Anticonvulsant and Related Central Nervous System Effects of the Aqueous Extract of the Stem Bark of Antiaris Toxicaria Pers. Lesch.(Moraceae).

ABSTRACT

Antiaris toxicaria is a plant traditionally used in Ghana for the treatment of various neurological conditions such as epilepsy and pain. This present study therefore seeks to screen for the anticonvulsant and neuropharmacological activities of the aqueous extract of Antiaris toxicaria (AAE) stem bark.

 

Priscilla Kolibea Mante PhDThe effect of AAE on pentobarbital-induced sleeping time, tail immersion test, spontaneous locomotor activity, motor coordination, PTZ-induced convulsions as well as the Irwin test was investigated in a preliminary screening.

The extract produced analgesia and Straub tail effect at 300-3000 mg kg-1 in the Irwin test suggestive of a morphine-like action. These effects were absent after 24 h. No deaths were recorded in the test estimating the LD50 to be above 3000 mg kg-1. Spontaneous locomotor activity of the mice in the activity meter test was increased at 300-3000 mg kg-1. It however showed no impairment on motor coordination in the beam traversal test. The extract potentiated duration of sleeping time in the pentobarbitone interaction test and showed susceptibility to metabolism by hepatic enzymes. Analgesic properties were also further confirmed in the tail withdrawal test while it inhibited PTZ-induced convulsions.

 

Based on the preliminary screening, the extract was further evaluated for anticonvulsant activity in rodents. Acute animal models used include maximal electroshock test (MEST); pentylenetetrazole-induced (PTZ) convulsions; picrotoxin-induced (PCT) convulsions; strychnine (STN) - and 4-aminopyridine-induced convulsions. The extract was relatively more effective in all models used except the maximal electroshock test and strychnine-induced convulsions. AAE (200-800 mg kg-1) produced a significant dose–dependent increase in time taken to the onset of clonic seizures in the PTZ and PCT-seizure tests. The frequency of seizures was also decreased significantly. AAE in addition produced significant decrease in the total duration of convulsions in all pretreated animals. The extract significantly delayed onset of 4-aminopyridine convulsions and improved survival of the animals. Flumazenil, a GABAA receptor antagonist, significantly reversed the anticonvulsant effect of AAE strongly suggesting that Antiaris toxicaria may be acting by enhancing the effects of the GABAergic system.

 

For chronic convulsion models, administration of AAE suppressed PTZ-induced kindling significantly. Pilocarpine and kainic acid-induced status epilepticus were reduced significantly by the extract as well. AAE, nonetheless, showed no protective effect against damage to hippocampal cells.

 

Drugs acting on GABA receptors find use as anxiolytics. Anxiolytic activity was assessed using the elevated plus maze (EPM), light/dark box (LDB) and social interaction tests. A. toxicaria (200-800 mg kg-1) decreased anxiety in mice by producing significant increases in open arm spatiotemporal and ethological parameters such as rearing in the EPM. Time spent in the light area of the LDB was also significantly increased. The extract had no effect on social interaction in mice, on the other hand.

 

Antidepressant property was assessed using the forced swimming (FST) and tail suspension tests (TST). Mobility time was significantly increased with a corresponding immobility time decrease in both tests. Swinging duration showed significant increase at the highest dose. A significant decrease in both pedalling frequency and duration was obtained implicating opioidergic mechanisms. Pretreatment with α-methyldopa (α-MD) reversed the antidepressant property of AAE as did ρ-chlorophenylalanine (PCPA), reserpine and reserpine combined with α-MD. The extract significantly increased the number of head twitches produced by 5-hydroxytryptophan in a manner to similar to fluoxetine, confirming possible serotoninergic mechanisms. The immobility time for the extract was not increased in the presence of d –serine ruling out glycine/NMDA mediated effects. Propranolol (10-7 -10-5 M) produced a non-parallel rightward shift of increasing concentrations of AAE on the isolated rat uterus indicating β2- adrenoceptor activity. Rotarod test results show that AAE at the doses employed has no significant effect on motor coordination.

 

Anticonvulsants are very effective in some painful conditions. Hence, the extract was tested for possible analgesic effect. Treatment of mice with AAE (200-800 mg kg-1, p.o.) produced a marked inhibition of both phases of formalin-induced nociception and similarly reduced the number of writhes induced by acetic acid in mice by 56.89 %.

 

Acute and sub-acute toxicity testing recorded no deaths over the 14-day period. Animals did not exhibit any sign of decreased mobility, respiratory depression or convulsions. Haemoglobin level was significantly decreased as well as the mean platelet volume in rats. All other parameters remained unaffected. Significant increases in Aspartate and Alanine Transaminases were also obtained in the rats. The extract decreased significantly urea and serum creatinine. None of these effects were, however, recorded in mice.

 

In summary, the aqueous stem bark extract of Antiaris toxicaria possesses anticonvulsant, anxiolytic, antidepressant and analgesic properties. Thus, Antiaris may be a potential source for novel drug discovery in the field of neuropsychiatric research.

 

Contact:

Priscilla Kolibea Mante

E-mail: mantepk@yahoo.co.uk

Department of Pharmacology,

Faculty of Pharmacy and Pharmaceutical Sciences,

KNUST, Kumasi.

 

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