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
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:55 |
|---|---|
| Enthalten in: |
Indian journal of pharmacology - 55(2023), 5 vom: 01. Sept., Seite 307-314 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Garg, Nitika [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 24.11.2023 Date Revised 29.12.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.4103/ijp.ijp_100_23 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364212527 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364212527 | ||
| 003 | DE-627 | ||
| 005 | 20240108135940.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.4103/ijp.ijp_100_23 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1242.xml |
| 035 | |a (DE-627)NLM364212527 | ||
| 035 | |a (NLM)37929409 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Garg, Nitika |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 24.11.2023 | ||
| 500 | |a Date Revised 29.12.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Fingolimod | |
| 650 | 4 | |a P-glycoprotein | |
| 650 | 4 | |a neuroprotection | |
| 650 | 4 | |a phenobarbital resistance | |
| 650 | 4 | |a refractory epilepsy | |
| 650 | 7 | |a Anticonvulsants |2 NLM | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B |2 NLM | |
| 650 | 7 | |a ATP Binding Cassette Transporter, Subfamily B, Member 1 |2 NLM | |
| 650 | 7 | |a Endothelins |2 NLM | |
| 650 | 7 | |a Fingolimod Hydrochloride |2 NLM | |
| 650 | 7 | |a G926EC510T |2 NLM | |
| 650 | 7 | |a Nitric Oxide |2 NLM | |
| 650 | 7 | |a 31C4KY9ESH |2 NLM | |
| 650 | 7 | |a Pentylenetetrazole |2 NLM | |
| 650 | 7 | |a WM5Z385K7T |2 NLM | |
| 650 | 7 | |a Sphingolipids |2 NLM | |
| 700 | 1 | |a Joshi, Rupa |e verfasserin |4 aut | |
| 700 | 1 | |a Bhatia, Alka |e verfasserin |4 aut | |
| 700 | 1 | |a Bansal, Seema |e verfasserin |4 aut | |
| 700 | 1 | |a Chakrabarti, Amitava |e verfasserin |4 aut | |
| 700 | 1 | |a Prakash, Ajay |e verfasserin |4 aut | |
| 700 | 1 | |a Saikia, Biman |e verfasserin |4 aut | |
| 700 | 1 | |a Modi, Manish |e verfasserin |4 aut | |
| 700 | 1 | |a Medhi, Bikash |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Indian journal of pharmacology |d 1982 |g 55(2023), 5 vom: 01. Sept., Seite 307-314 |w (DE-627)NLM078779812 |x 1998-3751 |7 nnns |
| 773 | 1 | 8 | |g volume:55 |g year:2023 |g number:5 |g day:01 |g month:09 |g pages:307-314 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.4103/ijp.ijp_100_23 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 55 |j 2023 |e 5 |b 01 |c 09 |h 307-314 | ||