Drug Repositioning: Antimalarial Activities of GABA Analogs in Mice Infected with Plasmodium berghei.

BACKGROUND: Drug repositioning is becoming popular due to the development of resistance to almost all the recommended antimalarials. Pregabalin and gabapentin are chemical analogs of gamma- aminobutyric acid (GABA) approved for the treatment of epilepsy and neuropathic pain. OBJECTIVE: This study investigates acute toxicities and antimalarial activities of pregabalin and gabapentin in the murine malarial model. METHODS: Acute toxicities were assessed using the method of Lorke, while curative activities were assessed by the administration of serial doses of pregabalin and gabapentin to Plasmodium berghei infected mice. Pregabalin was further investigated for its prophylactic activity, and curative potential when combined with either artesunate or amodiaquine. All drugs were freshly prepared and administered orally. Thin films were collected, stained, and observed under the microscope for the estimation of parasitemia and calculation of percentage chemoinhibition or chemoprevention. In pregabalin -artesunate or -amodiaquine combination aspect of this study, survival day post-infection (SDPI) was recorded, while parasitemia was re-estimated for animals that survived till day 28. RESULTS: The oral LD50 of gabapentin, as well as pregabalin, was >5,000 mg/kg. Gabapentin at 100 and 200 mg/Kg demonstrated 35.64% and -12.78% chemoinhibition, respectively, while pregabalin demonstrated 75.60% and 100.00% chemoinhibition at doses of 12.5 and 25 mg/Kg, respectively. Moreover, pregabalin at individual doses of 25, 50 mg/Kg, and in combination with either artesunate or amodiaquine demonstrated 100.00% chemoinhibition. In its prophylactic study, pregabalin was found to be 100% chemopreventive at individual doses of 12.5 and 25 mg/Kg. CONCLUSION: Both GABA analogs have antimalarial properties, but pregabalin proved to be more efficacious.

Potential Mechanisms Involved in the Anticonvulsant Effect of Methanol Extract of Pyrenancantha staudtii in Mice.

OBJECTIVE: To determine the potential effect of Pyrenancantha staudtii extract on experimentally induced seizures in mice and to evaluate the role of benzodiazepines, naloxone, and serotonin within these pathways. METHODS: Animal behaviours were evaluated using open field, hexobarbitone-induced sleep model, and anticonvulsant activity using picrotoxin-, or strychnine-, or isoniazid-induced convulsions. Attempt to understand the mode of action of the anticonvulsant activity of the plant, three notable antagonists (flumazenil, 3 mg/kg; naloxone 5 mg/kg, i.p., and cyproheptadine, 4 mg/kg, i.p) were used. RESULTS: The results revealed a significant (p < 0.05) reduction in the frequency of rearing and grooming episodes compared with the control. The extract of P. staudtii potentiates the sleeping time of hexobarbitone-induced hypnosis in a dose-related manner. P. staudtii stem bark extracts significantly (p<0.05) prolonged the onset of a seizure and attenuated the duration of seizure in a dose-dependent manner in picrotoxin- and or isoniazid-induced seizures. While, P. staudtii stem bark extract at all doses (100, 200, and 400 mg kg-1) though significantly prolonged the onset of action, but did not confer any significant changes on the duration, as well as mortality in this strychnine-induced seizure model. However, the anticonvulsant activity of the methanolic extract of P. staudtii was significantly reversed following intraperitoneal pre-treatment with flumazenil (GABA receptor antagonist) and naloxone (opioid receptor antagonist) but not cyproheptadine (5-HT2 receptor antagonist) in picrotoxin-induced convulsion. CONCLUSION: The data obtained suggest that methanol extract of P. staudtii possessed significant anticonvulsant effect, thereby confirming the traditional uses of P. staudtii in the treatment of epilepsy; mechanisms of which could involve the interaction with GABAergic and or opioidergic system.