{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:09:33Z","timestamp":1791216573223,"version":"4.1.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood\u2013brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin\u2013sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MATERIALS AND METHODS:<\/jats:title>\n                    <jats:p>PTZ kindling (30 mg\/kg; i.p.) and PB (40 mg\/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood\u2013brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase\u2013polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Fingolimod significantly (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood\u2013brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION:<\/jats:title>\n                    <jats:p>The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/ijp.ijp_100_23","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T15:56:49Z","timestamp":1716479809000},"page":"307-314","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin\u2013sphingolipid pathway in an animal model of pharmacoresistant 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