esveratrol, a polyphenol phytoalexin, possesses diverse biochemical and physiological
actions, including estrogenic, antiplatelet, and anti-inflammatory properties. Several recent
studies determined the cardioprotective abilities of resveratrol. Both in experiments (acute) and
in chronic models, resveratrol attenuates myocardial ischemic reperfusion injury, atherosclerosis,
and reduces ventricular arrhythmias. It appears that resveratrol-mediated cardioprotection is
achieved through the preconditioning effect (the best yet devised method of cardioprotection),
rather than direct protection. Thus, resveratrol likely fulfills the definition of a pharmacological
preconditioning compound and gives hope to the therapeutic promise of alternative medicine.
Dipak K. Das and Nilanjana Maulik
Cardiovascular Research Center, University of Connecticut School of Medicine,
Farmington, CT 06030-1110
Resveratrol: A Preconditioning Agent
Evolution Of Discovery To
. Resveratrol can scavenge hydroxyl radicals with a reaction rate
constant of 9.45 x 108 M-1sec-1, which is slower than the potent scavenging demonstrated by ascorbic acid (13)
. Depending on the
Almost 4500 years ago, Ayurveda
, the ancient medicinal book of
biological system, resveratrol can also scavenge the superoxide anion
Hindus described "darakchasava" (fermented juice of red grapes) as
2 ) (13–15)
. Consequently, The Bible
described grape juice or red
Although resveratrol behaves as a poor in vitro scavenger of
wine as a "gift of god," which was presumably used to purify body
ROS, it functions as a potent antioxidant in vivo. The in vivo anti-
and soul. In 1940, resveratrol was first identified as the medicinal
oxidant property of resveratrol probably arises from its ability to
component of grapes, and it was extracted from the dried roots of
increase nitric oxide (NO) synthesis, which in turn functions as an
(popularly known as Ko-jo-kon in Japan) and
in vivo antioxidant, scavenging superoxide radicals. In the ischemic
used to treat hyperlipidemic diseases (2)
. In the modern era, resvera-
reperfused heart, brain, or kidney, resveratrol induces NO synthesis
trol has been rediscovered as an antiproliferative agent for cancer (3,
and lowers oxidative stress (11, 16)
. Having an unpaired electron,
. The cardioprotective ability of resveratrol stemmed from epidemi-
NO behaves as a potent antioxidant in vivo, rapidly reacting near
ological studies indicating that mild-to-moderate alcohol consump-
the diffusion-limited rate (6.7 x 109 M-1s1) with O –
2 that is presum-
tion is associated with reduced incidence of morbidity and mortality
ably formed in the ischemic reperfused myocardium. The affinity of
from coronary heart disease (5)
. The first experimental evidence
2 is far greater than the affinity of superoxide dismutase
of cardioprotective ability of resveratrol was apparent from studies
2 . In fact, NO may compete with SOD for O2 , thereby
showing that resveratrol could directly protect isolated hearts from
2 and sparing SOD for other scavenging duties.
ischemia reperfusion injury (6)
. Subsequently, resveratrol was found
The effects of resveratrol have been tested in specific cells
to protect most of the vital organs including kidney, heart, and brain
lines and differentiated cell types. For example, resveratrol inhibits
from ischemic reperfusion injury (7–9)
. The protective mechanism
-tetradecanoylphorbol-13-acetate (TPA)-induced free radical
of resveratrol includes its role as intracellular antioxidant, anti-
formation in cultured HL-60 cells (17)
. In DU 145 cells––a prostate
inflammatory agent, its ability to induce nitric oxide synthase (NOS)
cancer cell line––administration of resveratrol inhibited proliferation
expression, and its ability to induce angiogenesis (10)
. A substantial
that had been accompanied by a reduction in NO production and
body of evidence strongly supports the notion that resveratrol medi-
inhibition of inducible nitric oxide synthase (iNOS) (18)
ated cardioprotection is achieved by preconditioning; the best yet
also inhibited the formation of O –
2 and H2O2 produced by mac-
devised method of myocardial protection (11, 12)
rophages stimulated by lipopolysaccharide (LPS) or TPA (15)
. In a related study, resveratrol inhibited reactive oxygen intermediates and lipid peroxidation induced by tumor necrosis factor (TNF) in a wide
Sources Of Resveratrol
variety of cells (19)
. Resveratrol also scavenges peroxyl and hydroxyl radicals in the postischemic reperfused myocardium, thereby lower-
The richest source of resveratrol is the roots of Polygonum cuspida-
ing malonaldehyde formation, a presumptive marker of lipid peroxi-
(Ko-jo-kon), mainly cultivated in China and Japan. The skins
dation (6, 20)
of grapes contain about 50–100 mg/resveratrol, and believed to be
Resveratrol can maintain the concentrations of intracellular
responsible for the cardioprotective properties of red wine, which
antioxidants found in biological systems. For example, resveratrol
contains about 0.2–7 mg/l of wine. In addition to grapes, a large
maintained glutathione (GSH) amounts in oxidation-stressed periph-
variety of fruits including mulberry, bilberry, lingonberry, sparkle-
eral blood mononuclear cells isolated from healthy humans (21)
berry, deerberry, partridgeberry, cranberry, blueberry, and jackfruit,
another study, resveratrol increased GSH amounts in human lym-
peanut, and a wide variety of flowers and leaves including gnetum,
phocytes that were activated by hydrogen peroxide (22)
white hellebore, corn lily, butterfly orchid tree, eucalyptus, spruce,
resveratrol restored glutathione reductase in cells subjected to TPA-
poaceae, scots pine, and rheum also contain resveratrol. Resveratrol
mediated oxidative stress (23)
. In human lymphocytes, resveratrol
is synthesized in response to environmental stressors that include
increased the amounts of several antioxidant enzymes, including
water deprivation, UV irradiation, and, especially, fungal infection.
glutathione peroxidase, glutathione-S
-transferase and glutathione
Thus, the production of resveratrol in plants can be considered part
of the defense mechanism.
A Natural Antioxidant
Resveratrol has been recognized as a phytoestrogen based on its
Resveratrol is capable of scavenging some intracellular reactive
structural similarities to diethylstilbesterol (DES). Resveratrol can
oxygen species (ROS). Although it possesses antioxidant proper-
bind to the estrogen receptor (ER), thereby activating transcription
ties, reseveratrol does not function as a strong antioxidant in vitro
of estrogen-responsive reporter genes transfected into cells (25–31)
Volume 6, Issue 1
Resveratrol functions as a superagonist when combined with estra-
chronic models of cardiac injury, resveratrol reduced myocardial
diol (E2) to induce the expression of estrogen-regulated genes (25);
ischemic reperfusion injury (38, 39). In addition to hearts, resvera-
however, several other studies showed conflicting results. Using
trol also protects kidney and brain cells from ischemia-reperfusion
the same cell line, Ashby et al. showed that resveratrol possessed
injury. Similar to its effect on the heart, resveratrol's stimulation of
antiestrogen activity because it suppressed progesterone receptor
NO production during ischemia-reperfusion is believed crucial for
expression induced by E2 (32). Another recent study showed that
protection of the kidney from ischemic reperfusion injury (40). The
both isomers of resveratrol possessed superestrogenic activity only at
maintenance of constitutive NO release is a critical factor in the
moderate concentration (>10 µM), whereas at lower concentrations
recovery of function after an ischemic injury. Release of constitu-
(<1 µM), antiestrogenic effects prevailed (33).
tive NO is significantly reduced after ischemia-reperfusion, thus the
Most of the in vivo studies have failed to confirm the estrogenic
maintenance of NO release by any means (e.g., induction of NO
potential of resveratrol. At physiologic concentrations, resveratrol
production with L-arginine) can restore myocardial function follow-
does not appear to induce any changes in uterine weight uterine
ing ischemia (41) (Figure 1).
epithelial cell height, or serum cholesterol (34). Only at very high
Although resveratrol protects brain, kidney, and heart cells, it
concentrations does resveratrol interfere with the serum cholesterol–
preferentially kills cancer cells. For example, intraperitoneal adminis-
lowering activity of E2. Elsewhere, resveratrol given orally or subcu-
tration of resveratrol increased apoptosis and reduced tumor growth
taneously did not affect uterus weight at any concentration (0.03 to
(42). In oral squamous carcinoma cells, resveratrol inhibited growth;
120 mg/kg/day) (32). In a related study, resveratrol reduced uterine
both alone and in combination with quercetin, an antioxidant found
weight and decreased the expression of ER-α mRNA and protein
in the skin of apples and red onions (43), and inhibited the growth
and progesterone receptor (PR) mRNA (35).
of highly metastatic B16-BL6 melanoma cells (44). In a rat colon
In contrast, resveratrol possesses estrogenic properties in
carcinogenesis model, resveratrol induced the expression of the
stroke-prone spontaneously hypertensive rats (36). When ovariecto-
proapoptotic protein Bax in aberrant cryptic foci of the colon (45).
mized rats were fed resveratrol at the concentration of 5 mg/kg/day,
In fact, resveratrol affects three major stages of carcinogenesis (i.e.,
treatment attenuated an increase in systolic blood pressure. In con-
initiation, promotion, and progression) and inhibits the formation of
cert, resveratrol enhanced endothelin-dependent vascular relaxation
preneoplastic lesions in a mouse mammary organ culture model (4).
in response to acetylcholine and, in a manner similar to estradiol,
Resveratrol inhibits the growth of cytotoxin-associated gene–
prevented ovariectomy-induced decreases in femoral bone strength.
carrying (CagA+) strains of Helicobacter pylori in vitro (46) as well as
Resveratrol also acts as an estrogen receptor (ER) agonist in breast
fifteen other strains of H. pylori (47), suggesting that its presumed
cancer cells stably transfected with ERα (37). Although more data
bacteriostatic activity might be part of its overall salutary effects.
accumulate on the estrogenic behavior of resveratrol, the controversy
Other beneficial effects of resveratrol include its ability to increase
continues to persist.
(13-fold) the activity of the anti-aging gene SIRT1 [the mammalian homolog of the S. cerevisiae gene silent mating type information regulation 2 (Sir2)] (48). Thus, resveratrol-mediated activation of
Health Benefits Of Resveratrol
life-extending genes in human cells may open a new horizon of res-veratrol research (Figure 2).
As mentioned earlier, several recent studies determined the cardio-protective abilities of resveratrol. Both in acute experiments and
Cardioprotection With Resveratrol
Adenosine A /A receptors
The role of NO in the cardioprotective abilities of grape products
first became apparent when certain wines, grape juices, grape skins,
or their components were found to relax precontracted smooth
muscle of intact rat aortic rings but had no effect on aortas in which the endothelium had been removed (49). The extracts of wine or
grape increased guanosine 3',5'–monophosphate (cGMP) amounts
in intact vascular tissue, and both relaxation and the increase in
cGMP were reversed by NG-monomethyl-L-arginine or by NG-nitro-
L-arginine––competitive inhibitors of the synthesis of the endothe-
lium-derived relaxing factor, NO––suggesting that vasorelaxation
Figure 1. Molecular Targets of Resveratrol. A number of signaling pathways
induced by grape products is mediated by the NO-cGMP pathway.
related to inflammation and gene expression are modulated by resveratrol.
A direct role for NO in vasorelaxation was identified when increased
Resveratrol: A Preconditioning Agent
ished such beneficial effects of
Antitumor activity, Chemoprevention
resveratrol. The results support
κB activation, Proliferation,
Causes S-phase arrest, Induces apoptosis
an anti-inflammatory action
of myeloid leukomia cells
of resveratrol through a NO-
Prevents prostate and
Reduces platelet adhesion,
The anti-inflammatory role
and thyroid cancer
of resveratrol is also evident from a research where resvera-trol effectively suppressed the
aberrant expression of tissue
Prevents LDL oxidation
factor (TF) and cytokines in
Protects lung from DNA
vascular cells (54). Resveratrol,
Damage and apoptosis
in a dose-dependent manner,
inhibited the expression of
TF in endothelial cells stimu-
Reversible inhibition of herpes
lated with a variety of agonists,
Inhibited growth of
simplex virus types 1 & 2 replication
including interleukin-1β (IL-
1β), tumor necrosis factor–α
(TNF-α), and lipopolysac-
Figure 2. Health benefits of Resveratrol. Reveratrol has been implicated as a therapeutic in a number of major diseases
charide (LPS). Nuclear run-on analyses in endothelial cells
NOS activity was found in cultured pulmonary artery endothe-
showed that resveratrol inhibited the transcription of the TF gene.
lial cells treated with resveratrol (28), suggesting that resveratrol
In another recent study, resveratrol attenuated the agonist-induced
could afford cardioprotection by affecting the expression of NOS.
increase of TF mRNA in endothelial and mononuclear cells, result-
Astringinin, an analog of resveratrol, also exhibits NO-mediated
ing from the inhibition of IκBα degradation, thus decreasing the
beneficial effects during ischemia and reperfusion damage in rat
DNA-binding occupancy by the transcription factor c-Rel/p65
heart (50). Pretreating rats with astringinin significantly dampened
(55). Elsewhere, resveratrol inhibited platelet aggregation induced
the incidence ventricular tachycardia (VT) and ventricular fibrillation
by collagen, thrombin, or ADP (56). Additionally, trans-resveratrol
(VF) and decreased the concentrations of lactate dehyodrogenase
interfered with the release of inflammatory mediators by activated
(LDH) found in the carotid artery. Consistent with these results,
polymorphonuclear cells (PMN) and decreased the adhesion-depen-
resveratrol protected perfused working rat hearts through increased
dent thrombogenic functions of PMN (57). ADP-induced platelet
iNOS expression (11). The cardioprotective ability of resveratrol was
aggregation in hypercholesterolemic rabbits can be blocked by
abolished with an iNOS inhibitor, aminoguanidine. Resveratrol also
treatment with resveratrol, suggesting a role for resveratrol in inter-
failed to provide cardioprotection in iNOS knockout mice (51). In
rupting the generation of eicosanoids involved in pathological pro-
a recent study, however, resveratrol reduced myocardial ischemia
cesses. Indeed, Pinto et al. showed that resveratrol could inhibit the
reperfusion injury through both iNOS-dependent and iNOS-inde-
dioxygenase activity of lipooxygenase and that oxidized resveratrol
pendent mechanisms by increasing the expression of iNOS, endo-
was as efficient as the reduced form in inhibiting lipoxygenase (58).
thelial NOS (eNOS), and neuronal NOS (nNOS) (52).
Similarly, trans-resveratrol inhibited, in a dose-dependent manner, the arachidonate-dependent synthesis of the inflammatory agents Thromboxane B2 (TxB2), hydroxyheptadecatrienoate (HHT), and
12-hydroxyeicosatetraenoate (12-HETE) (59).
The cardioprotective ability of resveratrol also stems from its anti-inflammatory functions in the ischemic heart. Treatment with the
polyphenol resveratrol significantly improved postischemic ventricu-lar function and reduced myocardial infarct size compared to non-
Resveratrol protects the heart against ROS-mediated menadione (i.e.,
treated control group (53). The amount of proadhesive molecules,
Vitamin K3) toxicity by inducing NAD(P)H:quinone oxidoreductase,
including soluble intracellular adhesion molecule-1 (sICAM-1),
also known as DT-diaphorase, a detoxifying enzyme for quinone-
endothelial leukocyte adhesion molecule-1 (sE-Selectin), and vas-
containing substances (60). The cardioprotective effect of resveratrol
cular cell adhesion molecule-1 (sVCAM-1) were each significantly
was also attributed to its ability to upregulate catalase activity in the
decreased during reperfusion in the resveratrol-treated group. Nitro-
myocardium. Resveratrol functions as in vivo antioxidant and can
L-arginine methyl ester (L–NAME), an NO blocker, completely abol-
scavenge peroxyl radicals in the heart (61, 62). A commercial prepa-
Volume 6, Issue 1
ration of resveratrol made from P.
Inhibits soluble adhesion
cuspidatum root extract (Protykin®)
molecule (ICAM, VCAM) formation
also scavenges peroxyl radicals and protects the heart from ischemia
reperfusion injury (63).
Prevents platelet aggregation
Inhibits MAPK activation
Resveratrol appears to induce an
Inhibits LDL peroxidation
Inhibits lipid peroxidation
anti-apoptotic signal for the pro-tection of the heart. In porcine coronary arteries, short term treat-
ment with resveratrol significantly
inhibited mitogen-activated protein kinase (MAPK) activities, and
immunoblot analyses revealed
consistent reduction in the phos-phorylation of extracellular signal-regulated kinases 1/2
Figure 3. Cardioprotection with resveratrol. The major contribution to health from resveratrol appears to be directed
(ERK1/2), Jun N-terminal
toward limiting progression of heart disease and atherosclerosis. See text for details.
kinase (JNK-1), and p38 MAPK (64). The same study found that resveratrol attenuated basal and
of adenosine-mediated regulation of coronary blood flow (i.e., the
endothelin-1 (ET-1)-mediated protein tyrosine phosphorylation.
adenosine hypothesis) remains controversial (74). This hypothesis
Anti-apoptotic function of resveratrol is further supported by several
is inconsistent with several findings that inhibition of KATP channel
other studies, which have demonstrated a reduction of apoptotic
blocks the effects of preconditioning and that a KATP channel opener
cardiomyocytes in the ischemic reperfused heart that had been pre-
can simulate ischemic preconditioning (73, 75). To reconcile the
treated with resveratrol (51, 63) (Figure 3).
adenosine hypothesis, an argument has been made that adenosine could trigger a secondary mechanism such as activation of Gi pro-tein, which, in turn, could open the KATP channel.
Another intriguing hypothesis has stemmed from the concept
of stimulating an endogenous protective mechanism by myocar-dial adaptation to ischemic stress. Preconditioning induces the
Preconditioning is the most powerful technique known to promote
expression of endogenous antioxidant enzymes such as superoxide
cardioprotection (64–69). The most generalized method of classical
dismutase (SOD) and glutathione peroxidase (GSHPx-1) (76, 77)
preconditioning is mediated by cyclic episodes of several short dura-
and the heat shock proteins (HSP) HSP27, HSP32, and HSP70 (78,
tions of reversible ischemia, each followed by another short duration
79). Additionally, preconditioning potentiates a signal transduction
of reperfusion. In most laboratories including our own, precondi-
cascade by inhibiting death signals and activating survival signals.
tioning is achieved by four cycles of ischemia (five minutes each) fol-
Thus, several proapoptotic and antiapoptotic genes and transcrip-
lowed by ten minutes of reperfusion (66, 70). Such preconditioning
tion factors, including JNK-1, c-Jun, NF-κB and AP-1, are likely to
makes the heart resistant to subsequent lethal ischemic injury.
play a crucial role in preconditioning (80–82), as does NO (83, 84).
The mechanisms underlying cardiac preconditioning have been
Recent studies from our laboratory determined that resveratrol
studied extensively, and several regulatory pathways have been iden-
may function as a pharmacological preconditioning agent as it fulfills
tified in different systems. Three important factors: the adenosine
several criteria for preconditioning, including activation of adenosine
A1 receptor, multiple kinases [including protein kinase C (PKC),
A1 and A3 receptors, PKC, MAPKs, and the KATP channel. Adenosine
MAPKs, and tyrosine kinases], and the mitochondrial ATP-sensitive
accumulates in tissues under metabolic stress. In myocardial cells,
potassium (KATP) channel are known to play a crucial role in precon-
the nucleoside interacts with various receptor subtypes (i.e., A1,
ditioning-mediated cardioprotection. For example, cardioprotection
A3, and perhaps A2A and A2B) that are coupled, via G proteins, to
achieved by preconditioning can be abolished by A1 receptor antag-
multiple effectors, including enzymes, channels, transporters and
onists (71, 72), whereas A1 receptor agonists can limit myocardial
cytoskeletal components. Studies using adenosine receptor agonists
infarct size (73). Although there is general agreement regarding the
and antagonists, as well as animals overexpressing the A1 recep-
beneficial role of adenosine on ischemic tissue, Berne's hypothesis
tor indicate that adenosine exerts anti-ischemic action. Adenosine
Resveratrol: A Preconditioning Agent
all of which can be elicited by preconditioning challenges.
Box 1. The Two Phases of Cardioprotection
The intracellular signaling mechanisms that mediate precondi-
Acute or classical preconditioning can produce
tioning require the activation of one or more MAPKs. Among these,
marked reduction of myocardial infarct size and
the stress-activated protein kinases (SAPKs, also termed JNKs, see
cardiomyocytes apoptosis in all species tested so
above) and p38 are known to be regulated by extracellular stresses,
far; however, its clinical potential is limited because
including environmental stress, oxidative stress, heat shock, and UV
of its short duration of approxiamtely 2–3 hours.
radiation (100). JNKs and p38 appear to be involved in distinct cel-
A delayed protective effect reappears after 12–24
lular functions, because they possess different cellular targets and are
hours, following early preconditioning and this car-
located on different signaling pathways. Thus, JNKs activate c-Jun
dioprotective effects last up to 72 hours.
whereas p38 stimulates MAPK-activated protein kinase 2 (MAPKAP kinase 2) (101). A recent study demonstrated that preconditioning triggered a tyrosine kinase-regulated signaling pathway that leads to
released during preconditioning, by short periods of ischemia fol-
the translocation and activation of p38 and MAPKAP kinase 2 (87).
lowed by reperfusion, induces cardioprotection to subsequently
Activation of KATP channels appears to be an adaptive mechanism
sustained ischemia. This protective action is mediated by A1 and A3
that protects the myocardium against ischemic reperfusion injury (102).
receptor subtypes and involves the activation and translocation of
The activation of this ion channel is at least partially responsible for the
PKC to sarcolemmal and to mitochondrial membranes, leading to
increase in outward K+ currents, shortening of action potential duration
PKC-dependent KATP channels. Other effectors possibly contribut-
(APD), and increasing extracellular K+ concentrations during anoxic
ing to cardioprotection by adenosine or preconditioning that seem
and globally ischemic conditions (103). It appears that delayed precon-
particularly involved in the delayed (i.e., second) window of cardio-
ditioning, irrespective of preconditioning stimulus, is always mediated
protection (Box 1) include MAPKs, heat shock proteins, and iNOS
by KATP channels (104). The mitochondrial KATP channel opener diazox-
and eNOS. Because of its anti-ischemic effects, adenosine has been
ide significantly reduced the rate of cell death following simulated
tested as a protective agent in clinical interventions such as percu-
ischemia in adult ventricular cardiac myocytes (73). Intravenous injec-
taneous transluminal coronary angioplasty (PTCA), coronary artery
tion of diazoxide ten minutes before induced ischemia greatly reduced
bypass grafting (CABG), and tissue preservation, and was found in
infarct size in the rabbit heart (105); however, the protective effects of
most cases to enhance the post-ischemic recovery of function. The
diazoxide could be blocked by 5-hydroxydecanoate (5-HD), a selective
mechanisms underlying the role of adenosine and of mitochondrial
blocker of the mitochondrial KATP channel.
function in preconditioning are not completely clear, and uncertain-ties remain concerning the role played by newly identified potential effectors such as free radicals, the sarcoplasmic reticulum, etc. In
Making A Case For Reseveratrol As A
addition, more studies are needed to clarify the signaling mecha-
Pharmacological Preconditioning Agent
nisms by which A3 receptor activation or overexpression may pro-mote apoptosis and cellular injury.
It should be clear from the above discussion that unlike pharma-
Several investigators have proposed a unifying hypothesis that
cological therapeutic interventions, preconditioning protects the
activation of PKC represents a link between cell surface receptor
heart by increasing its endogenous defense mechanisms (106).
activation and a putative end-effector sarcolemmal or mitochondrial
Unfortunately, ischemic preconditioning–mediated cardioprotection
KATP channels (85, 86). Possible involvement of protein tyrosine
has a limited duration––early preconditioning lasts for several hours,
kinases in preconditioning was proposed for the first time by Maulik
and delayed preconditioning lasts for several days (107). There is a
et al. (87). Now, it is increasingly clear that protein tyrosine kinases
definite need to identify a pharmacological preconditioning agent
play a crucial role in mediating preconditioning in some animal
to render the preconditioning stimulus everlasting. Recently, mono-
species (88). Protein tyrosine kinases may act in parallel to (89, 90),
phosphoryl lipid A (MLA) was found to induce dose-dependent
downstream of (91, 92) or upstream of (93) PKC in eliciting pre-
cardioprotection against myocardial infarction (108, 109). Such car-
conditioning; however, the identity of these protein tyrosine kinases
dioprotection was achieved through the ability of MLA to increase
remains unclear. Among a large number of tyrosine kinases, Src
endogenous NO formation, which participates in mediating ischemic
family tyrosine kinases have received much attention (94). Src has
preconditioning. Similarly, resveratrol protects the ischemic myocar-
been implicated in the mechanism of cell survival and death, which
dium through NO (11). In this study, preconditioning of the hearts
is regulated by complex signal transduction processes (95). Rapid
with resveratrol provided cardioprotection, as evidenced by improved
activation of Src family tyrosine kinases after ischemia has also been
postischemic ventricular functional recovery (i.e., developed pressure
documented in the isolated guinea pig heart (96). Members of the
and aortic flow), reduced myocardial infarct size, and cardiomyocyte
Src family can be activated by many effectors, including stimulation
apoptosis. Additionally, resveratrol diminished the amount of ROS
of G protein–coupled receptors (97), increased intracellular Ca2+
activity, which was demonstrated through reduced malonaldehyde
(98), oxidative stress (99), and enhanced nitric oxide synthesis (84),
formation. These results suggest resveratrol may act to pharmacologi-
Volume 6, Issue 1
cally precondition the heart in a
A report by Imamura et
al. showed that iNOS knockout
Triggers survival signal through
mouse could not be precondi-
tioned with resveratrol, further indicating that this polyphe-
nol provides cardioprotection through NO and specifically through the induction of iNOS
Inhibits LDL peroxidation
(51). In this study, control experi-ments were performed with wild type mouse hearts and with
Potentiates redox signaling
Potentiates MAPK signaling
iNOS-null mouse hearts that were not treated with resveratrol. Resveratrol treated wild-type
mouse hearts displayed signifi-
cant improvement in post-isch-emic ventricular functional
Figure 4. Preconditioning with resveratrol. Mechanisms of reveratrol preconditioning involve a number of well-defined
recovery compared to those of molecular signaling events. The therapeutic implications of preconditioning are discussed in the text.
non-treated wild-type hearts. Both resveratrol-treated and non-treated iNOS-knockout mouse hearts exhibited relatively poor
yl-8-cyclopenthylxanthine) and an adenosine A3 receptor blocker
recovery in ventricular function as compared to that in wild-type
resveratrol-treated hearts. Myocardial infarct size and the number of
1,4-(+/–)-dihydropyridine-3,5-dicarboxylate], but not adenosine
apoptotic cardiomyocytes were lower in the resveratrol-treated wild-
A2A receptor blocker [CSC; 8-(3-chlorostyryl)caffeine], abrogated the
type mouse hearts as compared to results from the other groups
cardioprotective abilities of resveratrol, suggesting a role of adenos-
of hearts. Cardioprotective effects of resveratrol were abolished
ine A1 and A3 receptors in resveratrol preconditioning. Resveratrol
when the wild-type mouse hearts were simultaneously perfused
induced the expression of Bcl-2 and caused its phosphorylation
with aminoguanidine, an iNOS inhibitor. Resveratrol induced the
along with phosphorylation of cyclic AMP response element binding
expression of iNOS (for several hours) in the wild-type mouse hearts
protein (CREB), Akt, and Bad. CPT blocked the phosphorylation
but not in the iNOS-knockout hearts, after only thirty minutes of
of Akt and Bad without affecting the phosphorylation of CREB,
reperfusion. Additionally, resveratrol-treated wild-type mouse hearts
whereas MRS 1191 blocked phosphorylation of all these proteins.
were subjected to lower amount of oxidative stress, as evidenced
A phosphatidylinositol 3'-kinase (PI3K) inhibitor LY 294002 par-
by reduced amount of malonaldehyde content in these hearts com-
tially blocked the cardioprotective abilities of resveratrol (12). These
pared to findings in iNOS-knockout and untreated hearts. These
results indicate that resveratrol preconditions the heart through the
results demonstrated that resveratrol was unable to precondition
activation of adenosine A1 and A3 receptors, the former transmitting
iNOS-knockout mouse hearts, but it could successfully precondition
a survival signal through PI3K-Akt-Bcl-2 signaling pathway, while the
the wild-type mouse hearts, indicating an essential role of iNOS in
latter protects the heart through a CREB-dependent Bcl-2 pathway
resveratrol preconditioning of the heart. The above results strongly
in addition to the Akt-Bcl-2 pathway.
support the notion that resveratrol mediated cardio-protection is achieved by preconditioning (Figure 4).
In normal tissue, resveratrol decreases the expression of iNOS;
Angiogenic Properties Of Resveratrol
however, as seen from the above studies, in ischemic heart, resve-ratrol induces iNOS, an observation that is consistent with isch-
Therapeutic angiogenesis describes the method of improving blood
emic preconditioning (101, 108). Recently, resveratrol was found
flow to ischemic tissue by the induction of neovascularization by
to protect the ischemic heart through the increased expression of
angiogenic agents administered as recombinant protein or by gene
adenosine A1 and A3 receptors (12), a property shared by ischemic
therapy. Indeed, therapeutic angiogenesis has recently emerged as a
preconditioning. The results of this study demonstrated signifi-
promising investigational strategy for the treatment of patients with
cant cardioprotection with resveratrol treatment, as evidenced by
ischemic limb and heart disease. In the past ten years, alternative
improved ventricular recovery, reduced infarct size, and cardiomyo-
revascularization/angiogenesis strategies have progressed from bench
cyte apoptosis. Specifically, an A1 receptor blocker (CPT; 1,3-dimeth-
to bedside, focusing on the capillary sprouting and growth of new
Resveratrol: A Preconditioning Agent
vessels to replace the old. However, most of the strategies involve
and physiological function including regulation of vascular tone and
the delivery of growth factors and, unfortunately, very little suc-
vascular remodeling (123). One potential therapeutic target for NO is
cess with these strategies has been demonstrated so far for various
angiogenesis (124). Incubation of human vascular smooth muscle cells
reasons. The approach of using resveratrol to induce angiogenesis
with NO donors enhances the synthesis of VEGF and inhibition of
and increased expression of growth factors and their receptors is an
NOS abrogates VEGF production (125). Not surprisingly, eNOS inhib-
exciting and potentially very important strategy for myocardial pro-
itors block VEGF-induced endothelial cell migration, proliferation,
tection. We have shown in the rat myocardial infarction model that,
and tube formation in vitro and VEGF-induced angiogenesis in vivo.
three weeks after infarction, resveratrol treatment leads to increased
Dimmelers et al. found that in the absence of eNOS inhibition, VEGF
expression of vascular endothelial growth factor (VEGF) and its
stimulates PI3K- and Akt-dependent phosphorylation of eNOS, result-
tyrosine kinase receptor Flk-1 (110). Pretreatment with resveratrol
ing in an activation of eNOS and increased NO production (126).
also increases the amounts of iNOS and eNOS expressed as well as
Although both tyrosine kinase receptors Flt-1 and Flk-1 are necessary
increases the expression of anti-apoptotic and pro-angiogenic factors
for VEGF signaling, there are differences between the intracellular
NF-κB and Sp-1. We also demonstrated increased capillary density
functions of the two receptors (126). Flk-1, rather than Flt-1, is pre-
and improved left ventricular function (again, three weeks after
dominantly involved in eNOS phosphorylation, based on mutation
infarction) by pharmacological preconditioning with resveratrol.
studies. Stimulation of Flt-1 (another VEGF receptor) is linked to cell
In one of our previous studies, we documented hypoxia-
migration, whereas Flk-1 activation is associated with both cell migra-
reoxygenation–mediated myocardial angiogenesis through an NF-
tion and proliferation through the MAPK cascade (127). Interestingly,
κB-dependent mechanism in a rat model of chronic myocardial
induction of the expression of VEGF and Flt-1 occurs within a very
infarction (111). In this study, the administration of pyrrolidine
short time, but induction of the Flk-1 does not occur until days
dithiocarbamate (PDTC), an NF-κB inhibitor, blocked angiogenesis,
later (128). One of our very recent studies showed that resveratrol
thus demonstrating the essential and important role of NF-κB in
could induce, in chronological order, the expression of iNOS and
myocardial angiogenesis. Again, notable induction of eNOS and
VEGF, followed by Flk-1, and lastly eNOS. Immunohistochemistry
iNOS by resveratrol in the myocardium provides evidence support-
detected increased expression of these proteins in the hearts from
ing the hypothesis that resveratrol regulates endothelial cell growth
resveratrol-fed rats subjected to thirty minutes of ischemia and two
as also evident by increased perfused capillaries (111). The eNOS
hours of reperfusion as compared to those in non-fed hearts (129).
isoform is constitutively expressed and its expression can be stimu-
Several other reports exist in the literature to show that resveratrol can
lated by pharmacological interventions whereas, iNOS is a cyto-
induce eNOS and iNOS expression. For example, resveratrol induced
kine-inducible isoenzyme (112). The eNOS isoform participates in
an expression of eNOS in the human umbilical vein endothelial cells
circulatory function during heart failure; the iNOS isoform may have
(HUVEC) (130). In addition, to its long-term effects on eNOS expres-
an important role in the hemodynamics early after myocardial infarc-
sion, resveratrol also enhanced the rapid production of bioactive NO,
tion (113). iNOS modulates arterial hemodynamics in large, conduit
which suggests a role for iNOS. Our results support these previous
arteries whereas eNOS is supposed to regulate peripheral resistance
observations; we have observed iNOS expression within twenty-four
of the vessel (114).
hours of resveratrol treatment, but eNOS expression was not apparent
Numerous experimental results have demonstrated that very
until three days later. Additionally, Hsieh et al. found that resveratrol
low concentrations of NO produced from eNOS or pharmacological
induced the expression of iNOS in cultured bovine pulmonary artery
concentrations of exogenous NO produced by NO donors reduce
endothelial cells (131).
apoptotic cell death (115, 116). In our study, besides eNOS induc-tion, iNOS was significantly induced in all resveratrol-treated groups. Recent studies have demonstrated that eNOS/NO play an important
role in many VEGF-induced actions. VEGF induces the produc-tion of nitric oxide (NO) from rabbit, pig, bovine, and human
It is becoming increasingly clear that resveratrol has two faces. On
vascular endothelial cells (117). The inhibition of NO production
one hand, it protects cells by potentiating a survival signal. On the
by eNOS inhibitors significantly reduced VEGF-induced mitogenic
other hand, it selectively kills cancer cells. It behaves as an antioxi-
and angiogenic effects (118). eNOS/NO have been implicated as
dant, yet it can induce redox signaling. It is an antiproliferative agent
important mediators for VEGF-induced hemodynamic changes and
for cancer; it induces apoptosis in tumor cells and sensitizes cancer
microvascular permeability. Recent studies indicate that a variety
cells by inhibiting cell survival signal transduction and antiapoptotic
of stimuli, including hypoxia, shear stress, inflammatory cytokines,
pathways. In contrast, the same compound triggers a survival signal
high glucose, and injury can modulate eNOS expression and activity
in the ischemic tissue by inducing antiapoptotic genes and blocks
(119, 120). In vitro experiments have shown that activation of Flk-1
apoptosis in ischemic heart. At low doses, resveratrol stimulates
induces proliferation and migration of endothelial cells as well as
angiogenesis, but at higher doses, it blocks angiogenic response.
expression of eNOS and iNOS (121, 122).
Resveratrol has been recognized as a phytoestrogen based on its
NO is a pleiotropic molecule that affects diverse biochemical
structural similarities to diethylstilbesterol (DES), yet many in vivo
Volume 6, Issue 1
provides evidence that resveratrol was used centuries ago in
studies failed to confirm estrogenic potential of resveratrol. At low
concentrations, resveratrol scavenges ROS, but at higher concentra-
Vastano, B.C., Chen, Y., Zhu, N., Ho, C.T., Zhou, Z., and Rosen, R.T.
tions, it behaves like a prooxidant.
Isolation and identification of stilbenes in two varieties of Polygonum
cuspidatum. J. Agri. Food Chem. 48, 253–256 (2000).
One likely explanation for the dichotomy of resveratrol action
Pezzuto, J.M. Plant-derived anticancer agents. Biochem. Pharmacol. 53,
could arise from wide-ranging differences in tissues in pharmacoki-
netics, bioavailability, and metabolism. In a recent study, rats were
Jang, M., Cai, L., Udenani, G.O. et al. Cancer chemopreventive activity of
resveratrol, a natural product derived from grapes. Science 275, 218–220
given red wine (4 ml containing 6.5 mg/l resveratrol) and sacrificed
at several time points post-ingestion (132). Resveratrol was absorbed
Renaud, S. and de Lorgeril, M. Wine, alcohol, platelets, and the French
rapidly, being detectable in plasma (18 ng/ml) and liver (20 ng/ml)
paradox for coronary heart disease. Lancet 339, 1523–1526, 1992.
Ray, P.S., Maulik, G., Cordis, G.A., Bertelli, A.A., Bertelli, A., and Das,
within thirty minutes, in kidney (20 ng/ml) within one hour, and
D.K. The red wine antioxidant resveratrol protects isolated rat hearts from
only detectable in heart after two hours and only at a concentra-
ischemia reperfusion injury Free Rad. Biol. Med. 27, 160–169 (1999). A
tion of 2 ng/ml. Thus, a low concentration of resveratrol is quite
pioneering study showing cardioprotective abilities of resveratrol.
Hung, L., Chen, J., Huang, S.S., Lee, R., and Su, M. Cardioprotective effect
sufficient for the preconditioning of the heart. In fact, at higher con-
of resveratrol, a natural antioxidant derived from grapes. Cardiovasc. Res.
centration, resveratrol could exert toxic effect in the heart. Red wine
47, 549–555 (2000).
containing 1.2 mg/l of resveratrol can inhibit platelet aggregation
Ignatowicz, E. and Baer-Dubowska W. Resveratrol, a natural chemopreventive agent against degenerative diseases. Pol. J. Pharmacol.
by 42%, even when it is diluted 100-fold (133). At a concentration
53, 557–569 (2001).
as low as 100 nmol/l, resveratrol can inhibit the TNF-α-mediated
Bertelli, A.A., Migliori, M., Panichi, V., Origlia, N., Filippi, C., Das, D.K.,
expression of intracellular adhesion molecules such as ICAM-1
and Giovannini, L. Resveratrol, a component of wine and grapes, in the
prevention of kidney disease. Ann. N.Y. Acad. Sci. 957, 230–238 (2002).
(134). At a concentration of 1 nM, resveratrol induces phosphoryla-
Bhat, K.P., Kosmeder, J.W., II, Pezzuto, J.M. Biological effects of resveratrol.
tion of ERK1/2, whereas at higher concentration of 50–100 µM, it
Antiox. Redox Signal. 3, 1041–1064. (2001). An excellent review on the
inhibits MAPK phosphorylation (135). Interestingly, preconditioning
diverse biological activities of resveratrol.
Hattori, R., Otani, H., Maulik, N., and Das, D.K. Pharmacological
is achieved only at a low amount of stress through the activation of
preconditioning with resveratrol: Role of nitric oxide. Am. J. Physiol. Heart
MAP kinase signaling (80).
Circ. Physiol. 282, H1988–H1995 (2002). A pioneer study showing the
It is tempting to speculate that NO may play a crucial role
ability of resveratrol to pharmacologically precondition the heart.
Das, S., Cordis, G.A., Maulik, N., and Das, D.K. Pharmacological
in the dual behavior of resveratrol. Similar to resveratrol, NO also
preconditioning with resveratrol: A role of CREB-dependent Bcl-2
has two entirely opposite actions. Constitutive expression of NO is
signaling via adenosine A3 receptor activation. Am. J. Physiol. Heart Circ.
protective, but it is equally destructive to the cells at higher doses.
Physiol. 288, H328–H335 (2005). Shows the signaling pathways of the
pharmacological preconditioning by resveratrol.
Activation of iNOS and eNOS play a crucial role in ischemic pre-
Leonard, S., Xia, C., Jiang, B.H., Stinefelt, B., Klandorf, H., Harris, G.K.,
conditioning. It appears that resveratrol-mediated cardioprotection
and Shi, X. Resveratrol scavenges reactive oxygen species and effects
is achieved through the increased expression of NOS, which exerts a
radical-induced cellular responses. Biochem. Biophys. Res. Commun. 309,
preconditioning-like effect, rather than direct protection.
Orallo, F., Alvarez, E., Camina, M., Leiro, J.M., Gomez, E., and Fernandez,
Preconditioning, the best method yet devised for cardioprotec-
P. The possible implication of trans-resveratrol in the cardioprotective effects
tion, is achieved by subjecting the heart to a therapeutic amount of
of long-term moderate wine consumption. Mol. Pharmacol. 61, 294–302
(2002). This article shows that the cardioprotective effect of red wine is
stress, thereby disturbing normal cardiovascular homeostasis and re-
derived from resveratrol.
establishing a modified homeostatic condition with increased cardiac
Martinez, J. and Moreno, J.J. Effect of resveratrol, a natural polyphenolic
defenses that can withstand subsequent stress insult. The most com-
compound, on reactive oxygen species and prostaglandin production.
Biochem. Pharmacol. 59, 865–870, (2000).
mon and well-studied method of preconditioning is ischemic precon-
Cadenas, S. and Barja, G. Resveratrol, melatonin, vitamin E, and PBN
ditioning. Such a method, however, cannot be extrapolated to clinics.
protect against renal oxidative DNA damage induced by the kidney
There has been a desperate search for pharmaceutical pre-
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Lee, S.K., Mbwambo, Z.H., Chung, H., Luyengi, L., Gamez, E.J., Mehta,
conditioning agents. Resveratrol appears to fulfill the definition of
R.G., Kinghorn, A.D., and Pezzuto, J.M. Evaluation of the antioxidant
a pharmaceutical preconditioning compound. Future studies will
potential of natural products. Comb. Chem. High Throughput Screen. 1,
reveal the mystery of two faces of resveratrol and pinpoint its precise
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This study was supported in part by NIH HL 22559, HL33889,
κB, activator protein-1, and apoptosis: potential role of reactive oxygen
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vasorelaxing activity of wine or other grape products. Am. J. Physiol. 265,
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effects of astringinin, a resveratrol analogue, on the ischemia and
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constituent resveratrol: Consideration of its superagonist activity in MCF-7
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Zhao, T., Xi, L., Chelliah, J., Levasseur, M.S., and Kukreja, R.C. Inducible
Sato, M., Ray, P.S., Maulik, G., Maulik, N., Engelman, R.M., Bertelli, A.A.,
nitric oxide synthase mediates delayed myocardial protection induced by
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activation of adenosine A1 receptors. Circulation 102, 902–908 (2001).
Cardiovasc. Pharmacol. 35, 263–268 (2000). Provides direct experimental
Carbo, N., Costelli, P., Baccino, M.F., Lopez-Soriano, F.J., and Argiles, J.M.
evidence for the red wine-mediated cardioprotection.
Resveratrol, a natural product present in wine, decreases tumor growth in a
Shigematsu, S., Ishida, S., Hara, M., Takahashi, N., Yoshimatsu, H., Sakata,
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prevents superoxide-dependent inflammatory responses induced by
on oral cancer cell growth and proliferation. Anticancer Drugs 10, 187–193
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Caltagirone, S., Rossi, C., Poggi, A., Ranelletti, F.O., Natali, P.G., Brunetti,
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M., Aiello, F.B., and Piantelli, M. Flavonoids apigenin and quercetin inhibit
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protykin, a novel extract of trans-resveratrol and emodin. Free Radic. Res.
Volume 6, Issue 1
32, 135–144 (2000). Provides evidence that a novel formulation of
resveratrol with emodin is an excellent cardioprotective agent.
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El-Mowafy, A.M. and White, R.E. Resveratrol inhibits MAPK activity and
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nuclear translocation in coronary artery smooth muscle: Reversal of
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endothelin-1 stimulatory effects. FEBS Lett. 45, 63–67 (1999).
Mitchell, M.B., Meng, X., Ao, L., Brown, J.M., Harken, A.H., and Banerjee,
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C-dependent activation of Src and Lck tyrosine kinases during ischemic
Flack, J.E., Kimura, Y., Engelman, R.M., and Das, D.K. Preconditioning the
preconditioning in conscious rabbits. Circ. Res. 85, 542–550 (1999).
heart by repeated stunning improves myocardial salvage. Circulation 84(5
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kinase is downstream of protein kinase C for ischemic preconditioning's
Sato, M., Cordis, G.A., Maulik, N., and Das, D.K. SAPKs regulation of
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ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 279, H901–
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Maulik, N., Wei, Z.J., Engelman, R.M., Lu, D., Rousou, J.A., and Das, DK.
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Interleukin-1α preconditioning reduces myocardial ischemic reperfusion
ischemic preconditioning only by combined inhibition of protein kinase C
injury. Circulation 88, 387–394 (1993).
and protein tyrosine kinase in pigs. J. Mol. Cell. Cardiol. 30, 197–209 (1998).
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defenses following preconditioning of the heart by repeated ischemia.
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Cardiovasc. Res. 27, 578–584 (1993).
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Hattori, R., Maulik, N., Otani, H., Zhu, L., Cordis, G., Engelman, R.M.,
Differential regulation of p90 ribosomal S6 kinase and Big mitogen-activated
Siddiqui, M.A.Q., and Das, D.K. Role of Stat 3 in ischemic preconditioning. J.
protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused
Mol. Cell. Cardiol. (in press)
guinea pig heart. Circ. Res. 85, 1164–1172 (1999).
Tanno, M., Tsuchida, A., Nozawa, Y., Matsumoto, T., Hasegawa, T., Miura, T.,
Abe, J., Takahashi, M., Ishida, M., Lee, J.D., and Berk, B.C. c-Src is required
and Shimamoto, K. Roles of tyrosine kinase and protein kinase C in infarct
for oxidative stress-mediated activation of Big mitogen-activated protein
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Akhand, A.A., Pu, M., Senga, T., Kato, M., Suzuki, H., Miyata, T.,
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Hamaguchi, M., and Nakashima, I. Nitric oxide controls Src kinase activity
tyrosine kinase in single or multiple cycles of preconditioning in rat hearts.
through a sulfhydryl group modification-mediated Tyr-527-independent and
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Professor and the Director of The
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Volume 6, Issue 1
Journal of Controlled Release 94 (2004) 323 – 335 Incorporation and release behavior of hydrophobic drug in functionalized poly(D,L-lactide)-block–poly(ethylene oxide) Jaeyoung Lee, Eun Chul Cho, Kilwon Cho* Department of Chemical Engineering, School of Environmental Engineering, Pohang University of Science and Technology, 790-784 Pohang, South Korea Received 22 May 2003; accepted 9 October 2003
repert med cir. 2 0 1 6;2 5(2):101–105 de Medicina y Cirugía Guía de práctica clínica Movimientos anormales y embarazo Eduardo Palacios a y Ángela Viviana Navas b,∗ a Servicio de Neurología, Hospital de San José, Sociedad de Cirugía de Bogotá, Fundación Universitaria de Ciencias de la Salud,Bogotá DC, Colombiab Servicio de Neurología, Fundación Universitaria de Ciencias de la Salud, Bogotá DC, Colombia