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The Synergistic Effect of Raloxifene, Fluoxetine, and Bromocriptine Protects Against Pilocarpine-Induced Status Epilepticus and Temporal Lobe Epilepsy

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Abstract

The present antiepileptic drugs pose several problems in the management of seizures owing to their meager neuroprotective potential, adverse effects on bone, detrimental effects on cognitive function, chronic toxicity, drug interactions, side effects including aggression, agitation, and irritability and sometimes exacerbation of seizures. We followed up progressive preclinical investigation in mice against pilocarpine (PILO)-induced status epilepticus (SE) and temporal lobe epilepsy (TLE). To determine the response of raloxifene (RF) (4 and 8 mg/kg), fluoxetine (FT) (14 and 22 mg/kg), bromocriptine (BC) (6 and 10 mg/kg), and their low-dose combinations, oral treatment was scheduled for 28 days followed by PILO (300 mg/kg, i.p). The response was stalked for intensive behavioral monitoring of convulsions, hippocampal neuropeptide Y (NPY), and oxidative stress discernment along with histomorphological studies. The resultant data confirmed the therapeutic potential of triple drug combination of raloxifene (4 mg/kg) with fluoxetine (14 mg/kg) and bromocriptine (6 mg/kg) compared to monotherapy with raloxifene (4 mg/kg), and bromocriptine (6 mg/kg) as otherwise monotherapy with fluoxetine (14 mg/kg) was ineffective to suppress convulsions; an effect better than sodium valproate (300 mg/kg), a standard AED, was validated. Most profoundly, PILO-induced compensatory increases in hippocampal NPY levels (20.01%), which was escalated (100%) with the triple drug combination. The same pattern of results was superseded for oxidative stress indices and neuronal damage. The results for the first time demonstrate the propitious role of triple drug combination in the management of SE and TLE. Therapeutically, this enhancing profile of drugs fosters a safer and more effective drug-combination regimen.

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Abbreviations

SE:

Status epilepticus

TLE:

Temporal lobe epilepsy

NPY:

Neuropeptide Y

PILO:

Pilocarpine

KA:

Kainic acid

SRS:

Spontaneously recurring seizures

RF:

Raloxifene

SV:

Sodium valproate

BC:

Bromocriptine

FT:

Fluoxetine

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Acknowledgments

The authors would like to acknowledge DST, New Delhi, for providing instrumental facilities under FIST scheme to PG Department of Pharmaceutical Sciences, University of Kashmir. The authors wish to express their gratitude to Unicure (India) Pvt. Ltd., Noida, for carrying out the pharmaceutical analysis of APIs.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Faculty of Applied Sc. and Tech., University of Kashmir, Srinagar, India

    Faheem Hyder Pottoo, Nahida Tabassum, Shah Nigar, Rouqia Rasheed & Ayash Khan

  2. Department of Pharmaceutics, School of Pharmaceutical Sciences and Research, Jamia Hamdard, New Delhi, India

    Md. Noushad Javed

  3. Department of Pharmacy, School of Medical and Allied Sciences, K.R. Mangalam University, Gurugram, India

    Md. Abul Barkat & Md. Sabir Alam

  4. Department of Zoology, Govt. College for Women, M. A. Road, Srinagar, India

    Amir Maqbool

  5. Department of Epidemic Disease Research, Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia

    Mohammad Azam Ansari

  6. Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia

    George E. Barreto

  7. Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile

    George E. Barreto

  8. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

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  1. Faheem Hyder Pottoo
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Corresponding authors

Correspondence to Faheem Hyder Pottoo or Nahida Tabassum.

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Pottoo, F.H., Tabassum, N., Javed, M.N. et al. The Synergistic Effect of Raloxifene, Fluoxetine, and Bromocriptine Protects Against Pilocarpine-Induced Status Epilepticus and Temporal Lobe Epilepsy. Mol Neurobiol 56, 1233–1247 (2019). https://doi.org/10.1007/s12035-018-1121-x

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  • DOI: https://doi.org/10.1007/s12035-018-1121-x

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