Pharmaceutical Biology

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Preclinical antitoxic properties of Spirulina

(Arthrospira)

Elizdath Martínez-Galero, Ricardo Pérez-Pastén, Angélica Perez-Juarez, Luis

Fabila-Castillo, Gabriela Gutiérrez-Salmeán & German Chamorro

To cite this article: Elizdath Martínez-Galero, Ricardo Pérez-Pastén, Angélica Perez-Juarez,

Luis Fabila-Castillo, Gabriela Gutiérrez-Salmeán & German Chamorro (2016) Preclinical
antitoxic properties of Spirulina (Arthrospira), Pharmaceutical Biology, 54:8, 1345-1353, DOI:
10.3109/13880209.2015.1077464

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Published online: 06 Oct 2015.

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PHARMACEUTICAL BIOLOGY, 2016
VOL. 54, NO. 8, 1345–1353
http://dx.doi.org/10.3109/13880209.2015.1077464

REVIEW ARTICLE

Preclinical antitoxic properties of Spirulina (Arthrospira)

Elizdath Martı́nez-Galero1, Ricardo Pérez-Pastén1, Angélica Perez-Juarez1, Luis Fabila-Castillo1,
Gabriela Gutiérrez-Salmeán2, and German Chamorro1
1
Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México DF, México and 2Facultad de
Ciencias de la Salud, Universidad Anáhuac México Norte, México

ABSTRACT ARTICLE HISTORY

Context: Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are Received 3 February 2015
mainly attributed to its antioxidant effect. However, Spirulina has also been reported (both in Revised 18 June 2015
preclinical and in clinical scenarios) to exhibit other bioactive effects, including an antitoxic Accepted 25 July 2015
potential. Published online 5 October
Objective: We performed a systematic review of the literature, conducted in TOXNET, 2015
PubMed/MEDLINE, and Science Direct-Scopus; all available years were included. Searching criteria KEYWORDS
included the effects of Spirulina on experimental poisonings from arsenic, cadmium, carbon Antidotes, environmental
tetrachloride, deltamethrin, fluoride, hexachlorocyclohexane, iron, lead, lindane, and mercury. pollutants, occupational pol-
Results: In all cases, it was established that the blue-green alga, and its isolated compounds, lutants, poisoning, therapy,
effectively counteracted these pollutants toxic effects on the exposed organisms. Some molecular toxicity
mechanisms are proposed, although they have not been fully elucidated yet.
Conclusion: Spirulina could be a useful coadjuvant agent within clinical practice for treatment of
these or other pollutants poisonings.

Introduction which are used in several ways: as a fertilizer, as feed

supplement in poultry and livestock, as a colorant within
In recent years, microalgae have attracted the attention
foods, and as aquafeed.
of researchers due to their various chemical, biological
Spirulina has been reported to be an excellent source
and nutritional properties. This has been the case of
of some macro and micronutrients (Hosseini et al.,
Chlorella, Dunaliella, Scenedesmus, and cyanobacteria
2013). The protein content of the algae ranges between
such as Nostoc, Aphanizomenon flosaquae, and Spirulina
60 and 70%, i.e., 10 times higher than soybean and three
(Kay, 1991).
more than beef; moreover, the amino acid profile is
Spirulina (Arthrospira), a cyanobacterium generally
considered to be of ‘‘high biologic value’’ according to
described as a blue-green algae of the Oscillatoraceae
the WHO/FAO reference values and some countries
family, grows in highly alkaline waters of tropical and
legislation (Becker, 1995). In addition, its protein
subtropical areas, and is further classified into the well-
efficiency, digestibility coefficient, and net protein util-
known species Spirulina platensis, Spirulina fusiformis,
ization are of substantial nutritional significance for use
and Spirulina maxima (Dillon et al., 1995). The latter has in humans (Uma et al., 2008).
been consumed in Mexico since Aztec civilization age, In terms of micronutrients, Spirulina contains signifi-
but nowadays its consumption is globally distributed cant amounts of vitamin B12, pro-vitamin A and vitamin
(Shukla et al., 2009). E; while regarding mineral content, iron, calcium,
Although it grows naturally, it is grown by using open magnesium, manganese, potassium, and zinc stand out.
ponds or bioreactors in Asia, Europe, North America, It is also one of the few sources of glycolipids and
and Latin American countries (Durand-Chastel, 1997) sulfolipids (Belay, 2008).
yielding a current production of Spirulina of As a food supplement, it has been widely tested in
&3000–4000 tons per year worldwide (Belay, 2008), combination with grains, beans, cottage cheese, bread,

Correspondence: German Chamorro, Ph.D., Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Avenida
Wilfrido Massieu s/n. Unidad Adolfo López Mateos, Del. Gustavo A. Madero, 07738 México DF, México. Tel:+ 52 55 5729 6000x52398.
gchamcev@yahoo.com.mx
ß 2015 Informa UK Limited, trading as Taylor & Francis Group
1346 E. MARTÍNEZ-GALERO ET AL.

pastries, juices, amino acids, and other basic food Concerning the anti-toxic activity of Spirulina in
components, usually at concentrations up to 15%, humans, it has been shown that the algae, in association
confirming its usefulness by the positive effects on with zinc, were useful in the treatment of chronic
nutritional quality, which is attributed mainly to its arsenicosis (Misbahuddin et al., 2006), a condition
protein content (Becker, 1995; Uma et al., 2008). affecting countries such as Bangladesh, Chile, India,
Today, Spirulina is also used as a source of natural Mexico, and Taiwan (Karkos et al., 2011).
dyes in pharmaceutical industry and it is included on Moreover, Yamani et al. (2009) found that human
food, pasta, snacks, chocolates, beverages, and other consumption of &10 g/d of Spirulina for 6 months
foodstuffs in food and beverages industries (Iyer et al., induced no adverse effects. Furthermore, there is
2008). evidence that regular consumption in several regions of
Furthermore, from preclinical studies in rats fed with Africa reaches up to 40 g (Ciferri, 1983) and no adverse
5% Spirulina (Tsuchihashi et al., 1987), it has been effects have been reported.
reported that animals significantly increased the cecum Many experimental studies have attributed the bene-
population of lactobacilli; other studies, for their side, ficial effects of Spirulina with its antioxidant capacity
have observed stimulatory effects of extracellular prod- (Chu et al., 2010; Kim et al., 2010; Ponce-Canchihuaman
ucts of the algae on lactic acid bacteria (Parada et al., et al., 2010), due to its content of phenolic compounds,
1998). such as g-linolenic acid, a-tocopherol, phycobiliproteins,
In addition to its nutritional properties, within the last and other phytochemicals (Dartsch, 2007; Kalafati et al.,
20 years, other bioactive properties of cyanobacteria have 2010). Consequently, it has been considered as a
been reported in animal – and other preclinical – models functional food, because of its ability to provide medical
of experimentation, including antioxidant, immunomo- or health benefits, including the prevention and/or
dulatory, hypolipidemic, hypoglycemic, antiobesity, anti- treatment of diseases (Baptista, 2008).
viral, anticarcinogenic, antigenotoxic, antibacterial, For instance, the algae has been proved to counteract
hepato-protective, and antiparasitic effects, among colitis in the trinitrobenzenesulfonic acid model (Coskun
others (Khan et al., 2006; Kulshreshtha et al., 2008; et al., 2011); it has also been proven to reduce not only
Madrigal-Santillan et al., 2014; Muga & Chao, 2014). the hepato and nephrotoxicity caused by 4-nitroquino-
However, clinical studies in humans have been limited. line-1-oxide (Viswanadha et al., 2011) but also the
Notable among clinical research, is the finding that rosiglitazone-induced bone loss in diabetic animals and
microalgae has been reported to significantly reduce the teratogenicity produced by hydroxyurea in mice
interleukin-4 (IL-4) concentrations, demonstrating pro- (Vazquez-Sanchez et al., 2009).
tective effects in allergic rhinitis (Mao et al., 2005). Therefore, the main purpose of this review is to
Moreover, Ishi et al. (1993) reported that Spirulina analyze the results published in recent years on the
increased the production of immunoglobulin A (IgA) in preclinical effect of Spirulina and its extracts against
saliva, indicating a role in secretory immunity. In specific toxicity induced by environmental and occupa-
addition, the increased production of interferon- tional toxic pollutants, in order to extrapolate them to
gamma (IFN-g) and the cytotoxicity of natural killer the prevention or treatment of poisoning caused by these
cells (NKC) have been suggested as a mechanism to contaminants in humans.
explain the immunological activity of the cyanobacteria
(Hirahashi et al., 2002). Related to this activity, it has
Materials and methods
been also found that when the algae is grown in deep
sea water, it increases its in vitro anticancer effect The query for existing literature was conducted in
by modulating the activity of inflammatory cytokines TOXNET, PubMed/MEDLINE, and Science Direct-
such as tumor necrosis factor alpha (TNF-a) and Scopus search engines and included all available years
interleukin-2 (IL-2) (Choi et al., 2013). in each one. To identify research on the nutritional,
It has also been shown, in humans, that the cyano- pharmacological, and toxicological field, the search
bacterium reduces total cholesterol, triglycerides, and profiles were Spirulina, Arthrospira, Spirulina toxicity,
low-density cholesterol, while increasing HDL choles- and Arthrospira toxicity. Only antitoxicity against
terol levels in patients with ischemic heart disease environmental pollutant studies were selected, other
(Ramaoorthy & Premakumari, 1996). Likewise, a lipid- interactions with chemicals such as drugs were excluded.
lowering effect was found together with reduction of In addition, toxicology books and summaries of
systolic and diastolic blood pressure in volunteers symposia concerning algae issues were consulted. Both
(Torres-Duran et al., 2007). in vivo and in vitro studies were included.
 ANTITOXIC PROPERTIES OF SPIRULINA 1347

Results and discussion alone or together thus resulting in synergistic effects

(Miranda et al., 1998).
Cadmium, mercury, lead, iron, and arsenic (metalloid)
C-Phycocyanin, one of the main biliproteins in
are the metals frequently involved in health problems
Spirulina, represents 20% of its dry weight and exhibits
(Goyer & Clarckson, 2001). Among their most common
a strong antioxidant activity as it is capable of scavenging
toxic effects are carcinogenesis, teratogenesis, inhibition
hydroxyl, alkoxy, and peroxyl free radicals, involved in
of immune function, injury to organs including liver and
the processes of lipoperoxidation and cytotoxicity
kidney; nervous and respiratory systems, endothelial
(Bhat & Madyastha, 2000); thus, C-phycocyanin, as
dysfunction, hypertension, vascular disease, and damage
an antioxidant, is 16 and 20 times more effective than
to the intestinal mucosa (Schäfer et al., 1998).
trolox and ascorbic acid, respectively (Romay et al.,
Regardless of the toxicity mechanisms involved in
2003).
each of the aforementioned agents, their systemic/oral
In addition, Spirulina also exerts a modulatory effect
administration, as well as that of carbon tetrachloride or
on metabolism, detoxification, and antioxidant enzymes.
hexachlorocyclohexane, produces oxidative stress. This Regarding the latter, the alga has been shown to increase
has been evidenced as increases in lipoperoxidation the activity of key antioxidant enzymes such as SOD,
levels and carbonylated proteins in different tissues; but CAT, GR, GPx, and GST (Premkumar et al., 2001,2004).
also as deficits in either non-enzymatic antioxidants such Although the therapeutic utility of antidotes currently
as sulfhydryl groups, reduced glutathione, vitamins C used, as those above mentioned, in the treatment of
and E, or in antioxidant enzymes like superoxide poisoning is irrefutable, they may also cause a variety of
dismutase (SOD), catalase (CAT), glutathione peroxidase adverse effects affecting the central nervous, cardiovas-
(GPx), glutathione S-transferase (GST), glutathione cular, neuromuscular, skeletal, and respiratory; more-
reductase (GR), and glucose-6-phosphate dehydrogenase over, they may also result in liver, kidney, optic, and otic
(G6PD) (Bhadauria et al., 2008; Sinha et al., 2010; injury, among other alterations (Burda et al., 2008).
Srivastava & Shivanandappa, 2005). Unlike current antidotes, Spirulina itself is not toxic, as it
Additionally, metals are capable of interacting with has been proven through different preclinical studies of
protein sulfhydryl groups, hence inhibiting crucial acute toxicity tests, subchronic toxicity, chronic toxicity,
enzymes, – e.g., ATPases, and thus interfering with key fertility and reproduction assessments, teratogenicity,
biological processes (Premkumar et al., 2004). Treatment multigenerational tests as well as in vivo mutagenesis
usually includes complexation and chelation therapy. assays were used doses much higher than those humans
Among the most commonly used chelating agents are can consume daily (Chamorro et al., 2002).
2,3-dimercaptopropanol (BAL), 2,3-dimercaptosuccinic Within the clinical scenario, human studies have
acid, ethylenediaminetetraacetic acid, (EDTA), diethyle- virtually reported no adverse reactions. For this reason,
netriaminepentaacetic acid (DTPA), deferoxamine, Spirulina has been listed in the FDA-GRAS group (Food
diethyldithiocarbamate (DTC), penicillamine, and and Drug Administration-Generally Recognized As Safe)
N-acetylcysteine (Goyer & Clarckson, 2001). (Belay, 2008). However, one isolated case of hepatotox-
As shown in Table 1, Spirulina showed a protective icity (Iwasa et al., 2002) and another one of rhabdo-
effect against arsenic, hexachlorohexane, and carbon myolysis have been related to the algae consumption
tetrachloride, regardless of its dose, route of administra- (Mazokopakis et al., 2008); C-phycocyanin was reported
tion, and animal model. Such beneficial effect of as the potencially allergenic protein if one case of
Spirulina has been attributed to its antioxidant capacity, anaphylaxis to Spirulina (Le et al., 2014; Petrus et al.,
as demonstrated in HgCl2 (Sharma et al., 2007a,b) and 2010).
lead (Ponce-Canchihuaman et al., 2010) poisonings.
The antioxidant capacity of Spirulina has been proven
both in vivo and in vitro experimental conditions, Conclusions
resulting in a decrease of up to 65% of lipid peroxidation, Poisoning by environmental and occupational pollutants
i.e., much higher than that exerted by a-tocopherol, or other compounds is, nowadays, treated with drugs or
butylated hydroxyanisole (45%) or b-carotene (Manoj antidotes that may eventually lead to undesirable effects.
et al., 1992). Furthermore, it has been shown that the The use of natural products is an interesting alternative
algae has greater antioxidant capacity than gallic and not only because of its safety profile but also because of
chlorogenic acids (Chopra et al., 2008). This property its efficiency and low cost. Spirulina, due to its high
has been certainly attributed to its carotene, tocopherol, antioxidants content, mainly phycocyanin, its activities
phenolic compounds, and C-phycocyanin content, on metabolism and detoxification, and virtually none
which are proposed to play an antioxidant role either toxicity, has advantages over other products. Thus the
 1348

Table 1. Spirulina protective effects against the toxicity induced by different contaminants.
Pollutant Test specie Exposition conditions Spirulina treatment Antitoxic effect References

Arsenic Duck 100 mg/L in drinking 30–120 mg/L in drinking water Improved body weight gain Islam et al. (2009)
water (90 d) and reduced altered hema-
tological parameters
Cadmium Mouse 1.5 mg/kg p.o. 62.5–500 mg/kg, p.o. (gesta- Decreased the frequency of Paniagua-Castro et al. (2011)
(gestation day 7) tion days 0–17) exencephaly and other
malformations by acting as
an antioxidant
Rat 6 mg/kg/d p.o. (30 d) 500 mg/kg/d p.o. (30 d) Partially prevented reduction Jeyaprakash and
E. MARTÍNEZ-GALERO ET AL.

of copper, zinc, iron, and Chinnaswamy (2005)

selenium serum concentra-
tions. Due to its ability to
decrease oxidative stress
and structural damage,
proved protective capacity
against liver and renal
damage
50 mg/L in tap water 300 mg/kg p.o. (30 d) Protected against liver Karadeniz et al. (2009)
(30 d) damage because of its
ability to decrease the
vacuolar degeneration, fat
infiltration, and fibrosis.
The effect was related to
the reduction of oxidative
damage
50 mg/L in tap water 300 mg/kg, p.o. (30 d) Improved hematological par- Simsek et al. (2009)
(30 d) ameters affected by
cadmium
Carbon tetrachloride Rat 1:5 v/v 1.5 mL/kg p.o. 50 or 100 mg/kg p.o. Ethanol extract prevented oxi- Kuriakose et al. (2011)
(5 weeks) dative damage; which was
explained by its antioxidant
and scavenging effects
1 mL/kg i.p. 800 mg/kg p.o. (30 d) S. platensis enriched in phen- Kepekçi et al. (2013)
olic compounds protected
more efficiently against
CCl4 hepatotoxicity than
that grown in conventional
cultured conditions, by
increasing its antioxidant
defenses
Deltamethrin Rat 30 mg/kg p.o. (5 d) 500–1000 mg/kg p.o. (1 h Provided near complete pro- Abdel-Daim et al. (2013)
before the insecticide tection in terms of serum
administration/5 d) and tissues biochemical
changes, antioxidant
enzymes, and free-scaven-
ging activity
Fluoride Rat 20 mg/kg p.o. 250–500 mg/kg p.o. Minimized the risk of neu- Banji et al. (2013)
(gestation day 6 to (gestation day 6 to roendocrinal and neurode-
postnatal 15) postnatal 15) velopmental disorders in
offspring of pregnant ani-
mals facilitating displace-
ment of the metal,
antioxidant formation, and
protecting Purkinje cells

Iron Human neuroblastoma 200 mM Fe (30 min) 100–500 mg/mL (30 min Scavenged reactive oxygen Bermejo-Bescós et al. (2008)
cells before ferrous sulfate) species and protected the
activity of antioxidant
enzymes
Lead Mouse 0.01–1.0 mg/kg i.p. 800 mg/kg p.o. (15 d before Reduced the affectation on Shastri et al. (1999)
and up to 30 after animal and testis weights
intoxication) and tubular diameter,
enhancing the survival time
Rat 2 g/L in drinking water 300 mg/kg in drinking water Decreased hematological par- Romay et al. (2001)
(1 month) (1 month) ameters affectation
100 ppm in drinking 1500 mg/kg in diet (30 d) Increased SOD, CAT, and Upasani and Balaraman (2003)
water (30 d) glutathione (GSH) in liver,
lungs, heart and kidneys;
additionally lowered brain
metal concentrations and
lipoperoxidation (LPO)
2 g/L in drinking water 300 mg/kg in drinking water Reduced the lead-induced Karaca and Simsek (2007)
(1 month) (1 month) increase in mast cells
number in the ovarian
cortex and medulla during
the estrous cycle
25 mg/animal i.p./ 20 g diet 5%/d/rat (30 d) Prevented body weight Ponce-Canchihuaman et al.
weekly/thrice decrease and liver impair- (2010)
ment; also protected
against oxidative damage
in both liver and kidney
5 mg/kg in drinking 5% + dandelion 2% in diet Spirulina or dandelion mini- Gargouri et al. (2012)
water (5th day of (5th day of gestation to the mised the lead deposition
gestation to the 14th day of lactation) and lead-induced oxidative
14th day of stress during gestation and
lactation) lactation
Lindane Rat 1000 ppm free vitamin Supplemented diet with Normalized both serum and Venkataraman et al. (1994)
A diet (7 weeks) 0.0628 – 3.18% (7 weeks) hepatic activity of aspartate
aminotransferase (AST),
alanine aminotransferase
(ALT) and alkaline phos-
phatase (ALP)
(continued)
ANTITOXIC PROPERTIES OF SPIRULINA
1349
Table 1. Continued
1350

Pollutant Test specie Exposition conditions Spirulina treatment Antitoxic effect References
Mercury Mouse 5 mg/kg i.p. 800 mg/kg p.o. (before and Reduced activity of both acid Saxena and Kumar (2004)
after HgCl2 exposition) and alkaline phosphatases
in testicles
800 mg/kg p.o. (10 d before Modulate or modify mercury- Sharma e al. (2005)
and 30 d after intoxication) induced biochemical alter-
ations in blood in terms of
calcium level, ion level, acid
and alkaline phosphatase
activity and lipid peroxida-
tion and GSH level in blood
E. MARTÍNEZ-GALERO ET AL.

800 mg/kg p.o. (10 d before Protected against renal Sharma et al. (2007a)
and 30 d after intoxication) damage reducing LPO, acid
phosphatase activity, tissue
degeneration, and increas-
ing ALP and lactate
dehydrogenase levels
800 mg/kg p.o. (10 d before Decreased oxidative stress Sharma et al. (2007b)
and 30 d after intoxication) reducing LPO and increas-
ing antioxidant enzymes
and GSH. Restored ALT and
AST activities near normal
Rat 5 mg/kg s.c. (3 times/ 300 mg/kg p.o. (10 d before Attenuated hepatotoxicity as Bashandy et al. (2011)
week/60 d) and 60 d after) well as altered lipid profile
through its antioxidant
activity
300 mg/kg p.o. (10 d before Protected against Hg testicular El-Desoky et al. (2013)
and 60 d after) damage, restoring oxida-
tive stress biomarkers,
sperm quality, and histo-
pathological alterations
 ANTITOXIC PROPERTIES OF SPIRULINA 1351

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Declaration of interest biochemical and histopathological effects of Spirulina
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COFAA/IPN Programs. E. M. G. is fellow of the EDD and platensis preparations. Phytother Res 22:627–33.
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