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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5365_Библиотеки_им_академика_М_И_Перельмана
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Biomarkers as Targeted Herbal Drug Discovery
elimination half-life of RA was found to be 0.75 h while Pharmacokinetic
parameters after IV were found to be AUC (0-tn) (mg. h/l) 6.6 ± 1.8, Mean
residence time (0-) (h) 0.32 ± 0.07, t
(h) 0.12 ± 0.04, Clearance (l/h/kg)
1/2
1.02 ± 0.32 26 (Li et al., 2007).
TABLE 10.2 Different Concentration of Rosmarinic Acid from Different Plants Belonging
to Labiatae Family
Plant Scientific Name Region of Collection in Concentration of Rosmarinic
IRAN Acid in mg gm
Lavendula angustifolia
Mellisa officinalis
Mentha aquatica
Mentha crispa
Mentha longifolia
Mentha piperita
Mentha pulegium
Mentha spicata
Oreganum vulgare
Perovskia artemisoides
Rosmarinus officinalis
Salvia hypoleuka
Salvia limbata
Salvia macrosiphon
Salvia officinalis
Salvia virgata
Tehran, Abali road 1.7 ± 0.2
Mazandaran, Salmanshahr 36.5 ± 0.8
Golestan, Gorgan 24.6 ± 0.2
Golestan, Gorgan 19.3 ± 0.2
Golestan, Gorgan 26.6 ± 0.3
Golestan, Gorgan 28.2 ± 0.3
Golestan, Gorgan 23.4 ± 0.3
Golestan, Gorgan 58.5 ± 1.4
Mazandaran, Salmanshahr 25.0 ± 0.1
Khorasan 31.3 ± 0.2
Tehran, Abali road 7.2 ± 0.1
Tehran, Damavand 4.3 ± 0.03
Semnan, Ahovan 7.5 ± 0.1
Tehran, Delichaee 6.4 ± 0.1
Mazandaran, Salmanshahr 39.3 ± 0.9
Mazandaran, Ghaemshahr 16.4 ± 0.9
–1
Source: Shekarchi et al. (2012).
Absorption, conjugation, and methylation of RA from Perilla Extract
took place and a small proportion of RA was found to be degraded into
various components, such as conjugated forms of CAA, FA (ferulic acid)
and COA (m-coumaric acid). Excretion of these metabolites was found in
the urine. Pharmacokinetics (PKs) studies on rosmarinic acid was applied to
the evaluation of RA, in rats following intravenous and oral administrations
demonstrated more rapid distribution and was eliminated more rapidly from
the systemic circulation with a t
administration as described in Table 10.1. After being administered orally,
,λZ of (56.45 ± 0.67) min after intravenous
1/2
RA was absorbed and eliminated more rapidly, with a T
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of 45 min, and a t
,λZ of (63.68 ± 13.11) min (Baba et al., 2005).
1/2
of 10 min, a T
max1
max2
On intravenous administration of S. miltiorrhiza depside salts in a dose of 60
mg/kg in Sprague-Dawley rats, concentration-time curves were obtained which
reected a two-compartment model. The elimination half-lives and AUC
0–6h
for
rosmarinic acid were 0.75 h and 6.6 h, respectively (Li et al., 2007).
Intestinal absorption of rosmarinic acid was investigated through oral
route where portal vein peaked at 10 mins having C (max) 1.36 micro mol/L.
AUC of the intact rosmarinic acid in portal vein was calculated from the
serum concentration-time prole and was found to be 60.4 micromol min L
–1
(Konishi et al., 2005).
Further, a study involving absorption, metabolism, degradation, and
urinary excretion of rosmarinic acid, administrated via oral route in rats
was conducted. The concentration of rosmarinic acid reached its peak in the
plasma in 0.5 h.
The majority of rosmarinic acid degraded into conjugated and/or methyl
ated forms of CAA, FA and m-coumaric acid before being excreted slowly
in the urine (Baba et al., 2004).
RA was found to have four phenolic hydrogen that are responsible for
controlling free radical oxidation. Further, it contains other two catechol
containing 1,2-dihydroxybenzene rings which gives polarity to it (Shahidi
et al., 1992).
For long natural compounds have been investigated in the treatment of
inflammations specially those having potential either to reduce or eliminate
the synthesis of leukotriene. These natural compounds ideally should have
no adverse effects.
Rosmarinic acid has been found to inhibit the activation of the complementary system both in vitro and in vivo using both classical and alternate
pathway (Englberger, 1988; Peake et al., 1991). In an in vivo study, rosmarinic acid has been found to inhibit cobra venom factor (CVF)-induced paw
edema in rats (Rampart, 1986; Bult et al., 1985).
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Biomarkers as Targeted Herbal Drug Discovery
Experimental Investigation reveals that rosmarinic acid actively binds
covalently with the activated complement component C3b surface, thereby
inhibiting the complement system (Sahu et al., 1999). NSAID and glucocorticoids (GCs) are the modulators that inhibit the complement activation
system through cyclo-oxygenase pathway while rosmarinic acid prevents
inammation through prostanoid pathway and does not meddle in the COX
pathway leading to reduction in side effects (Kuhnt et al., 1995).
Natural compounds such as chlorogenic acid, rabdosiin, and rosmarinic
acid have CAA which exerts anti-allergic activities that encompasses free
radical oxygen scavenging and inhibition of release of β-hexosaminidase and
hyaluronidase. Rabdosiin showed the highest hyaluronidase-inhibitory activity.
Among the compounds that were tested for radical scavenging activities,
involving oxygen species were superoxide anion radicals and hydroxyl radicals.
These radical oxygen species were also inhibited by rabdosiin. More than 90%
of β-hexosaminidase release from cultured cells was inhibited by both rabdosiin
and CAA at a concentration of 2 mM (Sanchez-Campillo et al., 2009).
Remarkable anti-bacterial activity of rosmarinic acid was noted against
Escherichia coli, Bacillus subtilis, and Micrococcus luteus.
Thus, the anti-bacterial and anti-inammatory activity of rosmarinic acid
makes it a good candidate in the treatment of skin infections of the epidermis
and oral mucosa (Kuhnt et al., 1995).
The UV radiation present in the solar spectrum generates ROS (reactive
oxygen species) that imbalances the homeostasis of the skin by causing
damage of DNA in the cell. The photoprotective activity of rosmarinic acid
is exerted by the free radical scavenging activity. Rosmarinic acid erects its
own defense wall by the stimulation of melanin synthesis and modulation of
tyrosinase activity (Sanchez-Campillo et al., 2009).
After screening of phyto compounds or extracts, those with anti-oxidant
and anti-inammatory properties may also be used to protect the skin from
getting damaged by UV radiations (Vostálová et al., 2010).
After performing some mutagenic assays, it was found that there was no
increment in the frequency of micronuclei as compared to the negative
237 Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
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controls, when different concentrations of rosmarinic acid were administered
to animals in an experimental protocol (Furtado et al., 2008)
Oral carcinogenesis was induced by 7,12-dimethylbenz anthracene (DMBA)
to investigate the inhibitory anti-cancer activities of rosmarinic acid. For this
study, the biomarkers involved in lipid peroxidation (LPO), Inhibitory effects
of rosmarinic acid against DMBA-induced oral carcinogenesis by evaluating
both the expression patterns of immunity (p53 and bcl-2) and biochemical
markers (LPO, antioxidants, and detoxication enzymes) (Anusuya et al.,
2011). Phytochemicals like carnosol, ursolic acid, carnosic acid obtained from
rosemary have anti-oxidant and chemoprotective properties. These act by
inhibiting the P-glycoprotein and can cause food-drug interaction (Nabekura
et al., 2010)
Anti-depressive activity was observed in rosmarinic acid that was obtained
from the leaves of Perilla frutescens Britton var. acuta Kudo (Perillae
Herba). CAA is the major metabolite of rosmarinic acid and both the
chemical moiety has been found to reduce the time of immobility of mice
in the forced swimming test. Histamine has been found to possess depression causing effect and rosmarinic acid inhibits its release from mast cells
thus exerts anti-depressive activity at a single dose while CAA inhibits the
synthesis and release of nitric oxide (NO) which is a vasodilator through
a1-adrenoreceptor.
It is speculated that brain adrenoreceptors may be the reason behind stress
and depression. Forced swimming in mice causes an increase of histamine
as well as its turnover in the brain while antagonism of H1 and H3 receptor
using different antagonists markedly reduced the period of immobility. From
different types of assay systems it was established that anti-depressants
such as amitriptyline, mianserin, and doxepin are potent competitive H1
receptor antagonists. Further studies are required to establish the mechanism
involving anti-depressant activities of rosmarinic acid and CAA in the brain
(Takeda et al., 2002)
As evident from the chemical structure, rosmarinic acid is a major polyphenolic compound and is one of the components of Perillae Herba (a leaf
of Perilla frutescens) having anti-depressant properties as found in animal
models (Takeda et al., 2002).
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Biomarkers as Targeted Herbal Drug Discovery
In one of the cellular studies, cell proliferation was induced using rosmarinic acid and is believed to be one of the probable pathways of exerting
anti-depressant effect (Makino et al., 2001).
Angiogenesis stems from the Greek word ‘Angeion’ which means vessel,
i.e., formation of new blood vessel from the existing one. It continues to
form (new blood vessels) through the life cycle of both healthy and diseased
person. It inhibits multiple steps involved in angiogenesis like proliferation,
migration, adhesion, and tube formation of human umbilical vein endothelial
cells (HUVEC). It also reduced the level of various biomarkers like IL-8
release of endothelial cells, intracellular ROS level, H
-dependent VEGF
2O2
expression (Huang et al., 2006).
Role of rosmarinic acid has not been properly brought to notice. It has been
widely investigated in various cardiovascular diseases (CVDs) as discussed
below.
Polyphenols obtained from dietary sources are potent and highly useful in
inhibiting the lipid membranes alteration caused due to oxidative stress.
Among the various polyphenols found in nature, rosmarinic acid founds
special mention and is widely studied. A study involving rosmarinic acid
confirms its LPO inhibiting activity.
An investigation by atomic force microscopy of transferred lipid/RA
monolayers showed that at nanoscale level, a concentration of 1 mol% was
insufcient in altering the structure of the membrane and further no sign
of changes in the permeability and uidity of the membrane was noted.
1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) vesicles loaded with
rosmarinic acid was prepared which showed that up to 1 mol% of Rosmarinic acid, when inserted spontaneously within the membrane, inhibited
LPO without causing any alteration in the membrane (Fadel et al., 2011).
Low-density lipoprotein (LDL) that gets modied due to oxidation possesses
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an atherogenic property which can be prevented by using anti-oxidants that
act by LDL inhibition. Rosmarinic acid was found to inhibit LDL oxidation
in a dose-dependent manner (Fuhrman et al., 2000)
Cardiac abnormalities and HTN prevention potential of rosmarinic acid was
investigated in fructose-fed rats (FFR). A high fructose-fed model of insulin
resistance was chosen and RA was found to be insulin-sensitizing as well as
anti-oxidant. Rosmarinic acid administered to FFR rats efficiently improved
insulin sensitivity, reduced lipid levels, oxidative damage, and the concentration of p22phox subunit of nicotinamide adenine dinucleotide phosphate
reduced oxidase, and prevented cardiac hypertrophy. A decrease in blood
pressure (BP) by rosmarinic acid was achieved by causing a decrease in
endothelin-1 and angiotensin-converting enzyme activity and increase of NO
levels. Histology studies showed significant lowering of myocardial damage
in fructose-fed rats when rosmarnic acid was administered thus, exhibiting
vasoactive and cardioprotective activity and lowering cardiovascular riskassociated with IR (Karthik et al., 2011).
The study used melaton to induce rat cardiopathology. Rosmarinic acid-like
luteolin and echinochrome could not provide cardioprotective activities and
increased survival probability (Tsibul’skiĭ et al., 2011).
At the mechanism level, another study was carried out to probe the inhibitory action of rosmarinic acid on adriamycin (ADR)-induced apoptosis in
H9c2 cardiac muscle cells causing a decrease in the liabilities of H9c2 cells,
with the development of apoptotic characters like nuclear morphological
changes and activation of caspase protease enzyme. Rosmarinic acid was
bestowed with the ability to inhibit these apoptotic characters by decreasing
the intracellular ROS generation and also by regaining the potential of mitochondrial membrane. These exhaustive studies revealed the pharmacological
abilities of rosmarinic acid to inhibit ADR-induced apoptosis. These results
concludes that
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Biomarkers as Targeted Herbal Drug Discovery
Rosmarinic acid is a potential chemotherapeutic agent that can prevent
cardiotoxicity in patients exposed to ADR (Kim et al., 2005).
A study involving the evaluation of the cardioprotective effect of
Prunella vulgaris ethylacetate fraction (PVEF) and its component, i.e.,
rosmarinic acid was executed on isolated rat cardiomyocytes with the
help of doxorubicin-induced oxidative stress. PVEF and rosmarinic
acid showed cytoprotective effect in the concentration range of 0.005 to
0.05 mg/mL. The data showed that the action of PVEF correlated with
the RA content. From the probable mechanistic point of view the extract
containing rosmarinic acid possessed remarkable cardioprotective effects
due to anti-oxidant property (high phenolic content) and inhibition of LPO
of membrane (Psotová et al., 2005). Promising results were obtained in
terms of chemoprotective effect of rosmarinic acid achieved by induction
of toxicity in rat cardiomyocytes by anthracycline (Chlopcíková et al.,
2004).
For addressing HTN, there are many drugs which are floating in the market
but still HTN is affecting millions all over the world. Medicinal plants are
slowly superseding the synthetic ones. The leverage being in terms of high
manufacturing cost of synthetic drugs, low cost of herbal-based medicine
and very few adverse affects of these natural products. One of the ways
to treat HTN is the use of ACE inhibitor. Lie et al. and Karthik et al. has
shown that rosmarinic acid inhibits or modulates ACE thus affecting BP but
unfortunately literature related to it is very less (Li, 2008; Karthik et al.,
2011). It has been reported that rosmarinic acid has endothelium-dependent
vasodilator effect (Ersoy et al., 2008). The vasodilator effect is attributed
to the polyphenolic group present in rosmarinic acid which exert this effect
through activation of NO, prostacyclin (PGI
) and endothelium-dependent
2
hyperpolarizing factor (EDHF) (Ersoy, 2008; Fernandes et al., 2005). One of
the pathways of rosmarinic acid’s working is by increasing the level of Ca
+2
in endothelial cells as well as activation of PI3-kinase/Akt, finally causing
NOS activation and subsequent hyperpolarization. Rosmarinic acid also
exerts anti-oxidant effect by inhibiting the oxygen free radical and peroxynitrate production thus leading to the prevention of damaging of the tissues
(Fernandes et al., 2005).
241 Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
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Acute myocardial infarction (AMI) and arrhythmia are a menace to the
society and a great cause of hospitalization and mortality respectively. The
cellular calcium level is regulated by both Sarcoplasmic reticulum Ca
2+
ATPase (SERCA2) and Ryanodine receptor (RyR2), respectively. The
protocol was designed in such a way so as to investigate whether rosmarinic
acid can safeguard cardiac functions against AMI and arrhythmia induced
by Isoproterenol, modulated by both SERCA2 and RyR2 genotypically. For
mechanism of rosmarinic acid in myocardial infarction refer to Figure 10.1
(Javidanpour et al., 2018).
To run this protocol male Sprague-Dawley rats were used for both in vivo
and ex vivo studies. Rosmarinic acid was administered to these rats in a dose
of 10, 15, and 30 mg/kg for 14 days, respectively. Isoproterenol in a dose of
100 mg/kg was administered subcutaneously in consecutive mode to induce
AMI. In vivo study was carried out to evaluate various parameters like heart
rate, BP, ECG parameters, antioxidative enzymes, plasma levels of cardiac
biomarkers. Langendorff set up was used to measure cardiac functions in
isolated heart. Left ventricle of the heart was explored for gene expressions
ofSERCA2 and RyR2.
A signicant fall in QRS voltage, BP, activities of antioxidant enzymes,
gene expressions of SERCA2 and RyR2 and cardiac function was noted
on administration of isoproterenol. The results reected an increase in
ST-elevation, heart rate, antioxidant enzymes, and cardiac biomarkers at a
dose of 30 mg/kg. This study reveals cardioprotective potential of rosmarinic acid against AMI and arrhythmia, the management of arrhythmic and
AMI is probably due to its potential to augment the expression of plasma
antioxidant enzymes and genes involved in Ca
2+
homeostasis. Basically, its
anti-adrenergic action is the main reason for its protective role (Javidanpour
et al., 2018).
Cardiac remodeling occurs when the heart adapts itself to the hostile stimuli
which causes failure of the heart and is the chief reason for enhanced death
after myocardial Infarction.
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Biomarkers as Targeted Herbal Drug Discovery
Protocol was designed to investigate whether Rosemary leaves had any
effect on cardiac remodeling after MI. For running the protocol male Wistar
rats were taken and divided into 6 groups. These groups were as follows:
• Group I: Sham group fed with standard chow (SR0, n = 23);
• Group II: Sham group-fed with standard chow along with 0.02%
rosemary (R002) (SR002, n = 23);
• Group III: Sham group fed standard chow along with 0.2% rosemary
(R02) (SR02, n = 22);
• Group IV: Induced to MI and fed with standard chow (IR0, n = 13);
• Group V: induced to MI and fed with standard chow supplemented
with R002 (IR002, n = 8); and
• Group VI: induced to MI and fed with standard chow supplemented
with R02 (IR02, n = 9).
The drug was administered to the animals for 3 months and after that
systolic pressure was evaluated. Echocardiography and euthanasia was
performed. Samples of Left ventricle were evaluated for cytokine levels,
brosis, apoptosis, oxidative stress, and energy metabolism enzymes. The
protocol constituting oral administration of Rosemary showed attenuation of
cardiac remodeling by enhancing metabolism of energy as well as lowering
the oxidative stress.
Hypertrophy after MI was found to be reduced along with improvement
of diastolic function to the tune of 0.02% when supplementation of Rosemary
was administered. Investigation has revealed that a dose of 0.02% and 0.2%
of Rosemary in humans is equivalent to 11 mg and 110 mg, respectively
(Murino et al., 2017).
Cardiac fibrosis is described as a transformation of cardiac fibroblast
to myofibroblast through unnecessary differentiation accompanied by
disturbed homeostasis between synthesis and degradation of the extracellular matrix (ECM) (Kong et al., 2014). The ECM is secreted by the
converted CF’s (cardiac fibroblasts) which gives support to the cardiomyocytes and non-structural components. When cardiomyoctes are subjected
to chronic stimuli (Rienks et al., 2014) excessive ECM deposition takes
place causing mechanical and electrical impulse disturbance and finally
succumbing to heart failure and Arrhythmia (Khan et al., 2006). CF’s are
243 Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
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the main rogue behind causing cardiac fibrosis. So if the CF’s are targeted
cardic fibrosis can be prevented, decrease the chances of cardiac remodeling, and delay the occurrence of heart failure (Nagpal et al., 2016). To
investigate Rosmarinic acid’s anti-fibrotic effect male mice aged 8–10
weeks with bodyweight 25. 5 ± 2 gm were used. To anesthetize mice, 3%
pentobarbital sodium at a dose of 50 mg per kg was administered intraperitoneally and arbitrarily assigned to the AB (aortic banding) surgery group
or sham-operated control group. Severe aortic constriction was produced
by surgery. The sham-operated group underwent the same process but no
ligation of the Aortic was done. For post-operative pain relief Temgesic
(qd) at a dose of 0.1 mg/kg was used subcutaneously. After one week, the
following operation Doppler was used to confirm adequate ligation. The
animals were administered rosmarinic acid in a dose of 100 mg per Kg
intragastrically once daily or a vehicle of the same volume for 7 weeks
(Govindaraj, 2016; Boonyarikpunchai et al., 2014). The animals were
segregated into 4 groups namely sham + vehicle, sham + rosmarinic acid,
AB + vehicle and AB+ rosmarinic acid. Each group comprised of 15 mice.
After one week of surgery, mice were provided with rosmarinic acid in a
dose of 100 mg/kg/d for 3 weeks so as to establish In vivo inflammatory
action. After the completion of experimental protocol, mice were sacrificed
for heart and tibia for HW/BW and HW/TL calculation. For the experi-
ment, AMPKα and AMPKα2 KO mice were employed to study cardiac
fibrosis (Ma et al., 2016). Transthoracic echocardiography was performed
using the advance My Lab 30 CV ultrasound (Ma, 2017; Xu et al., 2017).
Further, for studying invasive hemodynamic, cardiac catheterization was
employed. Western blot quantitative real-time PCR and immunofluorescence staining was also used. The result sharply indicates that rosmarinic
acid improved cardiac dysfunction and Cardiac Fibrosis. Cardiac fibrosis
was found to be inhibited through AMPK activation and Smad3 inhibition
(as shown in Figure 10.2).
Rosmarinic acid has been extracted from different plant species but its effect
on cardiovascular disease has always been underestimated. This chapter
gives an assimilated account of its cardiovascular disease-modifying potential. Rosmarinic acid showed cardioprotective effect due to its anti-oxidant
property. It also possessed endothelium-dependent vasodilator effect which
acted through NO, PGI
, and EDHF pathway. It was also found to protect
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