Seizure 2002; 11: 285–302

doi:10.1053/seiz.2001.0644, available online at http://www.idealibrary.com on

Anticonvulsant profile and mechanism of action of

propranolol and its two enantiomers

W. FISCHER

Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstraße 16-18,

Leipzig, Germany

Correspondence to: Wolfgang Fischer, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig,
Härtelstraße 16-18, D-04107 Leipzig, Germany. E-mail: [email protected]

The anticonvulsant properties of the ß-adrenoceptor antagonist propranolol and its two enantiomers were examined in various
screening tests in order to characterize the anticonvulsant profile as well as the possible molecular mechanism of action.
These compounds dose-dependently raised the threshold for tonic electroshock seizures in mice and were effective in the
traditional maximal electroshock test (ED50 s 15–20 mg kg−1 i.p.). In combination with clinically used antiepileptics, the
anticonvulsant effectiveness of the latter was significantly increased. In the pentylenetetrazol (85 mg kg−1 s.c.) seizure threshold
test, (±)- and (+)-propranolol were not effective in preventing clonic seizures. In unrestrained rats with chronically implanted
electrodes in the dorsal hippocampus, propranolol and its (+)-enantiomer equieffectively reduced the duration of electrically-
evoked hippocampal afterdischarges (10 and 20 mg kg−1 i.p.) and raised the focal stimulation threshold (20 mg kg−1 i.p.).
In amygdala-kindled rats, both drugs (≥10 mg kg−1 i.p.) reduced the seizure severity from stage 5 (generalized clonic–tonic)
to stage 3 (unilateral forelimb) seizures. Furthermore, whole-cell patch-clamp experiments showed that (+)- as well as (−)-
propranolol (10−6 to 10−4 M) depressed the fast inward sodium current in a concentration- and use-dependent manner in
cultured rat cardiomyocytes and inhibited picrotoxin-induced burst firing activity of mouse spinal cord neurones in culture. In
conclusion, propranolol and its two enantiomers have anticonvulsant effects in models for generalized tonic–clonic and complex
partial seizures which may be accounted for by the sodium channel blocking and not by the ß-adrenoceptor blocking activity.
c 2002 Published by Elsevier Science Ltd on behalf of BEA Trading Ltd.

Key words: propranolol; (+)- and (−)-propranolol; anticonvulsants; seizure models; whole-cell patch-clamp; sodium channel.

INTRODUCTION and carbamazepine block high-frequency repetitive

firing of action potentials and sodium channels are
Propranolol is a prototype, non-selective ß1 /ß2 - the likely molecular targets of these antiepileptics 9, 10 .
adrenoceptor antagonist, having an established indica- Some authors described anticonvulsant effects of
tion in a variety of cardiovascular diseases including propranolol against sound-induced seizures in DBA/2
essential hypertension, cardiac arrhythmias and angina mice or pentylenetetrazol (PTZ)-induced convulsions
pectoris for more than 30 years 1, 2 . It is known that this in rats, in which the (−)-enantiomer was more potent
lipophilic drug exhibits marked central actions, such than the (+)-enantiomer 11, 12 . However, the majority
as anxiolytic, antiaggressive and antipsychotic effects, of other studies in several animal models suggests
with possible indications in neurology and psychia- that the anticonvulsant action of propranolol does not
try 3–5 . Interestingly, pronounced anticonvulsant prop- result from ß-adrenoceptor blockade 13, 14 and may be
erties in various seizure models were also documented due to the ‘membrane stabilizing’ properties of this
(for review, see Reference 6). Propranolol potently drug 8, 15 .
prevents maximal electroshock (MES) seizures in Anecdotal reports show that propranolol may be
rodents and raised the after discharge threshold in useful for treatment of seizures in humans 16, 17 .
rats 7, 8 . These basic observations indicate that the In particular, this substance might also be used in
profile of anticonvulsant activity seems to be similar patients suffering from epilepsies associated with
to that of phenytoin and carbamazepine, established increased blood pressure and cardiac dysfunctions.
antiepileptic drugs in the treatment of generalized The objective of the present work was to determine the
tonic–clonic and partial seizures in humans. Phenytoin antiepileptic profile of propranolol and the mode of ac-

1059–1311/02/$22.00/0 c 2002 Published by Elsevier Science Ltd on behalf of BEA Trading Ltd.

286 W. Fischer

tion in a series of appropriate screening models. Apart Maximal electroshock seizure threshold (MES-T)
from various, mostly not very extensive, studies using test (mice)
electroshock- and pentylenetetrazol-induced seizure
tests, detailed investigations with different seizure The stimulus train was applied via ear-clip electrodes
threshold and chemoshock tests as well as complex (sinusoidal pulses 5–10 mA, 50 Hz, 0.2 seconds
partial seizure models like the amygdala kindling duration) by means of a constant current stimulator
are missing (see Reference 6). In order to clarify (rodent-shocker type 221; Hugo Sachs Elektronik,
whether the blockade of ß-adrenoceptors is involved March-Hugstetten, Germany). The stimulus intensity
in the mechanism of action, experiments with (−)- was varied by an up-and-down method in which the
and (+)-propranolol (the latter is essentially devoid current was raised or lowered in 1 (or 2) nA-steps
of ß-adrenolytic effects but shares the membrane if the preceding animal did not or did show tonic
stabilizing properties of the (−)-enantiomer) were hindlimb extension, respectively (see Reference 18).
performed. Since propranolol may be useful as an Groups of 15–20 mice were used. Current intensity-
adjunctive drug in epilepsies, the modulation of the effect curves were constructed on the basis of the
protective efficacy of conventional antiepileptic drugs percentage of animals responding with the endpoint
by combined treatment was also analysed. Finally, the at the corresponding current value. The calculation
inhibitory effects of propranolol on the fast inward of CC50 values (current intensity in mA, necessary
sodium current, which could be inferred from previous to induce tonic hindlimb extension in 50% of the
studies, were examined in detail using whole-cell mice tested) and the statistical comparisons were
patch-clamp technique. performed using a computer-supported probit analysis
according to the method of Litchfield and Wilcoxon 19 .
In the case of multiple comparisons between different
METHODS drug-treated and the corresponding control group,
α-correction was performed.
Animals

In most of the screening tests (MES, PTZ, Ro- Maximal electroshock seizure test (mice)
tarod; see later) male albino mice (strain 01,
Leipzig-Probstheida, Germany), weighing 19–25 g Maximal electroshock seizure was induced in mice
(27- to 32-day-old) were used. Two special seizure via ear-clip electrodes by a constant suprathreshold
models (maximal N-methyl-DL-aspartate (NMDLA) current (rectangular 20 msecond impulses, 50 mA,
and quinolinate (QUIN) seizure test) were carried out 35 Hz, 0.4 seconds duration) following the method
on male SHR mice (bred from Swiss strain, Rappolovo of Swinyard et al. 20 . The prevention of the hindlimb
farm, St Petersburg, Russia), weighing 18–22 g. (For tonic extensor component was regarded as the
the patch-clamp experiments on spinal cord neurones, endpoint of protection. The dose–response curves
foetal 12- to 13-day-old NMRI-Han mice (Hanover, were estimated by testing four to five doses and eight
Germany) were used.) After adaptation to laboratory (sometimes 10–16) animals per dose. The calculation
conditions for some days, the experimental groups of ED50 values (dose that protects 50% of the animals
were chosen by means of a randomized schedule. against MES-induced tonic hindlimb extension) and
Each mouse was used only for one experiment. The the statistical analysis were performed according to
EEG-studies (hippocampal afterdischarges) as well as the traditional method of Litchfield and Wilcoxon 19 .
the pharmacokinetic investigations were carried out
with male Wistar rats (own breeding stock, formerly
‘Jelei: WIST’), weighing 250–300 g at the time Pentylenetetrazol (PTZ) seizure threshold test
of surgery. The studies with amygdala-kindled rats (mice)
were performed on female Wistar rats (strain ‘Shoe:
WIST’, Schönwalde, Germany), weighing 150–220 g In all chemically-induced seizure models the convul-
at the beginning of the experiments. The animals sants were given after the optimal pretreatment time
were kept in colony cages under standard laboratory of the test drug (or vehicle). Unrestrained mice were
conditions on a natural light–dark cycle with free injected with the convulsant PTZ (85 mg kg−1 ) s.c.
access to commercial food pellets and tap water. The in the neck. The animals were placed under separate
screening experiments were carried out between 9 glass funnels and the appearance of the first general-
and 12 hours to avoid circadian influences. Animal ized clonus (repeated clonic seizures of the fore- and
care and handling was conducted in compliance with hindlimbs lasting ≥5 seconds with an accompanying
the German Animal Welfare Act and was approved by loss of righting reflex) was recorded during individual
the relevant local governmental body in Leipzig. observation for 30 minutes (see Reference 21). The
Anticonvulsant profile of propranolol 287

number of animals in the group (n = 12 mice) with in which 50% of the animals show impaired motor
clonic seizures and the latency time were analysed for performance) were calculated with three to four doses
statistical significance using Fisher’s exact probability (10 mice per dose) on the basis of dose–response
test and the Log rank test, respectively. curves using the method of Litchfield and Wilcoxon 19 .

Maximal pentylenetetrazol (PTZ) seizure test Electrically-evoked hippocampal afterdischarges

(mice) (rats)
Clonic–tonic convulsions were induced by admin- Anaesthetized rats (ketamine-HCl 100 mg kg−1 i.p./
istering PTZ (125 mg kg−1 ) s.c. in the neck of xylazine-HCl 15 mg kg−1 i.p.) were placed in a
mice (see Reference 22). In all chemically-induced stereotaxic apparatus (TSE, Bad Homburg, Germany).
tonic seizure models the following criteria were A bipolar deep electrode for intracerebral stimulation
used for quantification of drug effects: the number and recording was implanted into the right dorsal
of animals in the group (n = 12) with tonic hippocampus (AP 2.5 to 3.0 posterior to bregma,
hindlimb extension (1), the latency time to the first L = 1.8 mm lateral to the midline and V = 2.7–
tonic seizure (2) and the survival time (3). Results 3.0 mm ventral to the skull surface; stereotaxic coordi-
were compared statistically by using Fisher’s exact nates according to Fifková and Maršala 26 ). Addition-
probability test (1) and the Log rank test (2, 3), ally, for EEG-recording six stainless-steel electrodes
respectively. were positioned epidurally above the bulbus olfacto-
rius, the sinus sagitalis superior (reference electrode;
Maximal N-methyl-DL-aspartate (NMDLA) and 2 mm frontomedially to the bregma), the sensomotor
quinolinate (QUIN) seizure test (mice) and visual cortex. At the end, an antibiotic (Retacillin
compositum, 200 000 IE, Jenapharm, Jena, Germany)
NMDLA (2 µg/5 µl) and QUIN (25 µg/5 µl), was administered. Two weeks after surgery, the rats
respectively, were injected i.c.v. in conscious mice by were habituated to the recording setup and EEG-
a semiautomatic apparatus 23 . Animals were placed in recordings (Bioscript BST 1, Zwönitz, Germany) were
separate boxes and observed individually for 15 min- performed within the following 2–3 days. Constant
utes. The doses of chemoconvulsants were chosen current stimulations were delivered to the deep
from our own pilot studies to induce tonic seizures electrodes in the hippocampus, when a stable EEG re-
and a short survival time. (It should be mentioned sponse has been established from the freely behaving
that in the vehicle-pretreated control groups (n = animals. The stimulus train (rectangular 1 msecond
15) normally one to three animals exhibited no tonic current impulses, 60 to 300 µA, 50 Hz, 5 seconds
hindlimb extension.) duration) was applied from a HSE-stimulator (type
215/1, HSE, March-Hugstetten, Germany) coupled
to a stimulus isolation unit and a constant current
Strychnine (STR) seizure pattern test (mice) unit. The individual stimulation threshold for hip-
Tonic seizures were induced by administering STR pocampal rhythmic spike activity (‘afterdischarges’)
(1.4 mg kg−1 ) s.c. in the neck of mice (see Refer- was estimated with a series of stimulations, com-
ence 24). Preliminary studies showed that 1.2 mg kg−1 mencing with 60 µA and increasing in 20 µA steps
did not produce a clear tonic hindlimb extension in every 2 minutes until an afterdischarge was elicited
all mice tested. As mentioned earlier, the occurrence (for further details, see Reference 27). Selected drugs
of the first tonic seizure (hindlimb extension) and could be studied when the duration and pattern of
the survival time were registered after individual the hippocampal afterdischarges remaining nearly
observation for 30 minutes. In this test, groups of nine constant over three to four tests. Each animal received
mice were used. no more than three drug applications (controls before
and after drug administration at intervals of 3–4 days;
at least 6 days were interposed between two drug
Rotarod ataxia test (mice) injections in order to avoid drug accumulation or
tolerance). Statistical differences between groups of
Sedation, decreased locomotor activity and ataxia data were established by the paired Student’s t-test.
were quantified by the rotarod test 25 . Mice were
tested and trained before drug application. Evidence
for ‘minimal neurotoxicity’ was indicated when the Amygdala-kindling (rats)
animals were unable to maintain their equilibrium on
the rotating rod (10/minute) in two of three subsequent Surgery and kindling procedures were performed
1 minute attempts. Respective TD50 values (dose as described elsewhere 28 . Briefly, rats were anaes-
288 W. Fischer

thetized and implanted with one bipolar electrode Heart cell culture (neonatal rats) and whole-cell
(stainless steel wires tightly twisted together) posi- voltage-clamp experiments
tioned stereotaxically into the right basolateral nucleus
of amygdala (AP 1.7 mm posterior to bregma, L = Ventricular myocardiocytes from 1- to 3-day-old
4.0 mm lateral to the midline and V = 8.0 mm ventral Wistar rats were prepared by using a combined
to the dura 26 ). Two weeks later, the animals were enzymatic (0.2% trypsin) and mechanical dissociation
stimulated once daily with rectangular 1 msecond procedure and cultured as monolayers on coverslips
current impulses (100 to 200 µA depending on at 37 ◦ C for 5 days (for methodical details, see Ref-
the individual threshold for afterdischarges, 60 Hz, erence 30). For the electrophysiological experiments,
1 second). The animals were considered to be kindled coverslips with cultured cardiomyocytes (2–3 days
after the achievement of at least three consecutive after plating) were transferred into a test chamber
generalized seizures with stages 4/5. The severity (room temperature 20–22 ◦ C), perfused with external
of seizures was classified behaviourally according to solution and mounted on the stage of an inverted
a modified ranking scale 6, 29 : 0 = no response to microscope (Telaval; Carl Zeiss Jena, Germany).
stimulation; 1 = immobility, eye closure, ear and The external (bathing) solution contained (in mM):
facial twitches; 2 = head nodding, more severe facial NaCl 130, KCl 4, MgCl2 1, CaCl2 1.8, HEPES 10,
clonus, lacrimation; 3 = unilateral forelimb clonus; glucose 5, buffered to pH 7.4 with NaOH. (In some
4 = rearing, bilateral forelimb clonus with loss of experiments the NaCl concentration was lowered to
postural control; 5 = repeated backward falling, 40 mM (substitution with Tris-HCl 90 mM, CoCl2
accompanied by generalized clonic–tonic convulsions. 5 mM) to reduce current amplitudes for optimizing
After completion of kindling, rats were grouped to six voltage-clamp control.) Patch pipettes were pulled
to 12 animals and injected with saline (control values) from filamented borosilicate glass capillaries (WPI,
and 1 day later with the test substance i.p. before the Sarasota, USA) and heat-polished (tip resistances
electrical stimulation. Results were expressed as mean of 2–4 M). The internal (pipette) solution was
(scaled pre-drug and post-drug seizure behaviour) of composed of (in mM): CsCl 110, HEPES 10, TEA-
the tested animal group. Significance of differences Cl 20, MgATP 5, EGTA 10, buffered to pH 7.0
was calculated using the paired Student’s t-test. with Tris-HCl. Sodium currents from selected car-
Electrode placements were confirmed histologically diomyocytes were studied using the whole-cell patch-
using the conventional Nissl-technique (cresyl violet- clamp technique 31 by means of an EPC-7 patch-clamp
stained frontal sections). amplifier (List Electronics, Darmstadt, Germany). The
experimental setup and the data acquisition have
been described in detail elsewhere 32, 33 . The drugs
Plasma levels of phenobarbital and tested, propranolol, its two enantiomers, valproate and
carbamazepine (rats) phenytoin (in DMSO), were dissolved and diluted
in external solution to the desired concentrations
Plasma concentrations were determined after injec- immediately before use. The drug solutions were
tion of the antiepileptic drug alone (phenobarbital applied with an automated application system.
10 mg kg−1 i.p., 60 minutes before or carbam-
azepine 10 mg kg−1 i.p., 30 minutes before; saline
instead of propranolol, 45 minutes before) and in com- Spinal cord neurone culture (neonatal mice) and
bination with propranolol (10 mg kg−1 i.p., 45 minutes picrotoxin (PTX)-induced burst activity
before). Individual blood samples of 300–500 µl,
taken from the retro-orbital venous plexus under short Spinal cord neurones from 12- to 13-day-old mice
diethylether anaesthesia, were collected into Eppen- were prepared by using a combined enzymatic (0.25%
dorf tubes and centrifuged at 10 800 rev minute−1 trypsin) and mechanical dissociation procedure and
for about 1 minute. Subsequently, 100 µl of the cultured on collagen-coated plastic dishes using
supernatant was pipetted into Abbott system cartridges methods described elsewhere 34 . For the electrophys-
and the total plasma level of phenobarbital or iological studies, the cultures (14 days in vitro) were
carbamazepine was determined by an Abbott TDx placed on the stage of an inverted microscope and
analyser (Abbott, Irving, TX, USA), which is based superfused with control (HEPES-buffered saline) or
on a fluorescence polarization immunoassay (FPIA) PTX-containing solution, respectively. All recordings
technique. The plasma levels were expressed in µM were carried out using the whole-cell patch-clamp
as means ± SEM (six to 10 rats for each group). For configuration in current-clamp mode (for further
comparison of the plasma levels of phenobarbital and details, see References 34,35). When picrotoxin
carbamazepine in saline- or propranolol-treated rats, (10 µM) was applied to the cell culture, the neurones
the Mann–Whitney rank sum test was used. within the neuronal network developed paroxysmal,
Anticonvulsant profile of propranolol 289

Fig. 1: Effect of (+)- and (−)-propranolol (2 and 10 mg kg−1 ) alone (left) or of combinations of (+)-propranolol (10 mg kg−1 ) with
various antiepileptic drugs on the threshold for tonic (hindlimb extension) electroshock seizures (MES-T) in mice. The columns
represent the CC50 -values (confidence limits for 95% probability) of drugs or drug combinations (15–20 animals per dose),
expressed in percent to the parallel estimated control MES thresholds (C = 100%, saline/vehicle 10 ml kg−1 i.p.; means of the
control MES thresholds 5.7–6.1 mA). Doses of drugs (in mg kg−1 i.p.) are indicated below the columns. (+)- and (−)-propranolol
((+)-P; (−)-P), carbamazepine (CBZ) and valproate-Ca (VP) were administered 30 minutes, phenobarbital (PB) 60 minutes and
phenytoin (PHT) 90 minutes before threshold determination, respectively. ∗ P < 0.05 (probit analysis).

burst-like firing activity within 10–15 minutes. The volumes of the vehicle (10 ml kg−1 in mice; 2 ml kg−1
effects of (+)- and (−)-propranolol (1–30 µM) were in rats) and were always tested together with the
tested by cumulative administration to the PTX- respective experimental group.
superfusion solution.

RESULTS
Drugs and solutions
Effects of (+)- and (−)-propranolol on the
The following substances were used: (±)-propranolol-
threshold for electroshock-induced tonic seizures
HCl, (+)-, (−)-propranolol-HCl (purity of the enan-
tiomers approximately 98%), N-methylpropranolol- Both (+)- and (−)-propranolol (10 mg kg−1
HCl (Isis-Chemie, Zwickau, Germany), carbam- i.p.), administered 30 minutes before testing,
azepine, ethosuximide, phenobarbital-Na, valproate- significantly raised the threshold for electrically-
Ca (Arzneimittelwerk Dresden, Germany), phenytoin- induced tonic (hindlimb extension) seizures in mice
Na (Gödecke, Freiburg, Germany); N-methyl-DL- from 5.8 mA (mean of two control groups with saline)
aspartate (IEM, St. Petersburg, Russia), pentylenete- to 7.7 and 7.4 mA, respectively (Fig. 1: presentation
trazol (Knoll, Ludwigshafen, Germany), picrotoxin in percent to the corresponding control group). At the
(Sigma, Deisenhofen, Germany), quinolinic acid lower dose (2 mg kg−1 i.p.) no strong influence on
(Sigma, St Louis, USA), strychnine-SO4 (Merck, the electroconvulsive threshold could be observed.
Darmstadt, Germany). The drug solutions or sus- In combination with phenobarbital, phenytoin,
pensions were prepared immediately before use. carbamazepine or valproate, the tested (+)-enantiomer
All doses refer to the salts. For the screening significantly increased the effectiveness of the latter.
experiments, propranolol, its enantiomers and N-
methylpropranolol were dissolved in distilled water
(phenytoin-Na by means of 1–2 drops of 1N NaOH), Anticonvulsant activity of (±)-, (+)- and
N-methyl-DL-aspartate (pH 7), quinolinic acid (pH (−)-propranolol as well as N-methylpropranolol
6-7), pentylenetetrazol, strychnine in 0.9% NaCl- in the maximal electroshock seizure test
solution, carbamazepine, ethosuximide and valproate-
Ca in a 2% suspension of hydroxyethylcellulose. (±)-Propranolol and its two enantiomers showed
Animals in the control groups received equivalent anticonvulsant effects in the traditional MES test in
290 W. Fischer

Table 1: Anticonvulsant activity of propranolol, its two enantiomers as well as N-methylpropranolol in comparison with antiepileptic
drugs in the maximal electroshock seizure (MES) test (mice).

Substance Route Time of application ED50 Confidence limits ED50

(min) (mg kg−1 ) (mg kg−1 ) (µmol kg−1 )
(±)-Propranolol-HCl ip 30 15.2 (13.8–16.8) 51.4
45 16.7 (15.0–18.6) 56.5
60 20.6 (19.0–22.3) 69.6
sc 45 14.3 (12.2–16.8) 48.3
po 45 32.2 (26.7–38.8) 108.9
(+)-Propranolol-HCl ip 45 16.0 (14.1–18.2) 54.1
sc 45 13.0 (11.1–15.2) 43.9
po 45 33.5 (27.5–40.9) 113.3
(−)-Propranolol-HCl ip 45 19.2 (16.7–22.1) 64.9
sc 45 14.5 (12.6–16.7) 49.0
po 45 35.6 (31.5–40.2) 120.4
N-Methylpropranolol ip 45 16.4 (12.9–20.9) 52.9

Phenobarbital-Na ip 60 16.0 (14.5–17.6) 62.9

sc 60 17.6 (15.6–19.9) 69.2
po 60 21.2 (17.1–26.2) 83.4
Phenytoin ip 90 8.8 (8.1–9.6) 32.1
Carbamazepine ip 60 11.2 (10.1–12.4) 47.4
Valproate-Ca ip 30 256.0 (245.7–266.7) 1568.6

mice. The animals exhibited no post-ictal depression tension) convulsions in different chemically-induced
(confusion and stupor) and quickly recovered after the seizure models in mice. For comparison, the effects
induced tonic seizure. N-methylpropranolol, which of some antiepileptics are also presented. When tonic
does not possess ß-adrenolytic properties, exerted a seizures were induced by systemic administration of
similar protective action. Table 1 summarizes the PTZ or central administration of NMDLA and QUIN,
estimated ED50 values of these drugs and some con- respectively, both drugs dose-dependently inhibited
ventional antiepileptics as reference substances after tonic convulsions (Fig. 3: upper diagram). In the re-
different routes of administration. The anticonvulsant maining animals with tonic seizures, the latency to the
activity of propranolol as well as its (+)-enantiomer first tonic seizure showed a tendency to increase (not
was roughly equipotent to phenobarbital in this test. demonstrated). The survival time was significantly
Interestingly, (−)-propranolol (the enantiomer with prolonged (lower diagram). On the other hand, in the
the marked ß-adrenoceptor blocking action), tended STR seizure test (±)- and (+)-propranolol revealed
to have a lower anticonvulsant activity than the (+)- only limited protective actions and, as expected,
enantiomer. the efficacy of conventional antiepileptics was also
The efficacy of clinically established antiepileptics limited.
was considerably increased when (±)- or (+)-
propranolol (10 mg kg−1 s.c.) were administered as
co-medication. The ED50 values were significantly
reduced in all cases (Fig. 2). Detailed studies with Influence of (±)- and (+)-propranolol as well as
phenobarbital and (±), (+)-, (−)-propranolol as well N-methylpropranolol in the pentylenetetrazol
as the N-methyl-derivative showed a dose-dependent seizure threshold test
decrease of the ED50 values (see Fig. 2: left part of the
diagram).
Neither (±)- and (+)-propranolol nor the N-methyl-
derivative exerted protective effects in lower or higher
Influence of (±)- and (+)-propranolol on doses in the s.c.-PTZ seizure threshold test in mice
pentylenetetrazol-, N-methyl-DL-aspartate-, (Table 2). At 20 mg kg−1 i.p. the latency to the
quinolinate- and strychnine-induced tonic first generalized clonus tended to decrease, indicating
seizures possible proconvulsant actions. On the other hand, the
reference antiepileptics ethosuximide and valproate
As illustrated in Fig. 3, the racemic propranolol and exhibited significant anticonvulsant effects against
the (+)-enantiomer can suppress tonic (hindlimb ex- clonic seizures.
Anticonvulsant profile of propranolol 291

Fig. 2: Influence of (±)-, (+)- and (−)-propranolol and of N-methylpropranolol on the anticonvulsant effectiveness of phenobarbital
(PB), as well as of (±)- and (+)-propranolol on the anticonvulsant effectiveness of phenytoin (PHT), carbamazepine (CBZ) and
valproate-Ca (VP) in the maximal electroshock seizure (MES) test in mice. The columns represent the ED50 -values (confidence
limits for 95% probability) of drug combinations, expressed as percent of the controls with the antiepileptic drug alone (C = 100%,
combination with vehicle 10 ml kg−1 s.c.). Propranolol compounds were administered s.c. 45 minutes before MES, all
antiepileptic drugs i.p.; see Fig. 1). The average control ED50 -values were: PB 16.1, PHT 8.8, CBZ 11.0 and VP 260 mg kg−1
i.p., respectively. ∗ P < 0.05 19 ; (±)-P = racemic propranolol; (+)-P = (+)-propranolol; (−)-P = (−)-propranolol;
M-P = N-methylpropranolol.

Fig. 3: Effect of (±)- and (+)-propranolol in comparison with some standard antiepileptic drugs on tonic seizures (TS) induced by
pentylenetetrazol (PTZ 125 mg kg−1 s.c.), N-methyl-DL-aspartate (NMDLA 2 µg i.c.v.), quinolinate (QUIN 25 µg i.c.v.) or
strychnine (STR 1.4 mg kg−1 s.c.) in mice. Upper part: number of animals with tonic seizures (dotted boxes) within the groups.
+ P < 0.05; ++ P < 0.01; +++ P < 0.001 (Fisher’s exact probability test).
Lower part: Corresponding survival times (means ± SEM) as percent of the control groups. (Regarding the differences in the
absolute values, depending on a short or longer survival time of the control animals in these various seizure test and the number
of protected animals (calculated with censored 30 or 15 minutes, respectively) in the drug treated groups, it seems necessary to
limit all data to 300% for a clear presentation.) The doses of the tested drugs are indicated below the columns. (The times of
administration of the drugs before application of the chemoconvulsants were always 30 minutes for (±)-, (+)-propranolol and
valproate and 60 min for phenobarbital and carbamazepine.) The average control values ± SEM were: PTZ 11.4 ± 0.8 minutes
(n = 5 control groups); NMDLA 1.4 ± 0.3(n = 5); QUIN 1.5 ± 0.3(n = 4) and STR 5.7 ± 0.3(n = 5). ∗ P < 0.05; ∗∗ P < 0.01;
∗∗∗ P < 0.001 (Logrank test).
292 W. Fischer

Table 2: Effect of propranolol, its (+)-enantiomer as well as N-methylpropranolol on pentylenatetrazol (PTZ)-induced clonic
seizures (mice).

Substance Dose Time of PTZ seizure threshold test (85 mg kg−1 s.c.) % Control
(mg kg−1 i.p.) application Number of mice/ Latency to the
before PTZ with seizure 1. generalized clonus
(min) (min)
NaCl — 30 12/12 7.90 ± 0.97 100 ± 12.3
(±)-Propranolol-HCl 2 30 12/12 8.06 ± 1.01 102.0 ± 12.8
10 30 12/12 8.20 ± 1.68 103.8 ± 21.3
20 30 12/12 6.12 ± 0.96 77.5 ± 12.2
(+)-Propranolol-HCl 2 30 12/12 8.05 ± 1.09 101.9 ± 13.8
10 30 12/12 8.14 ± 1.01 103.0 ± 12.8
20 30 12/12 6.88 ± 0.99 87.1 ± 12.5
N-Methylpropranolol-HCl 10 30 12/12 7.34 ± 1.24 92.9 ± 15.7

NaCl-Cellulose — 30 12/12 8.83 ± 1.05 100 ± 11.9

Ethosuximide 50 30 12/11 12.20 ± 2.33 138.2 ± 26.4
150 30 12/2+++ 14.79 ± 3.38∗ 167.5 ± 38.5∗
Valproate-Ca 50 30 12/12 10.40 ± 1.24 117.8 ± 14.0
200 30 12/2+++ 19.54 ± 4.88∗∗ 221.3 ± 55.3∗∗

All data are given as means ± SEM. Statistical significance: +++ P < 0.001 (Fisher’s exact probability test); ∗ P < 0.05, ∗∗ P < 0.01
(Logrank test). NaCl-Cellulose = 0.9% NaCl in 2% hydroxyethylcellulose suspension.

Adverse effects of (±)- and (+)-propranolol effects of racemic propranolol and its (+)-enantiomer
on the duration of hippocampal afterdischarges (initial
Impairment of motor function and an increasing phase) are shown in Fig. 5(a). The influence on
sedation could be observed in mice after application the stimulation threshold to induce afterdischarges is
of higher doses (≥30 mg kg−1 i.p.) of (±)- or (+)- illustrated in Fig. 5(b). Both drugs revealed activities
propranolol. In the rotarod ataxia test, TD50 values equalling or exceeding those of phenobarbital and
of 41 and 42 mg kg−1 i.p. were determined, respec- phenytoin.
tively. The calculated protective indices (TD50 /MES- Further studies with (+)-propranolol (10 or
ED50 ) for (±)- or (+)-propranolol were in the order 20 mg kg−1 i.p.) given in combination with pheno-
of 2.5 and 2.6 (for comparison: phenobarbital 4.6, barbital and phenytoin, respectively, showed that this
phenytoin 6.0, carbamazepine 4.7 and valproate 1.3, co-medication enhanced markedly the effectiveness
respectively). Combination of relatively high doses of the two antiepileptics (Fig. 6). The higher dose of
of both drugs (34 or 32 mg kg−1 ; i.e. twice (+)-propranolol did not only completely inhibit the
as high as their MES-ED50 s) with phenobarbi- afterdischarge activity, but in addition, significantly
tal did not significantly alter the TD50 value of elevated the stimulation threshold.
the latter (TD50 phenobarbital/saline: 72 mg kg−1
i.p., phenobarbital/(±)- or (+)-propranolol: 72 and Effects of (±)- and (+)-propranolol in the
69 mg kg−1 i.p., respectively). amygdala-kindling model

In amygdala-kindled rats, (±)- and (+)-propranolol

Effects of (±)- and (+)-propranolol upon exerted anticonvulsant activity against secondarily
electrically-evoked hippocampal afterdischarges generalized clonic–tonic seizures (stage 4/5). At doses
of 10 mg kg−1 i.p. both drugs reduced seizure
In unrestrained rats stimulated by chronically im- severity to stage 3, but did not suppress the facial and
planted hippocampal electrodes, (±)- and (+)- unilateral forelimb cloni (Fig. 7). The efficacy of some
propranolol (10 and 20 mg kg−1 i.p.) reduced or antiepileptics was presented for comparison.
completely suppressed the initial phase of generalized
polyspike-wave and spike discharges. A representative Effects of propranolol on the plasma level of
EEG-recording with (+)-propranolol is illustrated in phenobarbital and carbamazepine
Fig. 4. The secondary (rebound) afterdischarge phase,
characterized by sharp-waves in the hippocampus and Propranolol (10 mg kg−1 i.p.) did not
visual cortex beginning about 80–90 seconds after the alter the total plasma levels (µM) both of
stimulation, was also suppressed. The calculated mean phenobarbital (10 mg kg−1 i.p.) (alone 48.9 ± 1.1
Anticonvulsant profile of propranolol 293

Fig. 4: Electrically-evoked epileptiform spike activity (‘afterdischarges’) following hippocampal current stimulation in the
unrestrained rat (EEG-recording example). After habituation of the animal for 15 minutes (relaxed wakefulness) the stimulus was
delivered to the right dorsal hippocampus (region 4–5). Top panel: control recording before and after stimulation
(rectangular 1 msecond current impulses of 180 µA and 5 seconds duration) without drug treatment. The evoked epileptiform
activity has a complex pattern which consists of (1) initial polyspike-wave and spike discharges (without convulsive response),
associated with postural freezing and with some head-shakes (HS) at the end, (2) a period free of afterdischarges (post-ictal
voltage depression), with pronounced forward locomotion, sniffing and rearing activity, and (3) a second (rebound) phase
after 80–90 seconds characterized by sharp-waves (see hippocampus, visual cortex), with a short arrest, some head-shakes and
after that again increased locomotor activity for 3 (5) minutes. Bottom panel: effect of a single dose of (+)-propranolol
(10 mg kg−1 i.p.) on electrically-evoked hippocampal afterdischarges, recorded 30 minutes after drug application (3 days after
predrug control). (+)-Propranolol markedly reduced the initial spike-wave phase and the second (sharp-wave) phase was
completely suppressed. SMC = sensomotor cortex; DH = dorsal hippocampus; VC = visual cortex; BO = bulbus olfactorius.
Voltage calibration on the right: 60 µV.

(n = 10) vs. 48.4 ± 1.5 (n = 6)) or carbamazepine in the reversal potential (decrease of the maximum
(10 mg kg−1 i.p.) (alone 19.8 ± 2.4 (n = 10) vs. INa amplitude by about 30% (10 µM) and 50–60%
18.8 ± 3.8 (n = 6)). There are no relevant pharma- (100 µM)). The onset of inhibition produced by (+)-
cokinetic interactions, in terms of total plasma levels, or (−)-propranolol occurred within 3 minutes, and the
between propranolol and the two tested antiepileptics. block was reversible within 5 minutes of washout in
drug-free extracellular solution.
Effects of (+)- and (−)-propranolol on fast
sodium inward current INa in cultured neonatal Frequency-dependent inhibition of peak INa
rat cardiomyocyte cells
Under control conditions, repetitive depolarizing test
pulses (25 mseconds; from −120 mV to −30 mV)
Current–voltage relationship of peak INa
produced little decrement in current amplitude (2–3%
Sodium currents (INa s) were evoked by a series of at 10 Hz in a train of 10 test pulses). After application
25 msecond depolarization pulses (0.1–1 Hz; holding of (+)- and (−)-propranolol, respectively, the drugs
potential of −100 mV) to different depolarizing led to a ‘tonic’ reduction of peak INa measured
potentials. INa s started to activate at −60 mV reaching after 3–5 minutes with some single test pulses. An
a maximum amplitude around −20 mV, and then increase of the test pulse frequency to 1 or 10 Hz,
declined towards the reversal potential near +40 mV. markedly increased the amount of current block by
The INa s were stable over a range of 15 minutes both (+)- and (−)-propranolol (Fig. 8(b)). At 1 Hz,
with only minimal ‘run down’ effect. The current– the peak INa decreased about 30% with 100 µM (+)-
voltage relationship for the peak INa before and or (−)-propranolol and at 10 Hz up to 80%. Thus,
after application of (+)-propranolol is shown in both enantiomers exhibited a pronounced frequency-
Fig. 8(a). (The two insets on the left illustrate dependent inhibition of peak INa , especially at higher
the pulse protocol (above) and a family of sodium drug concentrations. These additional blocking effects
currents elicited by voltage-steps after this protocol always recovered after the reduction or cessation of
from a selected experiment (below) under control higher frequency stimulation.
conditions and after exposure to 100 µM of the test
substance.) (+)-Propranolol and the (−)-enantiomer Steady-state inactivation of peak INa
(in the same magnitude; not documented) reduced the
INa amplitude over the entire membrane potential axis The voltage-dependence of INa block was estimated
without a shift of the curve maximum or a change by applying a conditioning 200 msecond prepulse
294 W. Fischer

Fig. 6: Effect of co-administered (+)-propranolol ((+)-P) on

the anticonvulsant effectiveness of phenobarbital (PB) and
phenytoin (PHT), respectively, in the hippocampal
afterdischarge model. The rats were tested 3–4 days before
the drug application (control values). Each animal received
Fig. 5: Effect of (±)- and (+)-propranolol ((±)-P; (+)-P) in (+)-propranolol (10 or 20 mg kg−1 ), the antiepileptic drug
comparison with phenobarbital (PB), phenytoin (PHT) and (PB or PHT) and the corresponding combination (COM) in a
carbamazepine (CBZ) on (a) the duration of random schedule. The interval between each drug
electrically-evoked hippocampal spike activity (initial phase) application was at least 6 days. Only animals with a constant
and (b) the stimulation threshold for hippocampal threshold over the whole series of experiments were included
afterdischarges. The rats were tested 3 days before (control in the analysis. (a) Duration of electrically-evoked
values = 100%) and 25–30 minutes ((±)-P; (+)-P), hippocampal afterdischarges (initial spike phase) before and
55–60 minutes (PB), 80–90 minutes (PHT) and 45–60 after drug application. Each column represents the mean ±
minutes (CBZ), respectively, after drug application SEM of four to five animals. Significance level: ∗∗ P < 0.01
(intra-individual comparison). Each rat underwent maximal (paired t-test). (b) Modulation of the stimulation threshold for
three drug tests, separated by one (two) control trials. The hippocampal afterdischarges. Data (means ± SEM) are
columns represent the means ± SEM of six to 11 animals. shown as elevation over individual control threshold. The
The doses of drugs (in mg kg−1 i.p.) are given always below doses of drugs are always given below the columns (at the
the columns (at the base of the columns in the lower diagram: base of each column: number of animals with increased
number of animals with increased threshold/total number of threshold/total number of animals per group). Means of
animals per group). The average control values (duration of control thresholds were for the three independent series of
initial spike phase) lay between 25 and 39 seconds, the experiments (in µA): PB/(+)-P 10 mg kg−1 = 169 ± 30;
means of control thresholds were between 162 and 226 µA. PB/(+)-P 20 mg kg−1 = 202 ± 39 and PHT/(+)-P
∗ P < 0.05; ∗∗ P < 0.01; ∗∗∗ P < 0.001 (paired t-test). 20 mg kg−1 = 195 ± 27. ∗ P < 0.05 (paired t-test).

(varying from −120 mV to different depolarizing At the physiological membrane potential of −80 mV,
potentials up to −10 mV in increasing 10 mV for example, the mean availability of INa was
steps) to the cell followed immediately by the about 80%. (+)-Propranolol (10−5 and 10−4 M)
15 msecond test pulse (from −120 to −30 mV). reduced the current to 50 and 30%, respectively, at
Both enantiomers shifted the voltage-dependence of this potential. The quantitative analysis revealed that
steady-state inactivation in a more hyperpolarized the (+)-enantiomer shifted V0.5 (membrane potential
direction without marked change in the slope of the where 50% of the channels are available; midpoint
curves. Figure 8(c) shows the relationship between the of the inactivation curve) from −70.1 ± 2.9 mV to
steady-state inactivation and the membrane potential −78.6 ± 2.7 (10−5 M) and −83.3 ± 3.3 mV (10−4 M;
before and after exposure to (+)-propranolol from two mean ± SEM from five cells). On the other hand, the
representative experiments. Under control conditions, (−)-enantiomer displaced V0.5 from −71.5 ± 2.5 mV
sodium currents began to inactivate at prepulse to −79.5 ± 2.9 (10−5 M) and −84.3 ± 4.1 mV
potentials positive to about −90 mV and steady- (10−4 M; n = 5 cells). After washout, the V0.5 values
state inactivation was complete at about −50 mV. in most cases recovered. Consequently, (+)- as well
Anticonvulsant profile of propranolol 295

Concentration-dependent inhibition of peak INa

The concentration-dependent inhibition of peak INa

by (+)- and (−)-propranolol in comparison with
phenytoin and valproate is shown in Fig. 9. The
concentration–response curves were obtained by
cumulative administration of drugs up to 10 µM;
before application of 100 µM, a washout period
was generally inserted to reduce long-lasting drug
influences and irreversible effects. The solid curves
represent the ‘tonic’ inhibition 3–5 minutes after
drug application (single depolarizing test pulses from
−120 to −30 mV). The dashed curves indicate the
Fig. 7: Effect of (±)- and (+)-propranolol ((±)-P; (+)-P) in additional, frequency-dependent reduction after the
comparison with phenobarbital (PB), phenytoin (PHT), last of 10 pulses with 10 Hz stimulation. A clear
carbamazepine (CBZ) and valproate-Ca (VP) in fully reduction of peak INa is already observed at 1 µM to
amygdala kindled rats with reproducible seizures of
stages 4/5. Control responses (saline) were measured 1(2)
10 µM. Half-maximal inhibition (IC50 ) values were in
days prior to drug administration in the same group of the range of 100 µM for both enantiomers. Compared
animals. Each double column represents the mean seizure to (+)- or (−)-propranolol, the inhibitory activity of
stage (scaled pre-drug and post-drug seizure behaviour phenytoin (IC50 90 µM) was only somewhat higher.
indicated as dashed line and solid line columns, respectively)
of tested groups (number of animals within the group at the
In contrast, valproate exhibited a smaller reduction
base of each column). The doses of drugs (in mg kg−1 i.p.) of peak INa , even at high concentrations (about 15%
and the pretreatment times are given below the columns. at 1 mM). The frequency-dependence was also not
Significance level: ∗ P < 0.05; ∗∗ P < 0.01; ∗∗∗ P < 0.001 very pronounced.
(paired t-test).

Effects of (+)- and (−)-propranolol on

picrotoxin-induced burst activity in cultured
neonatal mouse spinal cord neurones

After application of 10 µM PTX, spinal cord neurones

in culture developed a paroxysmal burst-like firing
activity (Fig. 10). The (+)- and (−)-enantiomers of
propranolol were nearly equieffective in inhibiting
this burst activity (concentration range 1, 10, 30 µM:
21.4/18.7, 45.1/42.6, 100/100% reduction of burst
duration, respectively; n = 4 cells). The results of
a representative experiment with (+)-propranolol are
Fig. 8(a): Effect of (+)-propranolol (10 and 100 µM) on the
current–voltage (I–V) relationship for peak sodium inward
shown in Fig. 10. The ß-blocker talinolol (100 µM),
current (INa ) in the absence (◦-◦) and presence (•-•) of the without marked local anaesthetic properties, exhibited
drug. Means ± SEM (at maximum values) of five rat no clear inhibitory influence (100 µM: 10% reduction
myocardial cells. The cells were voltage-clamped at a of burst duration; n = 2 cells) (not shown).
membrane potential of −100 mV and sodium currents were
elicited by a series of 25 msecond test pulses at intervals of
3 seconds, in 10 mV steps to +40 mV. The I–V relationship
was obtained by plotting the peak INa as a function of the DISCUSSION AND CONCLUSION
test pulse potential. (Leak currents were subtracted using
average values of steady leak currents elicited by
hyperpolarizing pulses to −120 mV.) The insets on the left The aims of the present study were to determine
illustrate the pulse protocol (top) and a family of INa curves (i) the anticonvulsant profile of propranolol and (ii) its
(bottom) from an individual cell before (control) and mechanism of action. The data show that propranolol
after 3–5 minutes exposure to 100 µM (+)-propranolol including its (+)-enantiomer with practically negligi-
((+)-PROP).
ble ß-blocking activity but similar lipophilic and local
anaesthetic properties 36 , exhibits anticonvulsant prop-
as (−)-propranolol decreased to the same extent the erties in screening models for generalized tonic–clonic
potential-dependent availability of sodium channels, seizures like the MES threshold test, the traditional
i.e. the number of channels for opening at the resting MES test as well as the maximal PTZ, NMDLA and
potential. QUIN seizure test. Furthermore, in the hippocampal
296 W. Fischer

Fig. 8(b): Frequency-dependent inhibition of peak INa by (+)-propranolol (upper panels) and (−)-propranolol (lower panels) at
concentrations of 1–100 µM, respectively. Means ± SEM of four to seven rat myocardial cells. Voltage-clamp pulses from −120
to −30 mV of 25 msecond duration were applied at 1 and 10 Hz, respectively, in trains of 10 impulses. The peak current
amplitude for each pulse (In ) in the train was normalized to the current amplitude elicited by the first pulse (Ist ) and plotted as a
function of the pulse number. The insets on the left (top diagram) show the pulse protocol and a family of INa curves from a
representative cell before (control) and after 3–5 minutes exposure to 10 µM (+)-propranolol, stimulated with 10 Hz (note the
marked reduction of peak INa pulse by pulse).

afterdischarge model, predictive for complex partial comparable to the effects of carbamazepine, whilst
seizures (see Reference 33), (±)- and (+)-propranolol phenobarbital and valproate reduced the seizure
reduced the duration of afterdischarges and increased severity up to stage 1 (facial twitches). On the other
the afterdischarge threshold. It should be mentioned hand, in the s.c.-PTZ (85 mg kg−1 ) seizure threshold
that in agreement with the results in both MES test, used as the standard model for myoclonic (and
tests, the co-medication of (+)-propranolol markedly absence) seizures (see Reference 38), propranolol
increased the effectiveness of the tested standard did not exhibit protective effects against generalized
antiepileptics. Previous investigations revealed ad- clonic convulsions. Altogether, the profile of action of
ditive anticonvulsant effects of (+)-propranolol in propranolol seems to be comparable to that of the two
combination with phenobarbital 37 . In fully kindled standard antiepileptics phenytoin and carbamazepine.
rats, (±)- and (+)-propranolol reduced the seizure It is now well accepted that propranolol possesses
severity down to stage 3 (unilateral forelimb seizures) anticonvulsant activity in various seizure models,
Anticonvulsant profile of propranolol 297

Fig. 8(c): Effect of (+)-propranolol on the steady-state

inactivation of peak INa . Data (mean values) from two
representative experiments are presented. Channel
availability was modulated by varying the conditioning
prepulse (200 mseconds) between −120 and −10 mV in
increasing 10 mV steps prior to a test pulse (15 mseconds)
to −30 mV (see pulse protocol on the left). The cells were
held at a membrane potential of −120 mV (interval
2 seconds). The peak INa during the test pulse was
normalized to the control current amplitude for the first
stimulus, when the prepulse potential was the same as the Fig. 9: Concentration-dependent inhibition of peak INa by
holding potential (−120 mV). The normalized current was (+)- and (−)-propranolol ((+)-P; (−)-P) as well as phenytoin
then plotted as a function of the prepulse potential and the (PHT) and valproate-Ca (VP). Data are given as
resulting data were fitted to the Boltzmann equation. Inset on means ± SEM (number of tested cells in parentheses). Solid
the right: families of INa curves from an individual cell before curves: ‘tonic’ inhibition 3–5 minutes after application of the
(control) and after 3–5 minutes exposure to 10 µM drug (single depolarizing test pulses from −120 to −30 mV
(+)-propranolol (numbers 4, 5, 6: prepulse potentials −90, of 25 mseconds duration). Dashed curves: additive,
−80, −70 mV, respectively). frequency-dependent inhibition (10 Hz stimulation, trains
of 10 impulses).

although conflicting results exist in the literature

regarding the effectiveness in diverse seizure pharmacokinetic properties of the enantiomers or an
tests. Surprisingly, there are no detailed studies increase in the ß-adrenoceptor density of DBA/2-mice
on kindling models of epilepsy in the literature. may be responsible for the different anticonvulsant
Only Gellman et al. 39 reported that propranolol potency of (−)- and (+)-propranolol 48 . Furthermore,
(2.5 mg kg−1 i.p.) did not alter the seizure response Louis et al. 12 and Papanicolaou et al. 49 reported
in fully amygdala-kindled rats. The majority of that the (−)-enantiomer of propranolol was seven
studies documented efficacy in electroshock seizure times more effective than the (+)-enantiomer (oral
tests like the MES and/or PTZ-induced tonic seizure administration of 0.05–1 mg kg−1 ) in decreasing the
tests 7, 13–15, 40–45 . As in some papers, the (+)- seizure duration in PTZ(50 mg kg−1 i.p.)-induced
enantiomer is an equally or more potent drug in tonic–clonic seizures in rats. They suggested that
this relationship, suggesting that the anticonvulsant propranolol exert an anticonvulsant effect through
effects are not related to ß-adrenoceptor blockade 7, 14 central ß-adrenoceptors, whereas at higher dose levels,
but rather due to the ‘membrane stabilizing’ additional anticonvulsant activity is associated with
properties 8, 15, 46 . There are, however, two remarkable membrane stabilization.
exceptions. In DBA/2 mice, a genetically sensitive As already discussed, the virtually identical
strain for sound-induced generalized tonic–clonic anticonvulsant potency of the non-receptor-active
seizures 47 , a stronger anticonvulsant potency for the (+)-enantiomer and the anticonvulsant activity of
(−)-enantiomer was observed (see References 11,48; N-methylpropranolol without marked ß-blocking
De Sarro et al., Eur. J. Pharmacol, 2002, in action 50 , argue against a relevant involvement
press). Because of the high doses required, these of central ß-adrenoceptors in the anticonvulsant
authors suggested that the ‘membrane stabilizing’ effectiveness of propranolol.
effects in this model also markedly contribute The following arguments also speak for this
to the anticonvulsant activity. Differences in the statement.
298 W. Fischer

1. The doses of propranolol causing anticonvul- anticonvulsant activity in the same screening models
sant effects (10–20 mg range) are about 10- as phenytoin and carbamazepine, it was of interest to
fold higher than those required for adequate investigate directly the possible influence of (+)- and
ß-adrenoceptor blockade (1–2 mg range). (−)-propranolol on the fast inward sodium current INa .
2. Pindolol and timolol, two lipophilic ß-blockers In earlier studies, Tarr et al. 57 found inhibitory effects
with stronger ß-adrenolytic potency than pro- of propranolol on the fast inward sodium channel in
pranolol 51, 52 , exhibited a smaller or no anticon- frog atrial muscle fibres using the sucrose-gap voltage-
vulsant effect, respectively. clamp technique. Further investigations showed that
3. A subchronic pre-medication with combi- this drug decreased the maximum upstroke velocity
nations of desipramine/phenoxybenzamine or (Vmax ) and amplitude of the action potential in
desipramine/yohimbine, which induced a rapid heart muscle fibres 58–60 and inhibited (veratridine-
decrease in rat brain ß-receptor binding 53 , stimulated) Na+ influx as well as batrachotoxinin
revealed no significant modulation of the an- binding in various brain membrane or cardiac tissue
ticonvulsant effectiveness of propranolol (data preparations in the low µM-range, indicating Na+
not shown, see Reference 6). channel blocking effects at the neurotoxin binding
site 2 61–63 . The present whole-cell patch-clamp exper-
iments were conducted primarily with cardiomyocytes
(see also Reference 27). Although sodium channels in
cardiac and nerve membranes are not fully identical,
sodium channels in the heart behave functionally very
much like those of neuronal cells 64, 65 . Interestingly,
the expression of cardiac sodium channel mRNA
was recently demonstrated in restricted areas of rat
and human brain, especially in limbic structures and
diencephalon 66, 67 . Hartmann et al. 66 suggested that
‘arrhythmias’ of heart and sensible brain regions
may be related and implicate these tetrodotoxin-
resistant sodium channels in some forms of primary
inherited epilepsy. The present studies demonstrate
that the two enantiomers of propranolol exhibit
equieffective sodium channel blocking effects and the
potency is very similar to that of phenytoin (10–
100 µM reduced the peak INa by approximately 20–
50%). Moreover, for both propranolol enantiomers
and phenytoin (see Reference 6), a clear voltage-
and frequency-dependence in blocking voltage-gated
sodium channels were observed. These phenomena
(decrease of the channel availability at stronger mem-
brane depolarizations, increase of channel inhibition
during higher stimulation frequency) may be very
important mechanisms in reducing the ability of cells
Fig. 10: Effect of (+)-propranolol ((+)-PROP) on picrotoxin to fire trains of action potentials at high frequency. The
(PTX)-induced burst activity in cultured mouse spinal cord present findings are in agreement with previous reports
neurones (representative tracings from a single experiment). on the complex interactions of phenytoin and carba-
Within 10–15 minutes of superfusion with 10 µM PTX, the
spinal cord neurones developed a characteristic, burst-like mazepine with sodium channels 9, 55 . Together, these
firing activity (a). Traces (b) and (c) show that (+)-PROP specific effects provide a good explanation for how
dose-dependently inhibited or suppressed this paroxysmal such drugs can reduce neuronal hyperexcitability and
activity (see burst duration and number of action
suppress seizures by selectively inhibiting sustained
potentials/burst). The burst activity recovered after 3–5
minutes of washout with (+)-PROP-free PTX-containing high-frequency firing in epileptic foci without altering
solution (d). The membrane potential (−60 mV; scale bar on normal neuronal brain function 10, 68, 69 .
the right) was unaffected by (+)-PROP. In addition, the whole-cell patch-clamp studies
Phenytoin and carbamazepine as well as a number on mouse spinal cord neurones in culture showed
of promising new compounds block voltage-sensitive that both (+)- and (−)-propranolol equieffectively
sodium channels in a complex voltage- and frequency- inhibited PTX-induced paroxysmal burst-like firing
dependent manner 10, 54–56 . Since propranolol exhibits activity in a concentration-dependent manner. The
Anticonvulsant profile of propranolol 299

potency of phenytoin and carbamazepine was in the example, in a case report of a young woman with
same order as determined by Binscheck et al. 35 . These complex partial seizures following head trauma,
authors suggested that in this model for rapid firing of the combination of carbamazepine and propranolol
action potentials within a neuronal network, the burst (120 mg twice daily) seems to produce synergistic
duration might especially be a sensitive parameter antiepileptic effects 16 . In the treatment of startle
allowing quantification of anticonvulsant drug effects. epilepsy, a rare but severe seizure disorder with
On the other hand, the peripheral ß-blocker talinolol, predominantly tonic and tonic–myoclonic seizures,
without marked local anaesthetic properties 70 , showed propranolol (up to 240 mg day−1 ) was reported
no clear inhibitory effects. Also these results underline to be an additional and safe drug 17 . Furthermore,
that the anticonvulsant activity of propranolol seems propranolol has been used effectively for the treat-
to be related to the known local anaesthetic properties ment of valproate-induced tremor and relevant drug
and not to the antagonism of ß-adrenoceptors in the interactions were excluded 79, 80 . Concerning the fact
CNS. Further studies must show if interferences of that complex partial seizures are frequently associated
propranolol with Ca2+ channels 71, 72 may play a role. with an increase in blood pressure and cardiac
One might argue that the concentrations of propranolol dysfunctions 81, 82 and ictal heart arrhythmias seem
necessary to block Na+ channels are very high. to be an important risk factor of epilepsy 83, 84 , the
However, propranolol is concentrated in the brain of co-medication of propranolol or its (+)-enantiomer
animals and man. A single dose of (±)-propranolol with pronounced cardioprotective effects 85 might be
(22 mg kg−1 s.c.; mice), causes a brain concentration of interest. Principally, an investigation of seizure
of 20.3 µg g−1 (8×10−5 M; brain–plasma relationship incidence in epileptic patients taking ß-blockers like
26 : 1) 73 . In humans (usual therapeutic dose range 80– propranolol for other indications should also be of
320 mg day−1 ) 74 , propranolol (80 mg p.o. twice importance. In addition, as suggested by Nutt 86 ,
daily) causes brain concentrations of 0.8–5.7 µg g−1 propranolol may have clinical value in patients
(0.3–2 × 10−5 M; brain–plasma relationship 17 : 1) 75 . experiencing post-ictal phenomena like confusion and
Moreover, in the treatment of therapy-resistant stupor.
schizophrenic patients excessive propranolol doses Taken together, the present results show marked
(means of 500–1600 mg day−1 ) were used 5, 76 . anticonvulsant properties of the lipophilic ß-
The anticonvulsant effects of propranolol were adrenoceptor antagonist propranolol and its two
observed in a dose range in which approximately 10– enantiomers in experimental models of generalized
20% reduction in heart rate (unrestrained rats) tonic–clonic and complex partial seizures. Moreover,
and 5–20% decrease in mean arterial blood pressure in combination with conventional antiepileptic drugs,
(urethan-anaesthetized rats) was determined after (−)- additive anticonvulsant effects can be observed.
propranolol (10–20 mg kg−1 i.p., 30 minutes after With regard to the possible mode of action, these
application) (for further details, see Reference 77). compounds were found to depress the INa in cultured
The haemodynamic effects of the (+)-enantiomer rat cardiomyocytes in a concentration- and use-
at higher doses were only somewhat smaller. In dependent manner and inhibited picrotoxin-induced
another study with a lower dose of (±)-propranolol burst firing activity of mouse spinal cord neurones in
(5 mg kg−1 i.p., daily for 10 days), Pessina et al. 78 culture. It can be suggested that the sodium channel
reported no significant influence on the systolic and blocking properties and not the ß-receptor antagonistic
diastolic blood pressure in normotensive as well as activity accounts for the anticonvulsant effects of
spontaneously hypertensive rats and only a significant propranolol.
reduction in heart rate in the latter. The possibility
that the changes of cardiovascular parameters can
be of relevance for the anticonvulsant properties of ACKNOWLEDGEMENTS
propranolol, however, seems to be very unlikely. For
example, various potent peripheral ß-adrenoceptor The author wishes to thank Dr G. Wallukat and
antagonists like bisoprolol, bunitrolol, talinolol and Dr R. Bodewei (Berlin-Buch) for supplying cultured
timolol, which can be assumed to produce similar rat myocardial cells and for the excellent support in the
patterns of haemodynamic effects in adequate doses, patch-clamp studies, respectively; Mrs Dr G. Keller
revealed no anticonvulsant properties in the MES and Mrs T. Großmann (Dresden) for the good
test 6 . collaboration in the amygdala-kindling experiments;
To the knowledge of the author, there exist no Dr I. V. Ryzov and Dr A. P. Garyaev (St Petersburg,
controlled clinical studies of antiepileptic effects of Russia) for skilful technical assistance in the QUIN-
propranolol. However, some findings in the literature and NMDLA-induced seizure models, respectively,
provide evidence for beneficial therapeutic effects and Prof. Dr H. Bigalke and Dr R. Ties (Hanover)
by the additive administration of this drug. For for making it possible to carry out some studies on
300 W. Fischer

cultured mouse spinal neurones. The author is also epileptic seizures. Journal of Neurology, Neurosurgery, and
indebted to Mrs U. Beier (deceased) and Mrs U. Psychiatry 1995; 58: 382–383.
18. Löscher, W., Fassbender, C. P. and Nolting, B. The role
Kermes (deceased) for technical assistance in the of technical, biological and pharmacological factors in the
screening experiments and Mrs M. Klausch (Leipzig) laboratory evaluation of anticonvulsant drugs. II. Maximal
for the determination of phenobarbital and carbam- electroshock seizure models. Epilepsy Research 1991; 8:
azepine plasma levels with the Abbott TDx analyser. 79–94.
19. Litchfield, J. T. Jr and Wilcoxon, F. A simplified method of
Furthermore, I would like to thank Prof. E. Schlicker evaluating dose-effect experiments. Journal of Pharmacology
(Bonn) for critically reading the manuscript. The gift and Experimental Therapeutics 1949; 96: 99–113.
of propranolol and its enantiomers by Isis Chemie 20. Swinyard, E. A., Brown, W. C. and Goodman, L. S. Compar-
(Zwickau) is gratefully acknowledged. ative assays of antiepileptic drugs in mice and rats. Journal
of Pharmacology and Experimental Therapeutics 1952; 106:
319–330.
21. Krall, R. L., Penry, J. K., White, B. G., Kupferberg,
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