Atropa belladonna neurotoxicity: Implications to neurological ...

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Atropa belladonna neurotoxicity: Implications to neurological disorders Gunnar F. Kwakye, Jennifer Jim?nez, Jessica A. Jim?nez, Michael Aschner

PII: DOI: Reference:

S0278-6915(18)30224-2 10.1016/j.fct.2018.04.022 FCT 9711

To appear in: Food and Chemical Toxicology

Received Date: 6 December 2017 Revised Date: 8 April 2018 Accepted Date: 9 April 2018

Please cite this article as: Kwakye, G.F., Jim?nez, J., Jim?nez, J.A., Aschner, M., Atropa belladonna neurotoxicity: Implications to neurological disorders, Food and Chemical Toxicology (2018), doi: 10.1016/j.fct.2018.04.022.

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1 Atropa belladonna neurotoxicity: implications to neurological disorders 2

3 4 5 Gunnar F. Kwakye a,1, Jennifer Jim?neza, Jessica A. Jim?neza, Michael Aschner b,1

6 7 a Department of Neuroscience, Oberlin College, Oberlin OH, USA 8 b Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

9 10 1 Please address correspondence to:

11 Gunnar F. Kwakye, Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 12 44074. (Ph) 440-775-6503 (email) Gunnar.Kwakye@oberlin.edu 13 14 and 15 16 Michael Aschner, Department of Molecular Pharmacology, Albert Einstein College of Medicine, 17 Forchheimer 209, 1300 Morris Park Avenue, Bronx, USA. (Ph) 718-430-2317 (Fax) 718-430-8922 18 (email) Michael.Aschner@einstein.yu.edu 19 20 21

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29 Keywords: Atropa belladonna, deadly nightshade, neurotoxicity, neurological disorders, atropine,

30 scopolamine, hyoscyamine, teething drugs

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31 Abstract

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Atropa belladonna, commonly known as belladonna or deadly nightshade, ranks among one of

33 the most poisonous plants in Europe and other parts of the world. The plant contains tropane alkaloids,

34 including atropine, scopolamine, and hyoscyamine, which are used as anticholinergics in Food and Drug

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35 Administration (FDA) approved drugs and homeopathic remedies. These alkaloids can be very toxic at

36 high dose. The FDA has recently reported that Hyland's baby teething tablets contain inconsistent

37 amounts of Atropa belladonna that may have adverse effects on the nervous system and cause death in

38 children, thus recalled the product in 2017. A greater understanding of the neurotoxicity of Atropa

39 belladonna and its modification of genetic polymorphisms in the nervous system is critical in order to

40 develop better treatment strategies, therapies, regulations, education of at-risk populations, and a more

41 cohesive paradigm for future research. This review offers an integrated view of the homeopathy and

42 neurotoxicity of Atropa belladonna in children, adults and animal models, as well as its implications to

43 neurological disorders. Particular attention is dedicated to the pharmaco/toxicodynamics,

44 pharmaco/toxicokinetics, pathophysiology, epidemiological cases, and animal studies associated with the

45 effects of Atropa belladonna on the nervous system. Additionally, we discuss the influence of active

46 tropane alkaloids in Atropa belladonna and other similar plants on FDA-approved therapeutic drugs for

47 treatment of neurological disorders.

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57 Introduction

58

Atropa belladonna is a large herbaceous perennial plant native to Europe, North Africa and

59 Western Asia, and sometimes cultivated as an ornamental plant in the United States. It belongs to the

60 solanaceae family and is commonly known as belladonna, deadly nightshade, devil's cherries, devils

61 herb, divale, dwale, dwayberry, naughty man's cherries, gray morel, and poison black cherry (Lackovi,

62 2017). The plant grows as a subshrub, up to 1.5 - 2 meters (m) tall, purple hermaphrodite bell-shaped

63 flowers pollinated by insects, and 0.18 m long leaves, with some similarity to the tobacco plant. Its large

64 leaves grow in pairs on either side of the plant stem; however, one of each leaf pair located near the

65 flowers is noticeably smaller in size. The fruits are cherry-like berries, dark purple/black, juicy, and

66 contain many seeds that are the most toxic part of the plant (Fatemeh Ashtiania, 2011; Lackovi, 2017)

67 (Figure 1). In Europe, Africa and Asia, where the plant grows in the wild, confusion between black/dark

68 belladonna fruit berries with other edible berries and the sweet and pleasant taste of belladonna berries

69 poses a danger to children and adults (Laffargue et al., 2011). The berries, leaves, and roots of Atropa

70 belladonna contain up to 20 different tropane alkaloid including atropine, scopolamine, and hyoscyamine

71 that function as the plant's chemical defense in conditions of stress (Wink and Roberts, 1998).

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S-(-)-Scopolamine (hyoscine) and S-(-)-hyoscyamine are the main alkaloids of various plants

73 from the solanaceae family including plants found in the United States such as Hyoscyamus

74 niger (henbane), Datura spp. (Jimsonweed), Scopolia carniolica, and Hyoscyamine spp. (commonly

75 known as daturine) (Burrows and Tyrl, 2012; Gupta, 2012). These alkaloids are biosynthesized from S-(-

76 )-phenylalanine. Upon ingestion of Atropa belladonna, hyoscyamine is converted to atropine, a racemic

77 mixture, consisting of 50% l-hyoscyamine and 50 % d-hyoscyamine (Ulbricht et al., 2004). The total

78 alkaloid content of hyoscyamine is reported to be 0.2% - 2.0% in the over ground parts of the plant, 0.2%

79 - 1.2% in the roots, and 65% in the belladonna berries. Hyoscyamine makes up 87.6% of the total alkaloid

80 complex in the leaves and 68.7% in the roots (Ulbricht et al., 2004). Thus, atropine and scopolamine are

81 the two most important alkaloids in Atropa belladonna.

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82

In medieval times Atropa belladonna was widely used by witches and sorcerors and professional

83 poisoners (Lee, 2007). Although the plant was largely confined to the world of witchcraft in the medieval

84 period, herbalists, and apothecaries began to study the plant in the sixteenth and seventeeth century.

85 Eventually, the alkaloids in Atropa belladonna was incorporated into non-FDA approved over the counter

86 drugs in the ninteenth century for human use as anticholinergic in cough-cold drug products, sedative to

87 stop bronchial spasms in asthma and whooping cough, analgesic in motion sickness, colic, Parkinson's

88 disease (PD), neuralgia, and rheumatism, as well as in plasters for treating psychiatric disorders

89 associated with hyperkinesis, excessive sweating and brochial asthma (Lee, 2007).

90

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