ENVIRONMENTAL BIOTECHNOLOGY 10 (1) 2014 , 26-43; doi:10.14799/ebms246 Neurotoxicity of cyanobacterial toxins Maciej Florczyk, Alicja Łakomiak, Maciej Woêny, Paweł Brzuzan Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, Poland Corresponding author: Maciej Florczyk, Department of Environmental Biotechnology, Faculty of Environmental Sciences, University of Warmia and Mazury in Olsztyn, Słoneczna 45G, 10-709 Olsztyn, Poland; Phone: +48 89 523 4164; Fax: +48 89 523 4131; E-mail: [email protected] Keywords: blue-green algae, cyanotoxins, drugs, medicine, microcystin, neurotoxicity Received in July 2014. Published in December 2014. ABSTRACT changes in protein phosphatase activity. These effects have been partially explained by the discovery in the blood-brain Eutrophication of marine- and fresh-waters can lead to excessive barrier of the same membrane transporters involved in development of cyanobacterial blooms, which may contain microcystins hepatotoxic mechanisms. Additionally, this paper strains that produce toxins. These toxins are secondary reviews other cyanotoxins that are known or suspected to target metabolites which can accumulate in the food chain and cholinergic synapses and voltage-gated channels, including contaminate drinking water, thus posing a potential threat to the anatoxin-a, anatoxin-a(s), antillatoxins, cylindrospermopsin, health of humans and aquatic organisms. These toxins include homoanatoxin-a, jamaicamide, kalkitoxin and saxitoxins. The a variety of compounds with different mechanisms. This review neurotoxic and cytotoxic effects of the cyanotoxins discussed focuses on the neurotoxicity of microcystin and other here are of particular interest because of their pharmacological cyanotoxins. Although the hepatotoxic action of microcystins is potential. This review also discusses the potential of these commonly known, its neurotoxic effects have also been compounds to serve as drugs for cancer and central nervous described, e.g. oxidative stress, cytoskeletal changes and system failure. ABBREVIATIONS Ach acetylcholine AchE acetylcholinesterase AldH aldehyde dehydrogenase ANTX-a anatoxin-a ANTX-a(s) anatoxin-a(s) ATX antillatoxin BMAA L- β-N-methylamino-L-alanine CoA coenzyme A CYN cylindrospermopsin EGFR epidermal growth factor receptor HSP heat shock protein MC microcystin © UNIVERSITY OF WARMIA AND MAZURY IN OLSZTYN Florczyk et al. Neurotoxicity of cyanotoxins 27 mWBC murine whole brain cells NADH nicotinamide adenine dinucleotide NMDAR N-methyl D-aspartate receptor NOD nodularin Oatp/OATP organic anion transporting polypeptide PPs protein phosphatases PSP paralytic shellfish poisoning ROS reactive oxygen species SLCO organic anion transporting family STX saxitoxin VGSC voltage gated sodium channels Introduction ........................................................................................................... 27 Cyanotoxins .......................................................................................................... 28 Stability of cyanotoxins in aquatic environment ................................................. 30 General mechanisms of cyanobacterial neurotoxicity ........................................ 31 Neurotoxic effects of cyclic peptides ................................................................... 33 Microcystins .......................................................................................... 33 Nodularin .............................................................................................. 34 Alkaloids ................................................................................................................ 35 Saxitoxin ............................................................................................... 35 Cylindrospermopsin ............................................................................. 35 Anatoxin-a and homoanatoxin-a ......................................................... 36 Phosphate esters ................................................................................................... 36 Anatoxin-a(s) ........................................................................................ 36 Lipopeptides .......................................................................................................... 36 Antillatoxins .......................................................................................... 36 Kalkitoxin and jamaicamide ................................................................. 36 Neurotoxic amino acids ........................................................................................ 37 L- β-N-methylamino-L-alanine (BMAA) ................................................ 37 Pharmaceutical potential of cyanotoxins ............................................................. 37 Summary ............................................................................................................... 38 IN TRO DUC TION absorption from water or via ingestion (Cazenave et al. 2005) (Figure 1). Several cyanobacterial toxins can be accumulated Cyanobacteria are important component of phytoplankton. by and transferred through the members of food webs They occur in almost every freshwater and marine (Figure 1), which may lead to short- or long-term environment. Cyanobacteria constitute up to 70% of the total destabilization of natural systems (Christoffersen 1996). phytoplankton biomass and they produce more than 30% of These toxins also cause organ damage, cancers or even total free O 2 and account for more than 30% of total primary human deaths. The problem of cyanobacterial blooms is a production (Paerl et al. 2001). growing concern worldwide as the abundance of cyanotoxin Accumulation of cyanobacteria in eutrophic conditions producing bacteria continues to expand with each summer may lead to toxicity of affected waters. Among phytoplankton, (Merel et al. 2013). This review focuses on the mechanisms cyanobacteria have the greatest share in the overall and effects of neurotoxic cyanotoxins, such as microcystins. It production of toxins in aquatic ecosystems (Paerl et al. 2001). describes the results of recent research and what still remains Cyanobacteria toxins may affect organisms by direct to be determined. 28 ENVIRONMENTAL BIOTECHNOLOGY 10 (1) 2014 Figure 1. Cyanotoxins in aquatic environment. Cyanotoxic strains and toxic secondary metabolites affect different aquatic organisms. The cyanobacteria compete with other algae species (red arrows), and their toxins are harmful (green arrows) to plankton-feeding organisms (e.g. zooplankton, benthos, fishes), as well as predators feeding on intoxicated organisms. Presence of cyanotoxins in drinking water may pose a risk for humans. CYANOTOXINS according to the effect that they provoke. Hepatotoxins cause liver damage, cytotoxins are responsible for cell dysfunction Cyanotoxins are produced within cells and are only released and damage, neurotoxins cause damage to nervous tissue, into water during cell senescence or cell death and lysis whereas dermatotoxins are linked with allergenic reactions (Sivonen and Jones 1999). The latter may be caused by water (Stewart et al. 2006). treatment processes such as algaecide application (Babica et al. Nonetheless, the toxic effects of cyanotoxins are not 2006; Gupta et al. 2001; James and Fawell 1991). It is known straightforward. For example, exposure to microcystins may that blooms of different cyanobacterial species (e.g. Anabaena cause hepatotoxic effects (Gupta and Guha 2006; Li et al. circinalis and Microcystis aeruginosa ) have been observed to 2005; Solter et al. 1998), as well as oxidative stress (Angeles occur in the same water body but also may overlap when et al. 2005), growth inhibition (Bury et al. 1995; Zhao et al. occurring in rapid succession to one after another (Dietrich et 2006), reproductive disorders (Ding et al. 2006) and kidney al. 2008). Moreover, many cyanobacterial species have been damage (Fischer and Dietrich 2000; Kotak et al. 1996). observed to be capable of producing several different toxin Many authors describe hematological and biochemical types as well as different toxin congeners. consequences (Malbrouck et al. 2003; Vajcova et al. 1998; Numerous bioactive compounds produced by cyanobacteria Zhang et al. 2007) including apoptosis in a variety of cell have been described: non-ribosomal peptides, alkaloids, types (McDermott et al. 1998). In case of sufficiently high lipopeptides, esters, amino acids and polyketides. They all doses, microcystins may cause even death (Lindholm et al. present a wide diversity of structures, variants and include 1999). A detailed examination of Caruaru case in Brazil potent toxins. Cyanotoxins are usually divided into groups (1996) after which 60 patients died after severe intoxication Florczyk et al. Neurotoxicity of cyanotoxins 29 with diverse cyanobacterial toxins showed that affected This review focuses on cyanotoxins which are capable of humans not only suffered from liver failure but also exhibited inducing adverse effects in nervous tissue. For this purpose, we symptoms of neurological disorders: dizziness, vertigo, classified them by similarities in their chemical structure: cyclic tinnitus, mild deafness, visual disturbance, blindness, and peptides, alkaloids, phosphate esters, lipopeptides, amino-acids grand mal convulsion (epilepsy), nausea, vomiting (Pouria et (Table 1). Here, we present cyanotoxins of proven neurotoxicity al. 1998).