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| RESEARCH ARTICLE |
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| Year : 2023 | Volume
: 55
| Issue : 5 | Page : 307-314 |
Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin–sphingolipid pathway in an animal model of pharmacoresistant epilepsy
Nitika Garg1, Rupa Joshi2, Alka Bhatia3, Seema Bansal4, Amitava Chakrabarti1, Ajay Prakash1, Biman Saikia5, Manish Modi6, Bikash Medhi1
1 Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Haryana, India
2 Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh; Department of Pharmacology, MM Institute of Medical Sciences and Research, Maharishi Markandeshwar (Deemed to be university), Mullana, Ambala, Haryana, India
3 Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Haryana, India
4 Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh; Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be university), Mullana, Ambala, Haryana, India
5 Department of Immunopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Haryana, India
6 Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, Haryana, India
Correspondence Address:
Bikash Medhi
Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_100_23
BACKGROUND: 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–brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin–sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats.
MATERIALS AND METHODS: 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–brain 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–polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury.
RESULTS: Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood–brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy.
CONCLUSION: 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.
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