European Journal of Medicinal Plants 14(3): 1-17, 2016, Article no.EJMP.25975 ISSN: 2231-0894, NLM ID: 101583475 SCIENCEDOMAIN international www.sciencedomain.org Ergot Alkaloids: A Review on Therapeutic Applications Niti Sharma 1* , Vinay K. Sharma 1, Hemanth Kumar Manikyam 1 1,2 and Acharya Bal Krishna 1Patanjali Natural Coloroma Pvt. Ltd, Haridwar, Uttarakhand - 249404, India. 2University of Patanjali, Haridwar, Uttarakhand - 249402, India. Authors’ contributions This work was carried out in collaboration between all authors. Authors NS and VKS designed the study, wrote the first draft of the manuscript. Authors ABK and HKM supervised the study. All authors read and approved the final manuscript. Article Information DOI: 10.9734/EJMP/2016/25975 Editor(s): (1) Marcello Iriti, Professor of Plant Biology and Pathology, Department of Agricultural and Environmental Sciences, Milan State University, Italy. Reviewers: (1) Nyoman Kertia, Gadjah Mada University, Indonesia. (2) Robert Perna, Texas Institute of Rehabilitation Research, Houston, TX, USA. (3) Charu Gupta, AIHRS, Amity University, UP, India. Complete Peer review History: http://sciencedomain.org/review-history/14283 Received 28 th March 2016 Accepted 12 th April 2016 Review Article st Published 21 April 2016 ABSTRACT Ergot of Rye is a plant disease caused by the fungus Claviceps purpurea which infects the grains of cereals and grasses but it is being used for ages for its medicinal properties. All the naturally obtained ergot alkaloids contain tetracyclic ergoline ring system, which makes them structurally similar with other neurotransmitters such as noradrenaline, dopamine or serotonin. Due to this structure homology these alkaloids can be used for the treatment of neuro related conditions like migraine, Parkinson’s disease etc. For hundreds of years, it has been used in obsctrics and gynecology as an uterotonics. Ergot drugs have important role in treating prolactinomas and type II Diabetes. Their role in cancer treatment has also been established. These drugs constitute an important group of compounds called “Smart drugs” used to improve cognitive function and memory and other age related brain disorders. Structural resemblance with various neurotransmitters allows them to interact with a number of receptors which makes them work on different target thus designing new ergot based drugs with receptor subtype selectivity will be more effective. _____________________________________________________________________________________________________ *Corresponding author: E-mail: [email protected]; Sharma et al.; EJMP, 14(3): 1-17, 2016; Article no.EJMP.25975 Keywords: Ergot alkaloids; smart drugs; ureotonic; type II diabetes; migraine; Parkinson’s disease; cancer. 1. INTRODUCTION Regardless of serious safety concerns, ergot has been used in various systems of medicine Ergot of Rye is a plant disease caused by the (Ayurvedic, Unnani and Western) for hundreds of fungus Claviceps purpurea which infects the years. Ergot contains no lysergic acid grains of cereals and grasses. "Ergot" is the diethylamide (LSD) but rather ergotamine, which French word for “spur” named after the similarity is used to synthesize lysergic acid, the precursor between sclerotia of fungus and spurs on rooster for LSD. Ergot alkaloids are dopamine agonists legs. In Ayurveda it is known as “Annaamaya”, or which activate dopamine receptors (in the basal “Sraavikaa” and in Unnani it is called “Agrat”. ganglia and other parts of the brain involved in Briefly, the life cycle of Claviceps purpurea starts motor function) and a prolactin inhibitor. Ergot is during spring season when the windborne a strong vasoconstrictor and thus helps to reduce ascospores infects the grain and initiates bleeding by narrowing of the blood vessels. In pathogenesis. The fungal sclerotia develop to both Ayurvedic and Unnani system of medicine produce mushroom-shaped stroma, which as in western herbal, ergot is employed to release spores. When a mature sclerotium drops stimulate uterine contraction in the final stages of to the ground, the fungus remains quiescent until labor. It is also employed though rarely for next spring and the process continues [1]. The arresting uterine hemorrhage. Ergot was perhaps ergot symptoms are manifested during kernel first used in medicine as an oxytocic drug, to formation, when ergot bodies are formed in place promote uterine contraction during child birth. of kernels. Interestingly, the fungus does not They have been used for treating migraine infect any other plant part except the ovary, headaches [6] since 1883 and also in treating which is replaced by purplish-black sclerotium, Parkinson's disease, restless leg syndrome and commonly referred to as an ergot. The ergot other purposes. Ergot-derived drugs commonly sclerotium contains high concentrations of the used to treat Parkinson’s disease include alkaloid ergotamine and several other peptide bromocriptine (Parlodel), pergolide (Permax), alkaloids of the ergotamine group (including and lisuride (Revanil) [7]. Presently lysergic acid- ergosine and ergocristine). It is possible that derived drugs are used to treat Alzheimer’s ergot infected grasses since farming began but it disease, dementia and hyperprolactinemia [8- was first documented only around 600 BC. 10]. One of the most recent studies indicates role Chronic ergot poisoning (ergotism) was prevalent of ergots (bromocriptine) in treating Type II in Europe during the middle ages due to the Diabetes [11]. In 2009, bromocriptine mesylate consumption of bread made from contaminated was approved by the FDA for treatment of type II rye. The disease was often referred to as “Ignis diabetes. sacer” , meaning “Holy Fire”, or “St. Anthony’s Fire” [2-5]. The infection resulted in symptoms Although ergotamine and ergometrine are the such as hallucinations, severe gastrointestinal two naturally obtained ergot alkaloids of medical upset with painful feelings of intense heat in the importance a number of new compounds have limbs due to severe restriction of blood flow with been synthesized by chemical modification of concomitant loss of limbs. existing structures [12]. This article thus aims to 2 Sharma et al.; EJMP, 14(3): 1-17, 2016; Article no.EJMP.25975 cover the role of different ergot alkaloids in the methyltransferase, followed by decarboxylation field of medicine. and closure of ring C in Chanovlavine I by Chanoclavine-I cyclase. In the next step 2. BIOSYNTHESIS Agroclavine-17-monooxygenase converts Agroclavine to Elymoclavine [19] which in turn is The steps involved in biosynthesis of ergot ring converted to Paspalic acid by Elymoclavine-17- formation are portrayed in Fig. 1 as described monooxygenase [20,21]. Both these enzymes earlier [13-17]. Limited information is available on are NADPH and dependent and molecular most of the enzymes involved in biosynthesis of oxygen thus can be considered as Cytochrome ergot as they are instable in cell free extract, P450-monooxygenase [22]. However, the except for Dimethylallyltryptophan (DMAT) presence of Elymoclavine-17-monooxygenase synthase. It catalyzes the condensation of L- was not detected in a Claviceps strain that tryptophan with dimethylallylpyrophosphate to produces Agroclavine and Elymoclavine but in a yield dimethylallyltryptophan. All of the enzymatic strain that produces D-lysergic acid amides and steps after dimethylallyltryptophan formation peptides [20,21]. This shows that the clavine- ultimately lead to ring formation in ergoline. The producing Claviceps strain is deficient in the DMAT-forming reaction is the committed step in enzyme that converts Elymoclavine to Paspalic biosynthetic pathway in ergot fungi and provides acid which isomerizes to form D-lysergic acid in the carbon skeleton of the ergoline ring system the next step. [18]. The following steps are catalyzed by a Fig. 1. Biosynthetic pathway of ergot alkaloids 3 Sharma et al.; EJMP, 14(3): 1-17, 2016; Article no.EJMP.25975 3. CHEMISTRY OF ERGOT ALKALOIDS by the reaction of an a-hydroxy-amino acid adjacent to lysergic acid with a carboxyl group of The nucleus common to all ergot alkaloids proline. In addition these ergot alkaloids are (lysergic acid) was isolated and characterized in composed of lysergic acid and a tripeptide 1934 by Jacobs and Craig of the Rockefeller moiety. This tripeptide moiety of ergopeptines Institute of New York [23]. All the naturally contains various amino acids such as L-alanine, obtained ergot alkaloids contain tetracyclic L-phenylalanine, L-valine, L-leucine, and L- ergoline ring system, which makes them isoleucine, as well as 2-aminobutyric acid. The structurally similar with other neurotransmitters compounds usually formed by these amino acids such as noradrenaline, dopamine or serotonin are ergotamine, ergotoxine, ergoxine, and (Fig. 2). This structure homology of ergot ergoannines [24,26] (iv) Ergopeptam alkaloids : alkaloids with these neurotransmitters implies have structure similar to ergopeptines however that these alkaloids can be used for the the major difference between them is the proline treatment of neuro related conditions like moiety i.e. D-proline (ergopeptam) than L-proline migraine, Parkinson’s disease etc. (ergopeptines) and the tripeptide chain is a noncyclol lactam. The examples are Structurally the most common features of these ergotamams, ergoxams, ergotoxams, and alkaloids are methylation at 6 th position of ergoannams [24,26,27] (Fig. 3) nitrogen and substitution at 8 th position of carbon in the tetracyclic