Anticonvulsant and antidepressant effects of an ethanolic extract of the leaves of Pseudospondias microcarpa (Engl.) A. Rich. (Anacardiaceae) in animal models

The search for novel pharmacotherapy from medicinal plants for central nervous system (CNS) disorders has become of importance since new agents with improved efficacy for more effective therapy are required. Pseudospondias microcapa has been extensively used in Ghana and other parts of Africa as medication for various diseases including CNS disorders. The present study examined the anticonvulsant, antidepressant, as well as some neurobehavioural properties of an ethanolic extract of the leaves of Pseudospondias microcarpa in animal models. Preliminary phytochemical screening of Pseudospondias microcarpa extract (PME) revealed the presence of saponins, tannins, glycosides, terpenoids, flavonoids and alkaloids. Neuropharmacological activities of the extract in mice was investigated. The extract produced sedation and analgesia in the Irwin test with an LD50 above 3000 mg kg-1. PME potentiated pentobarbitone sleeping time and was metabolised by hepatic enzymes. It however showed no effect on locomotor activity or motor coordination. Furthermore, the extract blocked convulsions induced by PTZ and showed analgesic activity in the tail withdrawal test. Based on the findings from the preliminary studies, the anticonvulsant activity of PME and possible mechanism(s) in animal models was further explored. The extract significantly delayed the onset as well as decreased the duration and frequency of pentylenetetrazole (PTZ)-, picrotoxin (PTX)- and strychnine (STN)-induced seizures. In addition, pretreatment of mice with PME before administration of 4-aminopyridine (4-AP) or isoniazid (INH) significantly increased the latency to seizures and reduced the incidence of mortality.The GABAA receptor antagonist, flumazenil, reversed the anticonvulsant effect of PME, further suggesting the possible involvement of the GABAergic system in its action. Furthermore, the extract protected against 6-Hz psychomotor seizures but had no effect in the MES test. Moreover, the anticonvulsant effect of PME (100 mg kg-1, p.o.) was prevented by pre-treatment with L-arginine or sildenafil. However, N-nitro-L-arginine methyl ester (L-NAME) or methylene blue (MB) augmented the anticonvulsant effect of PME. Acute treatment with PME reduced immobility of mice in the TST and FST. The antidepressant-like effect of PME (100 mg kg-1, p.o.) in the TST was blocked by p-Chlorophenylalanine and cyproheptadine but not prazosin, propranolol or yohimbine, thus suggesting 5-HT pathway may be involved in the action of PME. This is further confirmed by the potentiation of 5-hydroxytryptophan-induced head-twitch response by PME in mice. Pretreatment with a combination of reserpine and α-methyl-p-tyrosine (AMPT) completely prevented the behavioural effects of PME, fluoxetine and desipramine. Concomitant administration of D-cycloserine and the extract potentiated the anti-immobility effect. In contrast, D-serine a full agonist of glycine/NMDA receptors abolished the effects. In the repeated open-space swim test, mice showed a progressive decrease of active swimming and a corresponding increase in immobility that persisted for several days. However, the increased inactivity was reversed selectively by the extract and the classical antidepressant drugs, in that they increased distance swum and decreased immobility. Moreover, the depressive-behaviour induced by the repeated open-space swim test impaired spatial learning and memory performance in the Morris water maze (MWM) test. This was however reversed by the extract. The long-term effects of chronic mild stress (CMS) and PME treatment on depressive, anxiety-like behaviour and cognitive function were also investigated. Exposure of mice to the CMS paradigm displayed decreased sucrose intake, poor coat state, decreased grooming frequency (splash test), increased immobility, increased anxiety and impaired cognitive function. These effects were however reversed by chronic PME treatment. Anxiolytic-like effects of the extract in behavioural paradigms of anxiety was also evaluated. P. microcarpa treated mice (30-300 mg kg-1, p.o.) exhibited anxiolytic-like activity similar to diazepam in all the anxiety models used. PME increased open arm activity in the elevated plus maze (EPM) as well as increasing the time spent in the lit area in relation to the time spent in the dark area of the light/dark box. The extract also increased the number of central entries and time spent in the center of the open field. In addition, an increase in social interaction and decreased stress-induced hyperthermia was obseverd for PME-treated mice. Acute and subacute toxicity in rats did not show deaths after 14 days treatment with the extract (30–3000 mg kg-1). Haematological or serum biochemical parameters were not affected except decrease in lymphocytes (100−3000 mg kg-1), triglycerides (100 mg kg-1) and very low density lipoproteins (100 mg kg-1). Histopathological examination did not reveal toxic effect on the stomach, heart, liver, brain, kidney and spleen. Results of the present study suggests that PME possesses sedative, analgesic, anticonvulsant, antidepressant and anxiolytic effects without affecting motor coordination.

Source: KNUST