Intern. J . NesroJcirnce. Vol. 90(3-4), pp. 223-232 Reprints availahle directly from the publisher Photocopying permitted hy license only

Q 1997 OPA (Overseas Publishers Association) Amsterdam B.V. Published in The Netherlands under license by

Gordon and Breach Science Publishers Printed in Malaysia

THE ANTICONVULSANT EFFECT OF DEPRENYL

SEIZURES IN LEWIS RATS ON PENTYLENETETRAZOL-INDUCED

AMNON HOFFMAN, MISHEL AFARGAN, JOSHUA BACKON and ITAY PERLSTEIN

Department of Phannaceutics, School of Pharmac.y, The Hebrew University of Jerusalem, Jerusalem 91 120, Israel

(Received in final form 24 February 1997)

There is recent evidence that deprenyl may have anticonvulsant action in a rat kindling model of epilepsy as well as in a maximal electroshock model. We therefore investigated the effect of deprenyl on the brain sensitivity threshold to pentylenetetrazol (PT2)-induced maximal seizures in Lewis rats, in a model that provides pharmacodynamic information free of pharmacokinetic interference. The novel finding of this investigation was the anticonvulsant effect of deprenyl following repetitive administration whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures. The data suggests that the mechanism of this effect is not associated with the dopaminergic activity of deprenyl since pretreatment with both bromocriptine (a dopamine Dz ago- nist) and haloperidol (dopamine antagonist) did not affect the seizure threshold, whereas levodopa caused a proconvulsant effect. It was also concluded that the mechanism is not related to changes in acetylcholine levels since prolonged pretreatment with deprenyl did not attenuate the brain sensitivity to pilocarpine-induced seizures. The fact that long term administration of deprenyl was needed to pro- duce its anticonvulsant effect may indicate that the anticonvulsant effect of deprenyl may be due to changes in levels of certain endogenous compounds or down or up-regulation of relevant receptor/ effector units.

Keywords: Deprenyl; pentylenetetrazol; PTZ; seizures; antiepileptic; pharmacodynamics

Deprenyl (selegiline) has been shown to be effective in the therapy of Parkinson’s disease when given either alone (Yahr, 1987) or given concurrently with levodopa and a peripheral decarboxylase inhibitor (Knoll, 1978). Deprenyl has also been

Mailing Address: Dr. Amnon Hoffman, The Hebrew University of Jerusalem, Department of Pharmaceutics, P.O. Box 12065, Jerusalem 91 120, Israel. Tel.: 972-2-6758667. Fax: 972-2-6436246. E-mail: ahoffman@cc.huji.ac.il.

Dr. Amnon Hoffman is affiliated with the David R. Bloom Center for Pharmacy.

223

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224 A. HOFFMAN et al.

found to be an effective antidepressant (Mendlewicz & Youdim. 1983) and pro- vides beneficial effect in Alzheimer’s disease (Mangoni, 1991). Although classi- cally considered a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B), an enzyme involved in the metabolic degradation of dopamine in the nigrostriatal dopaminergic tract in the brain (Knoll, 1978; Knoll, 1987), more recent research indicates that some effects of deprenyl are unrelated to MAO-B inhibition (Knoll, 1992). Indeed a potent anticonvulsive effect of deprenyl in both a rat kindling model of epilepsy as well as in a maximal electroshock model was suggested to be due to its effect on noradrenergic transmission (Loscher & Honack, 1995). Our preliminary data also suggested a non-dopaminergic effect of deprenyl (Hoffman, Afargan. & Gilhar. 1993).

Although the paper by Loscher and Honack (1995) shows evidence that acute and possible long-term treatment with deprenyl has anticonvulsant and antiepileptic activity. a stronger case could be assumed if another model of seizure threshold is used. since published pre-clinical studies tend to vary according to the experimental model and the animal species studied (Woodbury, 1980). More problematic is the finding that the anticonvulsant activity of milacemide (a novel glycine prodrug) against seizures induced by hyperbaric oxygen is significantly reduced by deprenyl when the deprenyl was given as a single dose (Youdim & Riederer, 1988). Moreover, acute adminis- tration of deprenyl does not inhibit dopamine metabolism whereas chronic administration produces a change in the apparent turnover of dopamine (Zsilla, Foldi. Held. Szekely, & Knoll, 1986). In rats. chronic administration of deprenyl results in a decrease in striatal MAO-A activity, an increase in the activity of superoxide dismutase and a progressive inhibition of dopamine uptake (Zsilla et al., 1986).

Since evaluation of concentration (unlike dose)-effect relationship provides pharmacodynamic information free of pharmacokinetic interference (Ramzan & Levy, 19851, we investigated the anticonvulsant activity of deprenyl using such a pharmacodynamic model. Brain sensitivity threshold to pentylenetetrazol (PTZ)- induced maximal seizures is a common method to evaluate the antiepileptic potency of therapeutic agents or their neurotoxicity (Hoffman & Alfon, 1992; Ramzan & Levy. 1985; Swinyard & Brown. 1952).

The objective of the present study was, therefore, to assess the acute vs. chronic anticonvulsant effect of deprenyl. In order to strengthen the evidence that the mech- anism of deprenyl is not dopaminergic. we contrasted its effect to bromocriptine ( a dopamine D-2 agonist), haloperidol (a dopamine antagonist). and pilocarpine (an acetylcholine agonist) on brain sensitivity threshold to PTZ-induced maximal seizures in rats.

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ANTICONVULSANT EFFECTS OF DEPRENYL 225

METHODS

Male Lewis rats (LEWMSD, Indianapolis, IN) weighing 220-300 g were used in this investigation. During the experimental period, all animals were housed in individual metal cages in an environment of constant humidity (50-55%) and temperature (20-22"c) in a light-controlled room (light from 7:OO to 19:OO hrs). They were maintained on laboratory chow and water ad libitum. The rats were allowed 2 weeks to adjust to the new environment and to overcome possible stress incurred during transport.

One day before the pharmacodynamic experiment, an indwelling cannula was implanted in the right external jugular vein, under light ether anesthesia. The can- nulas were filled with heparin-free saline solution.

The pharmacodynamic investigations were divided into three separate experi- ments, in order to evaluate the effects of a) repetitive pretreatment of either deprenyl or bromocriptine on PTZ threshold seizures; b) pretreatment with a single dose of either deprenyl or bromocriptine on PTZ threshold seizures; c) pretreatment with a single dose of levodopa or haloperidol on the PTZ threshold seizures; and d) repetitive pretreatment of deprenyl on brain sensitivity to pilocarpine-induced maximal seizures.

STUDY A: The rats were pretreated over 8 consecutive days with oral doses of either deprenyl (2.5 mg/kg/day) or bromocriptine (12.5 mg/kg/day). STUDY B: One hour before the pharmacodynamic experiment, the rats received either a sin- gle oral dose of deprenyl(l2.5 mgkg) or bromocriptine (50 mgkg). STUDY C: Half an hour before the pharmacodynamic experiment, the rats received a single oral dose of either haloperidol (7.5 mgkg) or levodopa together with carbidopa (200 and 40 mgkg respectively). STUDY D: The rats were pretreated over 8 consecutive days with an oral daily doses of deprenyl(2.5 mg/kg/day).

All the drugs used for pretreatment were prepared from commercially available tablets (deprenyl-YumexR Dexxon Ltd., Herzliya, Israel; bromocriptine- ParilacR and levodopa with carbidopa-DopicarR, Teva Pharmaceutical Industries Ltd., Kfar Jaba, Israel; haloperidol-HaldolR, Abic Ltd, Netanya, Israel) suspended in water and freshly prepared before administration; the drugs were administered by gavage between 11:OO and 13:OO. The control group in each of the 4 studies received an equivalent volume (0.5 ml) of water. The doses of the drugs employed in this investigation were reported to effectively produce other pharmacological effects in rats (Knoll, 1978; Knoll, 1987; Meldrum, Anlezark, & Trimble, 1975; Warter et al., 1989).

The treated and control rats in each pharmacodynamic experiment were studied in random order. To determine the effect of the above mentioned pretreatments on

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'26 A. HOFFMAN et a1

the phamacodynaniics of PTZ convulsive action subsequent to the last pretreatment, a PTZ solution ( 1 8.54 mg/ml in saline) was infused intravenously at a constant rate of 37 nig/hr, delivered into unanesthetized and unrestrained rats by a microprocessor-based syringe pump (Pump 22, Harvard Apparatus, South Natick, MA) until the onset of maximal seizures. This pharmacological endpoint was evidenced by forelimb flexion and usually tonic hindlimb extension. At that time, the rats were lightly anesthetized with ether, (unless they died following maximal seizures), and blood (for serum) was promptly collected from the vena cava, and stored at -20"~. pending analysis. Serum FTZ concentrations were assayed using an HPLC method (Hoffman & Alfon, 1992). The standard curve was linear in the range 50-400 mgL.

In order to assess protective activity of deprenyl against pilocarpine-induced seizures. pilocarpine solution (125 mg/ml in saline) was infused i.v. at a constant rate of 137.5 mg/hr until onset of maximal seizures. The infusion time and the total dose of pilocarpine (normalized by weight) were used as parameters to eval- uate the effect of deprenyl on the brain sensitivity to pilocarpine-induced seizures (Turski, Cavalherio. Turski. & Meldrum, 1986).

Serum urea nitrogen, total serum protein concentrations, and the activity of transaminase enzymes were determined by commercially available kits (No. 535, 530, 505 respectively, Sigma Chemical Co. St. Louis, MO). The rectal tempera- ture was monitored just before the pharmacodynamic experiments and the ani- mal's body temperature was maintained throughout these experiments by placing the rat on isothermal pads. The rat's response to the increasing analeptic agents concentration during the pharmacodynamic experiment was recorded.

The non-parametric Mann-Whitney test was used in all cases to evaluate the statistical significance of the difference between the values of each group and that of the corresponding control ( p < 0.05 was considered statistically significant). Results were reported as mean k SE.

RESULTS

The rats used in study A are described in Table I. Following 8 days of pre- treatment with bromocriptine ( 1 2.5 mg/kg/day) the body weight as well as the serum total protein concentration were significantly reduced relative to control values ( p < 0.01). possibly due to the anorexic effect of the drug. However, no changes were noted in any of the physical and other biochemical parameters that were measured. Consecutive pretreatment with deprenyl (2.5 mg/kg/day), accord- ing to the same experimental protocol, did not attenuate any of the measured phys- ical or biochemical indices. No apparent behavioral changes were noted following pretreatment with both drugs. The pharmacodynamic investigation revealed that

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ANTICONVULSANT EFFECTS OF DEPRENYL 217

TABLE I Description of male Lewis rats used to study the effect of repetitive administration of either deprenyl or bromocriptine on the pharmacodynamics of PTZ, and the total PTZ dose required to induce maximal seizures.

Variable Study A

No. of animals Body weight (g) Rectal temperature ("c) Serum total protein (g/100ml) Serum urea nitrogen (mg/100ml) PTZ infusion time (min) PTZ total dose (mgkg)

Deurenvl Bromocriprine Coritrol

12 258 f 5 36.9 k 0.2 5.6 k 0.2

15.4 * 0.8 52.4 f 4* 125 f 8*

12 226 ? 5* 37.1 f 0.1 4.5 k 0.3*

18.1 ? 1.3 42 k 3

1153~8

12 267 ? 5.4 37.1 f0 .1 5.2kO.1

14.3 f 0.5 42.0 f 0.7 100+5

Results pe reported as mean * S.E. *Significantly different from respective control value, p < .02.

following repetitive deprenyl administration for 8 days, the PTZ infusion time and consequent PTZ dose required to produce maximal seizures were significantly greater in the deprenyl pretreated rats than in the control group. Serum PTZ con- centrations required to induce maximal seizures were found to be about 32% higher in deprenyl pretreated rats than the corresponding control values (p < .02) (Fig. 1). The same consecutive treatment schedule with bromocriptine did not affect the total PTZ dose required to induce onset of maximal seizures (Table I) and the serum PTZ concentration at that pharmacological endpoint (Fig. 1).

The results of the pretreatment with a single dose of either deprenyl(l2.5 mgkg) or bromocriptine (50 mgkg) are summarized in Table I1 and Figure 1. Administra- tion of only single doses of these drugs had no apparent effect on the total FTZ dose (Table 11) and serum PTZ concentrations (Fig. 1) at the onset of the pharmacologic endpoint. Significantly lower infusion time and PTZ dose were required in order to provoke maximal seizures in levodopa treated rats in comparison to control animals (Table III), and consequently much lower PTZ serum concentration were detected at that endpoint (Fig. 1) (p < .Ol). Pretreatment of the rats with haloperidol under the same experimental conditions induced a significant ( p < .05) hypothermia (Table HI), while this drug failed to affect the PTZ seizure threshold (Fig. 1).

Consecutive treatment with deprenyl did not affect the duration of pilocarpine infusion as well as the total pilocarpine dose that was required to produce maxi- mal seizures in normal rats (Table TV).

DISCUSSION

We found an anticonvulsant effect of deprenyl evidenced by the significant eleva- tion of the seizure threshold to PTZ-induced maximal seizures. This finding was demonstrated by the elevated PTZ dose required to produce the onset of maximal

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200

150

100

50

A. HOFFMAN et al

* T

study X study B stuey c

FIGURE 1 Effect of pretreatment with dopaminergic drugs on serum PTZ concentrations at the onset of maximal seizures in rats infused with PTZ. STUDY A: Rats were pretreated with deprenyl2.S mg/kg/day R . or bromocriptine 12.5 mg/kg/day 0 , or water I. for 8 consecutive daq s. STUDY B: Rats received a single dose of either deprenyl 12.5 mgkg H. or broniocriptine SO mgkg 0 , or water I. 0.5 h before PTZ infusion started. STUDY C: Levodopa 200 mgkg m. or haloperidol 7.5 mgkg I. or water 1, were administered 0.5 h before PTZ infusion started. All the drugs were administered orally. Values are mean k SE. * p < .02.

TABLE I1 Description of rats used to study the effect of a single dose of either deprenyl or bromocriptine on PTZ pharmacodynamics, and the total PTZ dose required to induce maximal seizures.

Vorinhle Stiidv B

Depreti~l Broniocriptirze Control

No. of animals 10 10 10 Body weight (g) 21s f 1 208 f 3 220 k 4 Rectal temperature ("cj 37 k 0.1 37.1 f 0.1 37.6 k 0.2 Serum total protein ( g / I O m l ) 6.9 f 0.2 6.6 f 0.3 7.2k0.1 Serum urea nitrogen (mg/IOOml) 16.4 f 0.8 17.1 f 1.3 14.8 f 0.5 PTZ infusion time (minj 24 f 2.7 30.9 f 2.6 28.2 f 1.6 PTZ total dose ( m g k g ) 76 f 7 91 f 5 8 5 f 4

Rewlt? dre reponcd aa mean I S E.

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ANTICONVULSANT EFFECTS OF DEPRENYL 229

TABLE I11 Description of rats used to study the effect of a single dose of either levodopa or haloperidol on PTZ pharmacodynamics, and the total PTZ dose required to induce maximal seizures.

Variable Studv C

Levodopa Haloperidol Control ~~

No. of animals 10 10 10 Body weight (g) 350 k 6 330 f 6 344 f 5 Rectal temperature (“C) 37.5 f 0.1 36.2 f 0.1* 37.4 f 0.1 Serum total protein (g1100ml) 7.8 f 0.2 7.2 f 0.2 7.8 f 0.1 Serum urea nitrogen (mg/100ml) 16.2 ir 0.5 15.8 f 0.5 14.8 f 0.5 PTZ infusion time (min) 43 f 2.1** 45.6 f 1.5 54.5 f 6.7 PTZ total dose (mgkg) 120 f 4** 138 f 4 157 f 7

Results are reported as mean f S.E. *Significantly different from respective control value, p < .05. **Significantly different from respective control value, p < .01

seizures, but was even more clear when the serum PTZ concentrations of deprenyl treated and control groups, at this pharmacological endpoint, were compared. The novel finding of the anticonvulsant effect of deprenyl was observed following repetitive administration of the drug, whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures. To validate this result we repeated this experiment with repetitive deprenyl administrations (according to the same experimental protocol). The outcome of the confirmatory study showed that repetitive deprenyl treatment lowers the brain sensitivity to PTZ-induced max- imal seizures by the same extent.

The discrepancy in results between single and repetitive administration may raise the question whether this anticonvulsant activity of deprenyl evolves from a direct effect of the drug itself. One possible explanation is that certain endoge- nous compounds are induced by its pharmacological activity, or to a down- or up- regulation of relevant receptor/effector units. The necessity for long term

TABLE IV Description of rats used to study the effect of repetitive admin- istration of deprenyl on pilocarpine-induced maximal seizures, and the total pilocarpine dose required to induce maximal seizures.

Variable Studv D

Deorenvl Control

No. of animals 10 10 Body weight (8) 296 f 5 280 k 9 Rectal temperature (“c) 37.9 f 0.2 37.6 f 0.1 Serum total protein (g/100ml) 7.9 f 0.2 7.5 ir 0.5 Serum urea nitrogen (mg1100ml) 15.6 f 0.4 14.9 f 0.4 Pilocarpine infusion time (min) 22.0 f 0.5 20.8 ir 1.5 Pilocarpine total dose (mgkg) 298 k 7 305 f 6

Results are reported as mean f S.E.

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230 A. HOFFMAN et al

administration of the drug in order to produce its pharmacological activity is in agreement with other pharmacological effects of deprenyl, such as the elevation of dopamine levels in the substantia nigra that provides its anti- Parkinsonian activity (Knoll. 1987).

Dopaminergic receptors exert opposing roles on seizure threshold with D- 1 receptor stimulation reducing (Starr & Starr. 1993) and D-2 stimulation increas- ing seizure threshold (Alam & Starr. 1994). Furthermore. D-2 agonists protect rodents against pilocarpine-induced convulsions ( Al-Tajir & Starr, 199 1). Since Zsilla et al. (1986) found differences in dopamine turnover between acute vs. chronic administration of deprenyl, the effect of deprenyl was compared to three other dopaminergic drugs. Bromocriptine ( a dopamine agonist) did not attenuate the seizure thresholds to PTZ-induced seizures following a single dose as well as to repetitive administration. Similarly. acute pretreatment with haloperidol failed to attenuate the pharnicodynamics of PTZ convulsive activity. On the other hand. levodopa exhibited proconvulsant activity, an outcome which is found to be in agreement with previous reports (Burley & Ferrendel, 1984). These results may contribute to the idea that the anticonvulsant effect of deprenyl in the PTZ model is probably not associated with dopamine neuro- transmission. This conclusion is also in accord with other studies where minor or no effect of dopamine neurotransmission in the PTZ model were found (Killam & Killam, 1984).

The indirect inhibitory effect of deprenyl on acetylcholine secretion in the sub- stantia nigra could be attributed, in theory. to its anticonvulsant action. To verify this premise, the activity of repetitive administration of deprenyl against pilo- carpine-induced seizures was investigated. The fact that deprenyl pretreated rats required the same pilocarpine dose to produce onset of maximal seizures as untreated controls clarifies that changes in acetylcholine neurotransmission are not related to the observed anticonvulsant activity of deprenyl.

Recent findings in our laboratory clearly show that the brain sensitivity to PTZ-induced seizures is not associated with oxidative stress or the tissue’s reduc- tive capacity (unpublished data). Therefore, the contribution of the antioxidant properties of deprenyl to its anticonvulsant effect in the PTZ model can, in our view. be ruled out.

It is very difficult to conclude the exact pharmacological mechanism from these experiments in intact animals. However, on the basis of the present results together with previous reports, it seems reasonable to assume that the anticonvul- sant effect of deprenyl is related to its ability to reduce the levels of monoamine neurotransmitter metabolites such as 6-HODA. a proconvulsant endogenous neuro- toxin (Corcoran, Fibiger. McGeer, & Wada. 1973). However, further investigations are required in order to substantiate this assumption.

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ANTICONVULSANT EFFECTS OF DEPRENYL 231

Clinically, the data presented here raise the possibility of utilizing the anticon- vulsant efficacy of deprenyl for the treatment of seizures. This could be a great contribution especially because of its negligible adverse effects in comparison to currently used antiepileptic medications. In addition, the data presented here indi- cates that utilization of the dopaminergic drugs bromocriptine and haloperidol do not alter the brain sensitivity to epileptic seizures while levodopa can increase the brain’s susceptibility to such episodes. These conclusions are subject to usual reservations in extrapolating animal data to humans.

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