Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures

doi:10.1016/j.pharep.2016.03.011

Pharmacological Reports

Volume 68, Issue 4, August 2016, Pages 680-685

https://doi.org/10.1016/j.pharep.2016.03.011 Get rights and content

Abstract

Background

Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice.

Methods

Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects.

Results

Caffeine (both acute and chronic at 23.1 and 46.2 mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2 mg/kg and chronically at 23.1 or 46.2 mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2 mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2 mg/kg.

Conclusion

The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance.

Introduction

Caffeine (1,3,7-trimethylxanthine) belongs to the group of purine alkaloids and is found in beverages such as coffee, tea, and many soft drinks as well as in chocolate products and desiccated coconut. This methylxantine (MTX) is probably the most consumed psychoactive substance in the world. It is estimated that in developed countries 90% of people ingest caffeine on a daily basis [1], [2], [3], [4]. The daily consumption of this MTX is about 200 mg per person, which produces pharmacologically active blood concentrations [1]. Caffeine, apart from its questionable impact on the improvement of cognitive function, has a number of adverse effects through stimulation of the sympathetic nervous system, leading to elevated blood pressure, enhanced lipolysis with an increase in the concentration of free fatty acids in plasma and psychomotor agitation. In addition to behavioral effects – irritability, increased tension, anxiety, caffeine can cause cardiac arrhythmias, panic attack, insomnia or hypertension [5], [6], [7], [8], [9]. Long-term use of caffeine leads to the development of dependence and tolerance to its central effects and the cessation of its use produces a discrete withdrawal syndrome – headache, irritability, drowsiness [1], [10].The most dangerous complication of caffeine overdose is seizure activity. This MTX has been shown not only proconvulsant in animal models of seizures [11], [12], [13] but also to increase seizure frequency in patients with epilepsy [14], [15].

The inhibitory role of adenosine in the control of seizure activity has been well characterized [16], [17]. There are four main adenosine receptors: A1, A2A, A2B, and A3. All these types are coupled to G-proteins and adenosine is their endogenous ligand [18], [19]. Caffeine has been documented to produce seizures per se [11], [12], [18] and induce epileptic discharges [20]. This effect of caffeine is correlated with its affinity to A₁ adenosine receptors.

Interestingly, caffeine may interact with antiepileptic drugs (AEDs) and reduce their anticonvulsant effects in basic seizure models. The experimental data indicate that this MTX administered acutely (11.55–92.4 mg/kg, which is an equivalent to 12.5–100 mg/kg of aminophylline) impairs the protective activity of conventional AEDs: carbamazepine, phenobarbital, phenytoin and valproate against maximal electroshock (MES)-induced seizures in mice [17]. However, caffeine remained ineffective upon the protective activity of some newer antiepileptics, lamotrigine, oxcarbazepine, and tiagabine against electroconvulsions in mice [21]. The aim of the present study was undertaken to ascertain whether caffeine could attenuate the anticonvulsant effects of other newer AEDs: gabapentin (GBP) and topiramate (TPM). Electroconvulsive mouse seizure model was used for the estimation of the anticonvulsant activity of studied drugs and adverse effects were ascertained by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects.

Section snippets

Animals

The experiments were conducted on male Swiss mice, weighing 22–27 g. Experimental groups, consisting of 8–10 animals, were chosen randomly. The animals were housed in colony cages, under standard laboratory conditions, with free access to food (chow pellets, Bacutil, Motycz, Poland) and tap water.

All mice were maintained at an ambient temperature of 20 ± 1° and on the natural light-dark cycle. Animals from appropriate groups were tested on the same day, in order to provide optimally objective

Acute and chronic caffeine and the convulsive threshold for electroconvulsions

Acute and chronic administration of caffeine (up to 46.2 mg/kg) did not affect the convulsive threshold. Its control value of 6.4 mA ranged insignificantly from 6.2 to 7.4 mA (results not shown).

Influence of caffeine upon the protective activity of TPM against MES

Caffeine (at doses of 23.1 and 46.2 mg/kg) significantly reduced the protective effects of TPM against MES. The ED₅₀ values for TPM were elevated from 44.8 (31.2–64.2) mg/kg to 72.1 (58.7–88.6) mg/kg for the acute caffeine and 78.4 (61.1–100.5) mg/kg for the chronic caffeine at 23.1 mg/kg. Similarly, the ED₅₀

Discussion

Available data point to the association between caffeine and seizure activity. This MTX may decrease the convulsive threshold, especially in chemically induced seizures [11], [12]. However, the threshold for electroconvulsions has been unaffected by caffeine [18] which is also the case in the present study. It has been also shown that caffeine reduces the protective activity of some classical and newer AEDs against MES-or pentylenetetrazol-induced convulsions in mice [17], [18], [21], [22], [27]

Conflict of interests

S.J. Czuczwar declares financial support from UCB, GlaxoSmithKline, Novartis, Sanofi-Aventis, and Janssen for lecturing. S.J. Cz. has also received an unrestricted grant from GlaxoSmithKline.

Funding

This study has been supported by a grant (DS. 475/16) from Medical University of Lublin.

References (49)

G.A. Bernstein et al.
Caffeine dependence in teenagers
Drug Alcohol Depend
(2002)
A. Nehlig et al.
Caffeine and the central nervous system: mechanism of action, biochemical, metabolic and psychostimulant effects
Brain Res Rev
(1992)
N.J. Richardson et al.
Mood and performance effects of caffeine in relation to acute and chronic caffeine deprivation
Pharmacol Biochem Behav
(1995)
C. Cutrufo et al.
Different effects of various xanthines on pentylenetetrazoleinduced seizures in rats: an EEG and behavioural study
Eur J Pharmacol
(1992)
L. Bonilha et al.
Heavy coffee drinking and epilepsy
Seizure
(2004)
K. Kaufman et al.
Caffeinated beverages and decreased seizure control
Seizure
(2003)
S.J. Czuczwar et al.
Modulation of the protective efficacy of common antiepileptic drugs by xanthine derivatives: implications for the clinical use of xanthines in epileptic patients
Pharmacol Res
(1990)
H. Koryntová et al.
Changes of cortical epileptic afterdischarges under the influence of convulsant drugs
Brain Res Bull
(2002)
M. Chrościńska-Krawczyk et al.
Effect of caffeine on the anticonvulsant effects of oxcarbazepine, lamotrigine, and tiagabine in a mouse model of generalized tonic-clonic seizures
Pharmacol Rep
(2009)
M. Gąsior et al.
Chronic caffeine and the anticonvulsant potency of antiepileptic drugs against maximal electroshock
Pharmacol Biochem Behav
(1996)

A. Goldlust et al.

Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA

Epilepsy Res

(1995)

W. Löscher et al.

Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain

Neurosci Lett

(1991)

N.S. Gee et al.

The novel anticonvulsant drug, gabapentin (neurontin), binds to the α₂δ subunit of calcium channel

J Biol Chem

(1996)

N.O. Dalby et al.

Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin

Epilepsy Res

(1997)

B. Ault et al.

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy

Brain Res

(1987)

R.M. Gilbert et al.

Caffeine content of beverages as consumed

Can Med Assoc J

(1976)

K. Jankiewicz et al.

Caffeine and antiepileptic drugs: experimental and clinical data

Przeg Lek

(2007)

N.L. Benowitz et al.

Symphatomimetic effects of paraxantine and caffeine in humans

Clin Pharmacol Ther

(1995)

P.A. Hameleers et al.

Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups

Hum Psychopharmacol

(2000)

R.N. Hughes

Drugs which induce anxiety: caffeine

N Z J Psychol

(1996)

G.B. Kaplan et al.

Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans

J Clin Pharmacol

(1997)

G. Burgin et al.

Koffee and Tee

(1970)

N.-S. Chu

Caffeine- and aminophylline-induced seizures

Epilepsia

(1981)

A. De Sarro et al.

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Naunyn-Schmiedebergs Arch Pharmacol

(1997)

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Original research articleInfluence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Animals

Acute and chronic caffeine and the convulsive threshold for electroconvulsions

Influence of caffeine upon the protective activity of TPM against MES

Discussion

Conflict of interests

Funding

Drug Alcohol Depend

Brain Res Rev

Pharmacol Biochem Behav

Eur J Pharmacol

Seizure

Seizure

Pharmacol Res

Brain Res Bull

Pharmacol Rep

Pharmacol Biochem Behav

Epilepsy Res

Neurosci Lett

J Biol Chem

Epilepsy Res

Brain Res

Caffeine content of beverages as consumed

Can Med Assoc J

Caffeine and antiepileptic drugs: experimental and clinical data

Przeg Lek

Symphatomimetic effects of paraxantine and caffeine in humans

Clin Pharmacol Ther

Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups

Hum Psychopharmacol

Drugs which induce anxiety: caffeine

N Z J Psychol

Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans

J Clin Pharmacol

Koffee and Tee

Caffeine- and aminophylline-induced seizures

Epilepsia

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Naunyn-Schmiedebergs Arch Pharmacol

Original research article
Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures