Combination of levetiracetam with sodium selenite prevents pentylenetetrazole-induced kindling and behavioral comorbidities in rats

Zohabia Rehman; Talha Farooq; Sana Javaid; Waseem Ashraf; Muhammad Fawad Rasool; Noreen Samad; Maryam Tariq; Syed Muhammad Muneeb Anjum; Farzane Sivandzade; Faisal Alotaibi; Faleh Alqahtani; Imran Imran

doi:10.1016/j.jsps.2022.03.003

Combination of levetiracetam with sodium selenite prevents pentylenetetrazole-induced kindling and behavioral comorbidities in rats

Saudi Pharm J. 2022 May;30(5):494-507. doi: 10.1016/j.jsps.2022.03.003. Epub 2022 Mar 10.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
² Department of Pharmacy, The Women University, Multan 60000, Pakistan.
³ Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
⁴ Department of Biochemistry, Faculty of Sciences, Bahauddin Bahauddin Zakariya University, Multan 60800, Pakistan.
⁵ The Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan.
⁶ Department of Foundation Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
⁷ Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Abstract

Introduction: The pentylenetetrazol (PTZ)-induced kindling model acts through the antagonism of central GABA_A receptors and is one of the most widely used experimental animal models to study the characteristics of seizure development, behavioral manifestations and evaluation of antiseizure effects of existing and new drug candidates.

Methodology: In the current study, we investigated the impact of chronically administered levetiracetam (50 mg/kg) and sodium selenite (Sod.Se: 0.25 and 0.5 mg/kg) alone and in combination during the kindling process (21 days) in rats. Moreover, the behavioral changes (through the integration of a wide array of behavioral tests) and markers of oxidative stress in isolated brain homogenates were assessed in PTZ- kindled rats.

Results: The outcomes from the fully kindled rats revealed the increased seizure score and severity over time with marked behavioral deficits. However, the animals treated with the selected dose of LEV alone showed partial protection from epileptogenesis and amelioration (P < 0.05) of anxiety-like behavior (open filed, light/dark, elevated plus maze tests), cognitive impairment (y-maze, novel object recognition and water maze tests) and depression (sucrose preference test). Moreover, combining the LEV with sodium selenite resulted in a significant neuroprotective effect in comparison to monotherapy by reducing the disease progression and ameliorating behavioral outcomes. The combination of Sod.Se in a dose-dependent manner with LEV produced additive effects as maximum animals remained seizure-free compared to kindled rats (P < 0.05). The attenuation of PTZ induced oxidative stress was evident from the reduced malondialdehyde and elevated superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) level with P < 0.05, as compared to control epileptic rats. These observed results of combination therapy might be due to the antioxidant and neuroprotective properties of Sod.Se, thus augmenting the seizure-modifying potentials of levetiracetam.

Conclusion: Overall, the current findings support the prominence of combining the Sod.Se with LEV, over monotherapy to deal with prevailing challenges of drug resistance and neuropsychiatric sufferings common in epileptic patients.

Keywords: Epilepsy; Levetiracetam; Morris water maze; PTZ-kindling; Sodium selenite.