Alstonia scholaris

Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com.

Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com.

Alstonia scholaris, a tree that grows 50-80 feet high and belongs to the Apocynaceae family, has a long history of use in traditional and homeopathic medicine, including Ayurvedic medicine in India, where it is known as sapthaparna (Integr. Cancer Ther. 2009;8:273-9), in traditional Chinese medicine (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81), and in traditional medicine in Africa and Australia (Integr. Cancer Ther. 2010;9:261-9). The bark contains the alkaloids ditamine, echitamine (or ditaine), and echitanines; and decoctions or other preparations of the bark have been used to treat gastrointestinal conditions (Grieve M. A Modern Herbal (Vol. 1). New York, Dover Publications, 1971, p. 29). Often called the devil’s tree, the bark of A. scholaris also has been used to treat malaria, cutaneous diseases, tumors, ulcers, chronic respiratory conditions (such as asthma and bronchitis), helminthiasis, and agalactia (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]).

In the study of A. scholaris most directly pertinent to potential dermatologic treatment, Lee et al. found that ethanolic bark extracts of A. scholaris significantly suppressed retinoid-induced skin irritation in vitro and in vivo, in human HaCat keratinocytes. The investigators identified echitamine and loganin as the primary components likely responsible for the anti-inflammatory effects.

Courtesy Wikimedia Commons/Binh Giang/Public Domain

Data showed that A. scholaris dose-dependently inhibited the all-trans retinoic acid–induced releases of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vitro. Also in vitro, A. scholaris extract potently suppressed radiation-induced increases in matrix metalloproteinase-1 (MMP-1). Importantly, in a cumulative irritation patch test, the botanical extract diminished retinol-induced skin irritation while enhancing retinoid activity in blocking MMP-1 expression, which is linked closely to cutaneous aging. The authors concluded that A. scholaris appears to have the dual benefits of decreasing irritation associated with retinoids while augmenting their antiaging impact (Evid. Based Complement. Alternat. Med. 2012;2012:190370).

The leaf extract of A. scholaris has been used to treat cold symptoms and tracheitis, and it has been prescribed in hospitals and approved for commercial over-the-counter sale by the State Food and Drugs Administration of China (SFDA) (J. Ethnopharmacol. 2010;129:293-8; J. Ethnopharmacol. 2010;129:174-81). The broad range of biological properties associated with A. scholaris has been ascribed to particular constituent categories, including alkaloids, flavonoids, and terpenoids (specifically, phenolic acids) (Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). These properties include, but are reportedly not limited to, antioxidant, anticancer, anti-inflammatory, antistress, analgesic, antimutagenic, hepatoprotective, immunomodulatory, and chemopreventive activity (Integr. Cancer Ther. 2010;9:261-9; Chin. J. Integr. Med. 2012 Mar 28 [Epub ahead of print]). Antineoplastic effects have been linked directly to phytochemical constituents including echitamine, alstonine, pleiocarpamine, O-methylmacralstonine, macralstonine, and lupeol (Integr. Cancer Ther. 2010;9:261-9).

In 2006, Jagetia and Baliga investigated the anticancer activity of A. scholaris alkaloid fractions in vitro in cultured human neoplastic cell lines. They also conducted in vivo studies in tumor-bearing mice. The in vitro data in HeLa cells revealed a time-dependent rise in antineoplastic activity after 24 hours of exposure (25 mcg/mL). Further, once-daily administration of A. scholaris (240 mg/kg) to tumor-bearing mice yielded dose-dependent remissions, although there were toxic presentations at this dosage. The next-lower dose of 210 mg/kg was found to be most effective, with 20% of the mice surviving for as long as 120 days after tumor cell inoculation, compared with none of the control animals treated with saline (Phytother. Res. 2006;20:103-9).

Using an acute-restraint stress model in mice in 2009, Kulkarni and Juvekar evaluated the effects of stress and the impact of a methanolic extract of A. scholaris bark. Pretreatments with the extract of 100, 250, and 500 mg/kg for 7 days were found to exert significant antistress effects. In addition, nootropic activities were observed, with memory functions clearly enhanced in learning tasks. A. scholaris also was associated with significant antioxidant properties. The extract at 200 mcg/mL exhibited maximum scavenging of the stable radical 1,1-diphenyl-2-picrylhydrazyl at 90.11% and the nitric oxide radical at 62.77% (Indian J. Exp. Biol. 2009;47:47-52).

Later in 2009, Jahan et al. reported on their investigation of potential antioxidant and chemopreventive activity displayed by A. scholaris in a two-stage murine model. Skin carcinogenesis development was initiated in Swiss albino mice through one application of 7, 12-dimethyabenz(a)anthrecene (DMBA) and then promoted two weeks later by repeated application of croton oil three times per week through 16 weeks. The investigators found a lower incidence of tumors, tumor yield, tumor burden, and number of papillomas in mice treated with A. scholaris extract as compared to untreated controls (Integr. Cancer Ther. 2009;8:273-9).

In 2010, Shang et al. conducted multiple studies using A. scholaris. In the first published report, they assessed the anti-inflammatory and analgesic properties of the ethanolic leaf extract to validate its use in traditional Chinese medicine and modern clinical medicine. The investigators first determined that analgesic activity was conferred as the ethyl acetate and alkaloid fractions significantly diminished acetic acid-induced reactions in mice and, along with the ethanolic extract, reduced xylene-induced ear edema.

The researchers also performed in vivo and in vitro assessments of anti-inflammatory activity again on xylene-induced ear edema and carrageenan-induced air pouch formation in mice, as well as cyclooxygenase (COX)-1, -2 and 5-LOX inhibition.

In the air pouch model, A. scholaris alkaloids were found to have significantly spurred superoxide dismutase activity while lowering nitric oxide, prostaglandin E2, and malondialdehyde levels. In vitro tests, supporting evidence from animal models, showed that the three primary alkaloids isolated from A. scholaris leaves (picrinine, vallesamine, and scholaricine) inhibited the inflammatory mediators COX-1, COX-2, and 5-LOX. The researchers also noted that the in vitro anti-inflammatory assay results reinforced the notion of these alkaloids as the bioactive fraction of the plant (J. Ethnopharmacol. 2010;129:174-81).

In their second published report that year, Shang et al. investigated the antitussive and anti-asthmatic activities of the ethanolic extract, fractions, and chief alkaloids of A. scholaris leaf.

The researchers tested for antitussive effects using ammonia-induced or sulfur dioxide-induced coughing in mice and citric acid-induced coughing in guinea pigs. They evaluated anti-asthmatic activity via histamine-induced bronchoconstriction in guinea pigs. They also measured phenol red volume in murine tracheas to assess expectorant activity.

The data indicated antitussive activity, with significant alkaloid suppression of ammonia-induced coughing frequency in mice. Latency periods of sulfur dioxide-induced cough in mice and citric acid-induced cough in guinea pigs increased, and cough frequency in guinea pigs decreased.

Anti-asthmatic effects, such as suppression of convulsion, were observed in guinea pigs. In the expectorant assessment, tracheal phenol red production was increased. The researchers identified picrinine as the primary alkaloid responsible for these activities (J. Ethnopharmacol. 2010;129:293-8).

In addition, Jahan and Goyal showed that pretreatment with A. scholaris bark extract protected the bone marrow of mice against radiation-induced chromosomal damage and micronuclei induction (J Environ. Pathol. Toxicol. Oncol. 2010;29:101-11).

Conclusion

Despite the dearth of research on A. scholaris, the existing data are intriguing, particularly the findings that A. scholaris may have the capacity to amplify the anti-aging activity of retinoids while blunting their irritating effects. Although more research is needed to determine the dermatologic value of A. scholaris, the pursuit may potentially prove fruitful.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com.