الفهرس 
Introduction and RationaleOnly 14 pages are availabe for public view
 |  | from | 128 |  |  |
| | | from | 128 | | |
Abstract
The present study was performed to evaluate the effect of cylooxygenase (COX) inhibition either with non selective COX inhibitor like indomethacin or with selective COX-2 inhibitor, like celecoxib on the level of P-glycoprotein (P-gp) expression and the extent of phenytoin that reaches the brain of rats in a model of pilocarpine induced epilepsy. A total of 56 adult male albino rats, weighing 170-200 gm were used and subdivided randomly into 7 groups of 8 animals in each group. group (1) control rats, received only normal saline. group (2) epileptic non treated rats, received only (i.p.) pilocarpine injection for the induction of epilepsy on the 4th day. group (3) phenytoin treated epileptic rats, were given phenytoin on the 4th day and 5th day respectively after the induction of epilepsy. group (4) indomethacin pre-treated epileptic rats, received indomethacin 2.5 mg/kg (i.p.) daily during the first 3 days before pilocarpine injection and continued with the same dose after the induction of epilepsy on the 4th day and 5th day respectively. group (5) Celexocib pre-treated epileptic rats, received celexocib in a dose of 20 mg/kg (i.p.) every 12 hours during the first 3 days before pilocarpine injection and celexocib continued with the same dose after the induction of epilepsy on the 4th day and 5th day respectively. group (6) Pre-indomethacin/combined with phenytoin treated epileptic rats, received indomethacin in a dose of 2.5 mg/kg (i.p.) daily, for 3 days before pilocarpine injection. After the induction of epilepsy, indomethacin dose continued in combination with phenytoin 50 mg/kg (i.p.) daily, during the 4th day and 5th day respectively. group (7) Pre-celecoxib/combined with phenytoin treated epileptic rats, received celexocib in a dose of 20 mg/kg (i.p). every 12 hours for 3 days before pilocarpine injection. After the induction of epilepsy, celexocib dose continued in combination with phenytoin 50 mg/kg (i.p.) daily, during the 4th day and 5th day respectively.
Phenytoin level was measured using high performance liquid chromatography (HPLC), while P-gp expression was detected by immunostaining. Also, ABCB1 gene expression and glutamate level were measured using Polymerase Chain Reaction (PCR) and Enzyme Linked Immunosorbent Assay (ELISA), respectively.
The results of the present study proved that the combination of both indomethacin and celecoxib decreased glutamate expression, ABCB1 gene expression and P-gp expression in the studied groups. The decrease in P-gp expression was associated with increase in the brain level of phenytoin in the groups that received phenytoin combined with either celecoxib or indomethacin. However, celecoxib has greater effect than indomethacin in increasing the brain level of phenytoin.
Taken all these results together, we can conclude that epileptic seizures increase glutamate expression in the brain. Glutamate in the presence of COX-2 enzyme, encodes for the transcription of ABCB1 gene, leading to excessive production of P-gp. P-gp is a major cause of drug resistance. P-gp inhibition with celecoxib or indomethacin, allowed higher concentration of phenytoin to pass through the blood brain barrier and reach the brain of rats. Also, both indomethacin and celecoxib showed marked neuroprotective effects. Celecoxib proved to have more beneficial effect than indomethacin in increasing the brain level of phenytoin.
Recommendations