Therapeutic doses of theophylline exert proconvulsant effects in developing mice
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Published on: June 12, 2018
H Yokoyama1, K Onodera, T Yagi
1Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
Abstract:
We studied the effect of therapeutic doses of theophylline on electrically-induced convulsions in developing mice. A theophylline dose as small as 3 mg/kg increased seizure susceptibility of 21-day-old mice, but not of 42-day-old mice. These findings were consistent with clinical reports that theophylline at the therapeutic blood concentrations occasionally induced convulsions in children. The age-dependent proconvulsant effect of theophylline was well inhibited by phenobarbital (PB), dose-dependently, but not by other well-established antiepileptic drugs (AEDs). PB may be a good choice of AED in patients with bronchial asthma and seizure disorders, if PB is indicative for their seizure types. The proconvulsant effect of theophylline in 21-day-old mice was counteracted by not only an adenosine A1 agonist, but also an NMDA antagonist and a histamine H3 antagonist. Several studies have established that the proconvulsant effect of theophylline intoxication is mainly due to the blockade of adenosine A1 receptors. The present findings suggested that the proconvulsant properties of therapeutic doses of theophylline in developing period were different from those of theophylline intoxication. Combination of therapeutic doses of theophylline and centrally-acting histamine H1 antagonists showed proconvulsant effects even in 42-day-old mice, suggesting that peripherally acting histamine H1 antagonists, such as astemizole, evastine and epinastine, were much safer than centrally acting histamine H1 antagonists for patients with both allergy and seizure history.
Insights
Therapeutic theophylline doses can increase seizure risk in young mice, an effect blocked by phenobarbital (PB). This age-dependent effect differs from theophylline intoxication, highlighting the importance of AED choice in patients with asthma and seizures.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Theophylline, a common asthma medication, has known proconvulsant effects.
- Clinical reports suggest theophylline can induce seizures in children at therapeutic doses.
- The mechanisms underlying theophylline's proconvulsant effects, especially in developing individuals, require further investigation.
Purpose of the Study:
- To investigate the effect of therapeutic theophylline doses on seizure susceptibility in developing mice.
- To explore potential interactions between theophylline and antiepileptic drugs (AEDs).
- To elucidate the specific receptor pathways involved in theophylline's age-dependent proconvulsant activity.
Main Methods:
- Electrically-induced convulsions were used to assess seizure susceptibility in 21-day-old and 42-day-old mice.
- Mice were co-administered theophylline with various AEDs, including phenobarbital (PB), adenosine A1 agonists, NMDA antagonists, and histamine antagonists.
- Seizure thresholds and susceptibility were measured to evaluate the effects of these combinations.
Main Results:
- A low dose of theophylline (3 mg/kg) increased seizure susceptibility in 21-day-old mice but not in 42-day-old mice.
- Phenobarbital (PB) dose-dependently inhibited theophylline's proconvulsant effect in young mice, while other AEDs did not.
- The proconvulsant effect in young mice was counteracted by adenosine A1 agonists, NMDA antagonists, and histamine H3 antagonists.
- Combination of theophylline with centrally-acting histamine H1 antagonists induced seizures even in older mice.
Conclusions:
- Therapeutic theophylline exhibits age-dependent proconvulsant properties in developing mice, consistent with clinical observations in children.
- Phenobarbital (PB) may be a suitable AED for patients with both asthma and seizure disorders, depending on seizure type.
- The proconvulsant mechanism of therapeutic theophylline doses differs from that of theophylline intoxication, involving pathways beyond adenosine A1 receptor blockade.
- Peripherally acting H1 antagonists are safer than centrally acting ones for patients with allergy and seizure history.
