Elsevier

Epilepsy & Behavior

Volume 75, October 2017, Pages 203-209
Epilepsy & Behavior

Pharmacokinetic and pharmacodynamic interaction of hydroalcoholic extract of Ocimum sanctum with valproate

https://doi.org/10.1016/j.yebeh.2017.08.018Get rights and content

Highlights

  • This study envisaged antiepileptic and neuroprotective potential of Ocimum sanctum (Tulsi) hydroalcoholic extract (OSHE).

  • The optimal dose of OSHE was determined using standard seizure models in Wistar rats.

  • OSHE optimal dose was administered for 14 days in combination with different doses of valproate for interaction study.

  • Ocimum, although having per se antiepileptic action, did not affect antiepileptic effect of valproate in combination

  • Combination treatment improved neurocognitive function and reduced oxidative stress, predicting adjuvant potential of Ocimum.

Abstract

For effective control of seizures, antiepileptic drugs (AEDs) are administered at higher dose which is associated with several adverse effects. This study envisaged antiepileptic and neuroprotective potential of Tulsi, a commonly used herb for its immunomodulatory property. The optimal dose of Ocimum sanctum hydroalcoholic extract (OSHE) was determined using maximal electroshock seizure (MES)- and pentylenetetrazol (PTZ)-induced seizure models in Wistar rats (200–250 g) after administering OSHE (200–1000 mg/kg) orally for 14 days. For interaction study, OSHE optimal dose in combination with maximum and submaximal therapeutic doses of valproate was administered for 14 days. Serum levels of valproate were estimated using HPLC for pharmacokinetic study. For pharmacodynamic interaction, antiepileptic effect on above seizure models, neurobehavioral effect using Morris water maze, passive avoidance and elevated plus maze tests, and antioxidant capacity were assessed. Ocimum sanctum hydroalcoholic extract 1000 mg/kg was found to be optimal providing 50% protection against both MES- and PTZ-induced seizures. Combination of OSHE with valproate did not alter antiepileptic efficacy of valproate significantly. However, the combination showed better memory retention potential in neurobehavioral tests and protection against oxidative stress compared with valproate-alone-treated groups. Pharmacokinetic parameters did not reveal any significant change in combination group compared with valproate alone. Ocimum, although having per se antiepileptic action, did not affect antiepileptic action of valproate in combination. However, combination treatment has an edge over valproate alone—better neurobehavioral function and reduced oxidative stress—predicting adjuvant potential of Ocimum in epilepsy treatment.

Introduction

Epilepsy is one of the most prevalent noncommunicable neurologic conditions worldwide (lifetime prevalence was 7.60 per 1000 persons) [1] and also in India (10 million people, 1% of population) [2]. Despite availability of several newer AEDs, 30% of patients with epilepsy still suffer from uncontrolled seizures and many experience sudden deaths [3]. For effective control of seizure, antiepileptic drugs (AEDs) are administered alone or in combination for years together, which is associated with several adverse drug effects. Cognitive dysfunction is commonly seen with all major AEDs at therapeutic doses [4], [5]. Valproate (VPA), a first-line and broad spectrum AED, is associated with adverse effects like hepatotoxicity, thrombocytopenia, gastrointestinal irritation, weight gain, transient alopecia, and neurological adverse effects including cognitive problems, ataxia, sedation, tremor, reversible parkinsonism, and dementia [6], [7]. As epilepsy needs chronic treatment and VPA is a potent inhibitor of cytochrome P450 (CYP) enzyme system, there is a possibility of clinically significant drug interaction of VPA with other drugs and nutritional supplements. These facts definitely put forth the need for drugs having per se or adjuvant role in suppressing epileptogenesis with the capacity for reducing cognitive impairment.

In Ayurveda, Ocimum sanctum (Tulsi) (also called as Ocimum tenuiflorum) is known as ‘The Incomparable One’ and ‘The Queen of Herbs’. Daily consumption of Tulsi is said to prevent disease and stresses of daily life and promote general health, wellbeing, and longevity [8]. The anticipatory potentials of Tulsi have been enumerated as chemoprotective, antistress [9], anticonvulsant [10], anxiolytic [11], antiulcer, antidiabetic [12], analgesic, antioxidant [13], anticancer, immunomodulatory, and antiinflammatory agent [14].

There are few previous in vivo studies [10], [15], [16], [17] which have thrown light upon the anticonvulsant potential of Ocimum extracts using different species (Ocimum basilicum, Ocimum gratissimum, and Ocimum sanctum) in the maximal electroshock seizure (MES) and pentylenetetrazol (PTZ) model. However, there are only few evidences comparing Ocimum with standard antiepileptic drugs; moreover, the combined effect of administering these drugs together has not been characterized in terms of seizure control, neurocognition parameters, and pharmacokinetic interaction. Thus, there is a need for thorough investigation of this widely exploited plant's potential as an antiepileptic and neurocognitive beneficial agent. This study was performed to find out the per se antiepileptic effect of Ocimum and its pharmacokinetic and pharmacodynamic interaction with valproate.

Section snippets

Experimental design

This experimental study for exploration of antiepileptic potential of Ocimum sanctum hydroalcoholic extract (OSHE) was conducted in rats using standard acute seizure models, i.e., maximal electroshock seizure (MES)- and pentylenetetrazol (PTZ)-induced seizure models. In the first phase, optimal dose of OSHE was screened using four different doses, i.e., 200, 400, 800, and 1000 mg/kg administered orally for 14 days. In the second phase, the optimal dose of OSHE from the first phase was used to

Effect of different treatments on seizure induction

All rats in the control group experienced seizure (Table 1). Though OSHE 800 and 1000 mg/kg provided 50% protection against both MES-induced tonic hind limb extension (THLE) and PTZ-induced generalized tonic–clonic seizure (GTCS), the comparative better outcome with respect to latency and duration of seizure, resulted in selection of optimum dose of Ocimum as 1000 mg/kg, which was then used in combination with valproate. Though Ocimum extract has shown per se antiepileptic potential (50%

Discussion

In spite of currently available armaments of AEDs, 20–30% of PWE continue to have seizures which affect subjects' quality of life, which put forth the need for novel therapies with better efficacy and lesser adverse effect profile [3], [29]. Valproate is a broad spectrum and first line antiepileptic drug and is associated with several adverse effects on chronic administration including cognitive dysfunction [4], [20], [30], [31].

In Ayurvedic practice, Ocimum sanctum (Tulsi) (also called as

Acknowledgment

The authors acknowledge Natural Remedies Pvt. Ltd., Bangalore, India for providing the Ocimum hydroalcoholic extract as a gift sample. We also thank Mr. NS Ganeshan for assisting in the estimation of valproate in serum by HPLC.

Funding

The study was funded by the Department of Pharmacology, AIIMS (Project no. A-428/2016/RS), New Delhi.

Conflicts of interest

None.

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