Potential complementarity of high-flavanol cocoa powder and spirulina
for health protection
Mark F. McCarty*, Jorge Barroso-Aranda, Francisco Contreras
Oasis of Hope Hospital, Tijuana, Mexico
a r t i c l ei n f o
Received 12 September 2008
Accepted 27 September 2008
s u m m a r y
Recent studies show that ingestion of flavanol-rich cocoa powder provokes increased endothelial produc-
tion of nitric oxide - an effect likely mediated by epicatchin – and thus may have considerable potential
for promoting vascular health. The Kuna Indians of Panama, who regularly consume large amounts of
flavanol-rich cocoa, are virtually free of hypertension and stroke, even though they salt their food. Of
potentially complementary merit is the cyanobacterium spirulina, which has been used as a food in cer-
tain cultures. Spirulina is exceptionally rich in phycocyanobilin (PCB), which recently has been shown to
act as a potent inhibitor of NADPH oxidase; this effect likely rationalizes the broad range of anti-inflam-
matory, cytoprotective, and anti-atherosclerotic effects which orally administered spirulina has achieved
in rodent studies. In light of the central pathogenic role which NADPH oxidase-derived oxidant stress
plays in a vast range of disorders, spirulina or PCB-enriched spirulina extracts may have remarkable
potential for preserving and restoring health. Joint administration of flavanol-rich cocoa powder and spi-
rulina may have particular merit, inasmuch as cocoa can mask the somewhat disagreeable flavor and
odor of spirulina, whereas the antioxidant impact of spirulina could be expected to amplify the bioactiv-
ity of the nitric oxide evoked by cocoa flavanols in inflamed endothelium. Moreover, there is reason to
suspect that, by optimizing cerebrovascular perfusion while quelling cerebral oxidant stress, cocoa pow-
der and spirulina could collaborate in prevention of senile dementia. Thus, food products featuring ample
amounts of both high-flavanol cocoa powder and spirulina may have considerable potential for health
promotion, and merit evaluation in rodent studies and clinical trials.
? 2009 Elsevier Ltd. All rights reserved.
Vascular-protective benefits of flavanol-rich cocoa powder
A growing number of clinical studies indicate that regular
ingestion of flavanol-rich cocoa exerts a range of effects potentially
favorable to vascular health – improving endothelial function,
reducing elevated blood pressure, increasing insulin sensitivity,
and suppressing platelet aggregation [1–14] There is recent evi-
dence that the epicatchin content of cocoa is primarily responsible
for its favorable impact on vascular endothelium, which reflects
both an acute and chronic up-regulation of nitric oxide production
[15,16]. As is well known, physiological levels of nitric oxide sup-
port vascular health and efficient tissue perfusion by promoting
vasodilation, opposing inflammation and structural remodeling in
the vascular wall, and stabilizing platelets . Other research
demonstrates that ingestion of flavanol-rich cocoa protects skin
from UV damage and has a positive cosmetic impact on the skin
of women, increasing its moisture content .
The fact that the Kuna Indians of Panama are virtually immune
from hypertension and the typical age-related rise of blood pres-
sure, so long as they live a traditional lifestyle, is likely attributable
to their regular heavy intake of flavanol-rich raw cocoa  More-
over, the Kuna appear to be virtually free of stroke  – a finding
consistent with evidence that cerebrovascular nitric oxide produc-
tion is a key determinant of stroke risk . Although a diet that is
nearly pesco-vegan undoubtedly has a favorable impact on the Ku-
na’s health status, hypertension and stroke tend to be quite com-
mon in many Asian groups whose traditional diets are quasi-
vegan – even though these groups enjoy considerable protection
from coronary heart disease, diabetes, and certain ‘‘Western” can-
cers [21–23]. It should be emphasized that, unlike all other unac-
culturated societies that have been found to be free of essential
hypertension, the Kunas make ample use of added salt in their
diets; thus, cocoa flavanols appear to confer important protection
from hypertension and stroke even in the context of a salty diet.
Although the prevalence of senile dementia among the Kuna
has not been formally assessed, other Third World cultures in
which hypertension and stroke are quite rare are characterized
by a near absence of dementia [20,24]. This phenomenon may
reflect a key role for intermittent or chronic cerebral hypoxia
0306-9877/$ - see front matter ? 2009 Elsevier Ltd. All rights reserved.
* Corresponding author. Oasis of Hope Hospital, 1185 Linda Vista Dr., 92078
E-mail address: email@example.com (M.F. McCarty).
Medical Hypotheses 74 (2010) 370–373
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in triggering and sustaining the inflammatory process that medi-
ates Alzheimer’s disease. Indeed, many commentators have noted
that a number of vascular risk factors are likewise risk factors for
Alzheimers, and that many measures which boost endothelial ni-
tric oxide function are linked to decreased risk for this disorder
[24–34]. Recent research has established that hypoxia boosts
neuronal expression of BACE1 (a.k.a. beta-secretase), a protease
whose activity can be rate-limiting for the production of the
amyloid-beta peptides thought to drive the inflammatory process
in Alzheimers [35,36]. Since amyloid-beta antagonizes endothe-
lium-dependent vasodilation in the cerebral microcirculation by
inducing severe endothelial oxidative stress [37–41], a vicious
cycle mechanism may act to sustain and exacerbate local hypox-
ia (and thus increased BACE1 activity) in regions of the brain
where Alzheimers inflammation becomes well established; in-
deed, endothelial nitric oxide is a mediator of the crucial aut-
matched to metabolic demand and maintained in the face of re-
duced central blood pressure [42–46]. A recent clinical study has
demonstrated an acute increase of brain perfusion following
ingestion of flavanol-rich cocoa [47,48]. Moreover, long-term
administration of cocoa flavanols to aging rats is associated with
preservation of youthful cognitive performance  – raising the
possibility that cerebral hypoxia (and/or suboptimal cerebrovas-
cular nitric oxide production) might also play a role in the more
modest fall-off in cognitive function associated with healthy
aging. These considerations suggest that regular consumption of
cocoa flavanols might have important potential for promoting
retention of cognitive function as humans age.
cerebralblood flow is
Spirulina has profound antioxidant potential
Another food with potential for superstar status as a health aid
is the cyanobacterium spirulina. While spirulina – once harvested
as a food by the Aztecs, and still used by Africans living near Lake
Chad – has been popular as a supplement in ‘‘health food” circles
for several decades, its true health-protective merit has only re-
cently been discovered: phycocyanobilin (PCB), the chromophore
bound to spirulina’s chief protein, phycocyanin, can function as a
potent inhibitor of NADPH oxidase, the enzyme complex that is
the chief source of pathological oxidant stress in a wide range of
health disorders [50,51]. In this regard, it appears to mimic the
physiological activity of free bilirubin [52–55]; PCB can be con-
verted within cells to phycocyanorubin, which is nearly identical
in structure to bilirubin . Although the clinical utility of ample
intakes of spirulina has so far received little research attention, in
numerous rodent studies orally administered spirulina or phycocy-
anin has shown potent anti-inflammatory, cytoprotective, and
anti-atherogenic activities; these effects are most likely attribut-
able to down-regulation of NADPH oxidase activity [50,51,57,58].
A consideration of the central role of NADPH oxidase over-activity
in a range of disorders suggests that ample intakes of spirulina may
have preventive and therapeutic potential with respect to many
vascular diseases (including atherogenesis, hypertension, and con-
gestive heart failure), cancers, complications of diabetes, and a
range of neurodegenerative, fibrotic, or inflammatory disorders
[50,51] It should be emphasized that measures which inhibit
NADPH oxidase activity could be expected to have a much more
profound health impact than antioxidant vitamins or phytochemi-
cals that act merely as oxidant scavengers – the latter, while help-
ing to preserve the structural integrity of membrane lipids or
proteins, have little influence on the signal-modulatory activity
of hydrogen peroxide, or on the nitric oxide-quenching activity of
superoxide. The versatile heath protection associated with statin
therapy or angiotensin II antagonism – seemingly greater than
would be predicted from their hypolipidemic or anti-hypertensive
activities – may be largely attributable to their down-regulatory
impacts on the NADPH oxidase activity of certain tissues .
Spirulina also is a source of polysaccharide that has immuno-
stimulant activity (reflecting the activation of TLR2 receptors on
macrophages) [60–62], and is very rich in zeaxanthin, a dietary
carotenoid that has been linked to decreased risk for macular
degeneration . A recent open clinical trial reports worthwhile
reductions in blood pressure and improvements in blood lipid
profile in healthy volunteers receiving 4.5 g spirulina daily; this
suggests that spirulina-bound PCB may have good oral bioavail-
ability in humans . The reduction in LDL cholesterol observed
in this study might reflect phycocyanin-mediated inhibition of
cholesterol and bile acid (re)absorption, as demonstrated in rats
Cocoa can mask spirulina’s flavor, while complementing its
Spirulina’s chief drawback as a food is that it has a foul odor,
and a flavor that most find unappealing. However, these authors
have observed that, when pre-blended with spirulina, cocoa pow-
der can do an excellent job of masking spirulina’s odor and flavor.
When blended with soy milk, cow’s milk, or rice milk, along with
an added sweetener, a cocoa–spirulina powder can yield a drink
with a rich and creamy chocolate flavor – though some may ini-
tially find its dark green color somewhat disconcerting!
Moreover, the antioxidant activity of PCB in the inflamed vascu-
lature – where NADPH oxidase is the chief source of oxidant stress
[66–68] – could be expected to nicely complement the impact of
cocoa-derived epicatechin on nitric oxide bioactivity. As is well
known, superoxide antagonizes the bioactivity of nitric oxide by
spontaneously reacting with it to generate the dangerous oxidant
peroxynitrite. Furthermore, by oxidizing the cofactor tetrahydrobi-
opterin, oxidant stress (i.e. peroxynitrite) transforms the endothe-
lial nitric oxide synthase into an enzyme that not only is less
competent at generating nitric oxide, but that also produces super-
oxide [69,70]. Hence, the protective impact of epicatechin on an in-
flamed vasculature would be expected to be greater if concurrently
administered PCB is employed to quell vascular oxidant stress. And
the antioxidant impact of PCB on vascular endothelium would be
expected to act in other ways, complementary to but independent
of nitric oxide, to minimize endothelial inflammation and thus pro-
mote vascular health [59,67,71,72].
Oral administration of phycocyanin or of whole spirulina has
exerted central neuroprotective effects in rodent studies – an
observation which strongly suggests that PCB can transit the
blood–brain barrier [73–75]. This is of considerable interest in light
of evidence that oxidant stress generated by NADPH oxidase in
activated microglia and possibly neurons as well plays an impor-
tant pathogenic role in many common neurodegenerative disor-
ders – including Alzheimers disease [75–81]. Indeed, oxidative
stress up-regulates transcription of BACE1, an effect mediated by
the stress-activated MAP kinases [82–87]; the resulting increase
in amyloid-beta production then triggers further oxidative stress
via activation of NAPDH oxidase, completing a feed-forward loop
[80,79,88,41,89,90]. Oxidative stress also promotes transcription
of presenilin-1, the catalytic component of the gamma-secretase
also required for amyloid-beta production . Evidently, PCB
has the potential to suppress this vicious cycle, and also would
likely antagonize the adverse impact of amyloid-beta on cerebro-
vascular endothelial function, which appears to be mediated by
NADPH oxidase activation . These considerations suggest that
cocoa flavanols and PCB could work in tandem to counteract the
cerebral hypoxia and oxidative stress that sustain excessive
M.F. McCarty et al./Medical Hypotheses 74 (2010) 370–373
amyloid-beta production and that mediate, at least in part, the
neuronal dysfunction and death that characterize Alzheimers
[76,77,80,79,88,25,91–93]. Thus, it is conceivable that spirulina
could complement the utility of flavanol-rich cocoa in dementia
prevention – only by aiding efficient cerebrovascular perfusion,
but also by blunting the key contribution of oxidative stress to Alz-
In regard to the UV-protective effect documented for cocoa flav-
anols, there is suggestive evidence that UV-induced skin damage is
mediated by activation of NADPH oxidase in keratinocytes, an ef-
fect contingent on concurrent activation of EGF receptors [94–
97]. If this is the case, PCB may be able to complement the utility
of cocoa flavanols in serving as an ‘‘internal sun screen”.
It is therefore proposed that commercial products combining
ample amounts of flavanol-rich cocoa powder and phycocyanin-
rich spirulina should be developed, and their effects assessed both
in rodent studies and in clinical trials. Consumed regularly, such
products may have considerable potential for preventing and treat-
ing the wide range of disorders in which excessive oxidative stress
plays a pathogenic role – and possibly for preserving youthful cog-
nitive function into ripe old age.
If this proposal proves to have merit, it may ultimately prove
feasible to provide the key active components of cocoa powder
and spirulina in capsule form. Flavanol-rich cocoa powder extracts
are already commercially available, and it seems likely that PCB-
enriched spirulina extracts could be developed for use in
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