pretreatment with CLMD attenuates PTZ-kindled convulsions and brain injury in mice. The mechanism may be related to the cyclooxygenase-2/prostaglandin E2/multidrug transporter pathway.
Highlights
Epilepsy is one of the most common and disabling neurological diseases and is characterized by recurrent seizure activity [1]
No mouse died after the 21-day behavioral analysis, and the control mice challenged with saline did not exhibit seizures
On day 21, the mean latency of epileptic seizures was significantly increased in the CLMDtreated mice compared with that in the nontreated kindled mice, especially at high-dose CLMD (P < 0:01, Figure 1(a))
Summary
Epilepsy is one of the most common and disabling neurological diseases and is characterized by recurrent seizure activity [1]. In spite of the clinical application of around 20 antiepileptic drugs (AEDs), 20–30% of patients still experience refractory epilepsy because of the unsatisfactory efficacy of these drugs [3]. This results in increased mortality and disability rates, declining quality of life, and increasing social and family economic burden. It is imperative to explore new prevention and treatment strategies for refractory epilepsy. The determination of effective concentrations of AEDs at traumatic brain lesions has become a key in the prevention of refractory epilepsy [4]. Multidrug transporters (MDTs), such as p-glycoprotein (PGP) and multidrug resistance-associated protein 1 (MRP1) in the central nervous system, are mainly expressed on the lumen surface of cerebral capillary endothelial cells and are associated with
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