The alkaloid alstonine: a review of its pharmacological properties

Abstract

Indole compounds, related to the metabolism of tryptophan, constitute an extensive family, and are found in bacteria, plants and animals. Indolic compounds possess significant and complex physiological roles, and especially indole alkaloids have historically constituted a class of major importance in the development of new plant derived drugs. The indole alkaloid alstonine has been identified as the major component of a plant-based remedy, used in Nigeria to treat mental illnesses by traditional psychiatrists. Although it is certainly difficult to compare the very concept of mental disorders in different cultures, the traditional use of alstonine is remarkably compatible with its profile in experimental animals. Even though alstonine in mice models shows a psychopharmacological profile closer to the newer atypical antipsychotic agents, it also shows important differences and what seems to be an exclusive mechanism of action, not entirely clarified at this point. Considering the seemingly unique mode of action of alstonine and that its traditional use can be viewed as indicative of bioavailability and safety, this review focuses on the effects of alstonine in the central nervous system, particularly on its unique profile as an antipsychotic agent. We suggest that a thorough understanding of traditional medical concepts of health and disease in general and traditional medical practices in particular, can lead to true innovation in paradigms of drug action and development. Overall, the study of this unique indole alkaloid may be considered as another example of the richness of medicinal plants and traditional medical systems in the discovery of new prototypic drugs.

Figure 1

Chemical structure of indolic alkaloid alstonine.

Figure 2

Effects of haloperidol (HAL), reserpine (RES), SP49000 (SP) and respective vehicles (SAL, TWE, PEG) on amphetamine-induced lethality in grouped mice. Drugs were administered intraperitoneally ^*P < 0.05, Fisher.

Figure 3

Effects of haloperidol (HAL), SP49000 (SP) and respective vehicles (SAL, PEG) on amphetamine- (A) and apomorphine-induced (B) stereotypies. Drugs were administered intraperitoneally ^*P < 0.05, ^**P < 0.01, Mann–Whitney.

Figure 4

Potentiation of barbiturate sleeping time by diazepam (DPZ), SP49000 (SP) and vehicles (TWE, PEG). Drugs were given intraperitoneally ^**P < 0.01, ANOVA.

Figure 5

Effects of classical (haloperidol and chlorpromazine) and atypical antipsychotics (clozapine and sulpiride), reserpine, barbiturate (pentobarbital) and benzodiazepine (diazepam), alstonine and vehicles (saline, tween) on amphetamine-induced lethality in grouped mice (doses in mg kg⁻¹). Drugs were administered intraperitoneally ^*P < 0.05, Fisher.

Figure 6

Effects of alstonine and vehicle (saline) on apomorphine- (A) and amphetamine-induced (B) stereotypies (doses in mg kg⁻¹). Drugs were administered intraperitoneally ^*P < 0.05, ^**P < 0.01, Mann–Whitney.

Figure 7

Effects of alstonine (A), sulpiride, clozapine (B) and vehicle (saline) on haloperidol-induced catatonia (doses in mg kg⁻¹). Drugs were administered intraperitoneally ^*P < 0.05, ^**P < 0.01, Mann–Whitney.

Figure 8

Effects of classical antipsychotics (haloperidol and chlorpromazine), atypical antipsychotics (clozapine and sulpiride), reserpine, benzodiazepine (diazepam), alstonine and respective vehicle (saline, tween and PEG) on barbiturate-induced sleeping time (doses in mg kg⁻¹). Drugs were administered intraperitoneally ^*P < 0.05, ^**P < 0.01, Mann–Whitney.

Figure 9

Influence of alstonine on [3H]SCH23390 specific binding to striatum (for D2 receptors), [3H]Spiperone specific binding to striatum (for D1 receptors) and [³H]Spiperone specific binding to frontal cortex (for 5-HT_2A receptors).

Figure 10

Effects of alstonine, diazepam, clozapine and sulpiride in mice models of anxiety. Alstonine (alsto, 0.5 and 1.0 mg kg⁻¹ i.p.), diazepam (diaz, 2.0 mg kg⁻¹ i.p.), clozapine (cloza, 0.1 mg kg⁻¹ s.c.) and sulpiride (sulp, 10.0 and 20.0 mg kg⁻¹ i.p.), or vehicles (saline or PPG) were injected 30 min prior to the behavior measurements: (A) head-dips; (B) time in the light zone; (C) latency for the first crossing. Each column represents the mean ± SEM. (N = 10–14). ^**P < 0.01, ^*P < 0.05 versus vehicle-treated group, ANOVA followed by Student–Newmann–Keuls.

Figure 11

Effect of the interaction of alstonine and antagonists in the mice hole-board model. Animals were treated with saline or the antagonists SCH23390 (SCH, i.p., 0.1 mg kg⁻¹), ritanserin (Rit, 2.0 mg kg⁻¹), MK-801 (MK, 0.1 mg kg⁻¹) and picrotoxine (Picr, 1.0 mg kg⁻¹) 30 min prior to vehicle (solution saline 0.9%) or alstonine (alsto, 1.0 mg kg⁻¹). The test was performed 30 min after the last drug administration. (A) Head-dips; (B) squares crossed. Each column represents the mean ± SEM. (N = 10–14). ^**P < 0.01, ^*P < 0.05 versus vehicle-treated group, a = P < 0.01, versus MK-801-saline, ANOVA followed by Student–Newmann–Keuls.

Figure 12

Effect of the interaction of alstonine and ritanserin in the light/dark model. Animals were treated with saline (sal) or the antagonist ritanserin (Rit, 2.0 mg kg⁻¹) prior to saline or alstonine (alsto, 1.0 mg kg⁻¹). The test was performed 30 min after the last drug administration. (A) Latency; (B) time spent in the light zone. Each column represents the mean ± SEM. (N = 10–12) ^**P < 0.01 vehicle-treated group. ANOVA followed by Student–Newmann–Keuls.

Figure 13

Effects of alstonine (alsto, 0.1, 0.5 and 1.0 mg kg⁻¹), clozapine (cloza, 0.1 and 0.5 mg kg⁻¹), sulpiride (sulp, 10.0 and 20.0 mg kg⁻¹) or saline on spontaneous locomotion (A) and MK-801-induced hyperlocomotion (B). Each column represents the mean ± SEM. (N = 10). ^**P < 0.01 versus vehicle-treated group, ANOVA followed by Student–Newmann–Keuls.

Figure 14

Number of myoclonic jerks (MJs) induced by repeated administration of alstonine (0.5 and 1.0 mg kg⁻¹), clozapine (1.0 mg kg⁻¹) and saline. Data expressed as media and standard error (SE). Observations were done in the hour following alternate days of drug administrations. N = 6 mice per group. ^*P < 0.5 and ^**P < 0.01, ANOVA/SNK.