Annonacin is a chemical compound with toxic effects, especially in the

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

, found in some fruits such as the paw paw, custard apples,

soursop Soursop (also called graviola, guyabano, and in Latin America ) is the fruit of ''Annona muricata'', a broadleaf, flowering, evergreen tree. It is native to the Tropics, tropical regions of the Americas and the Caribbean and is widely propag ...

, and others from the family ''

Annonaceae The Annonaceae are a Family (biology), family of flowering plants consisting of trees, shrubs, or rarely lianas commonly known as the custard apple family or soursop family. With 108 accepted genera and about 2400 known species, it is the largest ...

''. It is a member of the class of compounds known as

acetogenin Acetogenins are a class of polyketide natural products found in plants of the family Annonaceae. They are characterized by linear 32- or 34-carbon chains containing oxygenated functional groups including hydroxyls, ketones, epoxides, tetrahyd ...

s. Annonacin-containing fruit products are regularly consumed throughout the

West Indies The West Indies is an island subregion of the Americas, surrounded by the Atlantic Ocean, North Atlantic Ocean and the Caribbean Sea, which comprises 13 independent island country, island countries and 19 dependent territory, dependencies in thr ...

for their

traditional medicine Traditional medicine (also known as indigenous medicine or folk medicine) refers to the knowledge, skills, and practices rooted in the cultural beliefs of various societies, especially Indigenous groups, used for maintaining health and treatin ...

uses.

Traditional medicine

Historically, plants and fruits of Annonaceae (particularly ''

Annona muricata Soursop (also called graviola, guyabano, and in Latin America ) is the fruit of ''Annona muricata'', a broadleaf, flowering, evergreen tree. It is native to the tropical regions of the Americas and the Caribbean and is widely propagated. It ...

'' and '' Annona squamosa'') have been consumed in various forms throughout the West Indies, usually as hot water extracts of leaves.Ross, I. A. (2003). Annona muricata L. Medicinal Plants of the World, Vol. 1: Chemical Constituents, Traditional and Modern Medicinal Uses,1, 133-142. These annonacin-containing herbal teas are thought to be useful in

folk medicine Traditional medicine (also known as indigenous medicine or folk medicine) refers to the knowledge, skills, and practices rooted in the cultural beliefs of various societies, especially Indigenous groups, used for maintaining health and treatin ...

. On the Caribbean island of

Guadeloupe Guadeloupe is an Overseas departments and regions of France, overseas department and region of France in the Caribbean. It consists of six inhabited islands—Basse-Terre Island, Basse-Terre, Grande-Terre, Guadeloupe, Grande-Terre, Marie-Galant ...

, such teas are consumed mainly for their sedative qualities. Use of annonacin products in Guadeloupe often lasts from early childhood through old age, and daily consumption is not uncommon. It was discovered in Guadeloupe that atypical Parkinsonism was predominant in elderly males, who regularly consume annonacin-containing herbal teas. Of 87 people with Parkinsonism transferred to one clinic between 1996 and 1998, 25% had Parkinson's, while 36% had progressive supranuclear palsy and 39% had atypical Parkinsonism.Caparros-Lefebvre, D., & Elbaz, A. (1999). Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study. The Lancet, 354(9175), 281-286.

Neurotoxicity

Annonacin is a disabling and potentially lethal

neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...

. Like other acetogenins, it is a mitochondrial complex I (

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

-dehydrogenase) inhibitor. As NADH-dehydrogenase is responsible for the conversion of

NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum, a series of geographic coordinate systems * North Atlantic Drift, an Atlantic Ocean current * Hobli, a subdivision of a taluka in southern Ind ...

+ as well as the establishment of a proton gradient in the mitochondria, annonacin disables the ability of a cell to generate ATP through oxidative phosphorylation, leading to cell

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

. The LC₅₀ of annonacin is 0.018 μM to dopaminergic neurons, and it is the damage done to these neurons that results in the neurodegenerative effects of the toxin. Annonacin is 100 times more toxic than 1-methyl-4-phenylpyridinium (MPP+), another potent mitochondrial

complex I Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...

inhibitor. Compared to MPP+, annonacin produces a wider and more dramatic loss of neurons, not only in the nigro-striatal system, but in the

basal ganglia The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...

and

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...

nuclei as well. Annonacin has been linked to the abnormally high incidence of

progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...

as well as atypical Parkinsonism in the Caribbean island of Guadeloupe where consumption of fruits, such as the

(''Annona muricata''), is common. An average-sized soursop fruit contains 15 mg of annonacin, while a can of commercial nectar contains 36 mg and a cup of infusion, 140 μg. Studies in rodents indicate that consumption of annonacin (3.8 and 7.6 mg per kg per day for 28 days) caused brain lesions consistent with

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. An adult who consumes a fruit or can of nectar daily over the course of a year is estimated to ingest the same amount of annonacin that induced brain lesions in the rodents receiving purified annonacin intravenously.

References

{{reflist, 30em Furanones Tetrahydrofurans Polyols Polyketides Neurotoxins NADH dehydrogenase inhibitors Respiratory toxins Plant toxins