INTRODUCTION:
Cardiovascular diseases
include cardiac and vascular disorders (CVDs). It is the leading cause of death
worldwide, CVDs have killed 32% of the global population (17.9 million people),
with heart attacks and strokes accounting for 85% of all deaths1.
Myocardial cell loss and necrosis can result from the myocardium receiving
insufficient oxygen for an extended period of time2. “Toxicity that affects the heart” is the
definition of cardiotoxicity given by National
Cancer Institute.
This definition includes
a direct effect of the drug on the heart but also an indirect effect due to
enhancement of haemodynamic flow alterations or due to thrombotic events3.
Isoproterenol (ISO) induced cardiotoxicity is the chemical induced and most
commonly used for acute and chronic cardiac injury. If given in fractionated
doses, ISP causes progressive cardiac damage; however, larger doses can cause
acute damage4,5. ISO is synthetic sympathomimetic drug nonselective
β‐adrenergic agonist. For induction of MI, it is administered in
high dose (85mg/kg-340 mg/kg) subcutaneously6. It produces cytotoxic
free radicals in myocytes, which induce apoptosis and necrosis upon
auto‐oxidation7. It has ability to produce endogenous and
exogenous free radicals which leads to generation of oxidative stress due to
excessive accumulation of catecholamines in the body. These free radicals
generated will initiate peroxidation of polyunsaturated fatty acids (PUFAs)
progressing into both structural and functional myocardial damage. Hence, it is
used as a standard inducing agent to study the protective and the preventive
effects against myocardial ischemia, MI and cardiac fibrosis8.
In the ancient Indian medical system of Ayurveda, Moringa
oleifera (MO) plays a significant role. It is a member of the Moringaceae
family, commonly known as "Sahajan or Drumstick". Seeds of MO contain
important bio-active compounds like flavonoids, glucosinolates, isothiocyanates
and thiocarbamates. The compounds have ability to regenerate membrane potential
by quenching ROS9,10. Previous studies have mentioned the presence
of flavonoids kaempferol, quercetin, moringin, ß-sitosterol in MO seeds11,12.
Since the flavonoids are present in MO seeds. Hence, the present study aims to
reveal the cardioprotective activity for the same.
MATERIALS
AND METHOD:
Plant material preparation and Qualitative chemical
analysis:
The dried seeds of MO were procured from S.V.
Ayurvedic Bhandar, Navi Mumbai and identified by Alarsin Pharmaceuticals,
Mumbai under voucher specimen number (PG/2022/015). Seeds were pulverized,
extracted using hydroalcohol, defatted using petroleum ether and stored at 40°C
and stored in desiccator.
The extract was subjected to preliminary phytochemical
test for presence of various
phytochemicals in compliance with Kokate and Harborne13,14.
Animals grouping, induction and treatment:
Forty-two adult male albino wistar rats of 150-200
grams were housed in sterile polypropylene cages in 12-hour light/ 12-hour dark
cycle, temperature 22±3°C, humidity 50%-60%. They were fed with
standard food pellet and water ad libitum. Following the guidelines of
the Committee for Control and Supervision of Experiments on Animals (CCSEA),
New Delhi, India, the Institutional Animal Ethics Committee (IAEC) at Bharati
Vidyapeeth’s College of Pharmacy approved the experimental protocol under
reference BVCP/IAEC/09/2022.
Animals were acclimatized for 7 days then randomized
in five groups with six animals per group. All drugs were administered orally
by gavage as pretreatment for 21 days except disease control, whereas
Isoproterenol (ISP) was injected subcutaneously in dose 85mg/kg15
for 2 consecutive days i.e., on day 20 and 21 in all the groups except control.
The treatment given were as
follows: Group I Vehicle control (1% CMC, p.o.)16, Group II Disease
control ISP injection (85 mg/kg body weight, s.c.), Group III Standard
treatment Terminalia arjuna tablet (250mg/kg body weight, p.o.), Group
IV low dose of hydroalcoholic extract of Moringa oleifera (HAMO)
(200mg/kg body weight, p.o.), Group V high dose of HAMO (400mg/kg body weight,
p.o.).
Electrocardiogram (ECG):
Basal ECG recording was performed on 24 hrs after
second injection of ISO. ECG was performed by Biopac Student Lab (Biopac 4.0.2)
data acquisition unit for MP35. Biopac electrode lead set×2 and disposable 3
vinyl electrodes per rat. The data was analyzed later after recording17,18.
Biochemical estimation:
After 21 days of treatment, blood was collected from
retro orbital plexus under Isoflurane anesthesia in sterile centrifuge tube.
The serum was separated for estimation of biochemical parameters: - Total
Cholesterol (TC), Serum Triglycerides (TG), High density lipoprotein (HDL-C),
Creatine kinase-myoglobin binding (CK-MB), Lactate dehydrogenase (LDH), Alanine
aminotransferase (ALT), Aspartate aminotransferase (AST) using ERBA Diagnostic
Kit. Low density lipoprotein (LDL-C) was calculated using below mentioned
formula 19.
Oxidative stress parameters and Histopathology of heart
tissue:
After blood collection, animals were sacrificed using
CO2 overdose and heart tissues were isolated, washed with ice-cold
saline, fixed with 10% formalin and embedded on paraffin wax. 5-mm paraffin
section was cut, stained with hematoxylin and eosin (H&E), and seen under a
light microscope[20]. 10% homogenate of tissue was prepared in
phosphate buffer solution (pH 7.4)21. All the biochemical estimation
of reduced glutathione (GSH)22, catalase (CAT)23, and
malondialdehyde (MDA)24 were performed using standard procedures.
Statistical analysis:
The data sets were analyzed using one-way ANOVA followed by Dunnett’s test and expressed as mean ± standard error mean (SEM). The p value of
<0.05 was considered as significant. All the statistics was performed using
GraphPad Prism, version 9.
RESULTS:
Qualitative
chemical analysis:
The preliminary phytochemical of HAMO has shown
presence of carbohydrates,
alkaloids, glycosides, tannins, flavonoids, phenols, triterpenoids, saponins
(Table 1).
Effect of hydroalcoholic extract of Moringa oleifera on ECG
parameters:
There was significant (p<0.0001) decrease in QRS
complex and significant (p<0.001) increase in ST segment elevation time and
heart rate in disease control when compared to vehicle control. Whereas QRS
complex significantly (p<0.001, p<0.05) increased in standard Terminalia
Arjuna tablets (250 mg/kg), HAMO (200 mg/kg, 400 mg/kg). The ST segment
elevation time and heart rate significantly (p<0.001, p<0.05) decreased
in standard and HAMO (200 mg/kg, 400 mg/kg) (Figure 1).
Effect
of hydroalcoholic extract of Moringa oleifera on lipid parameters:
Serum levels of TC, TG and LDL-C of disease control
increased significantly (p<0.0001) increased when compared to the vehicle
control. Whereas, HDL-C levels of disease control decreased (p<0.0001) as
compared to vehicle control. In groups previously treated with standard Terminalia
Arjuna tablets (250 mg/kg), HAMO (200 mg/kg, 400 mg/kg) the significant
change in lipid profile was seen when compared to disease control (Table 2).
Effect of hydroalcoholic extract of Moringa oleifera on
oxidative stress parameters:
The disease control group has shown significant
(p<0.0001) increase in MDA levels whereas, significant decrease
(p<0.0001) was observed in GSH and catalase levels in comparison to vehicle
control. In contrast groups pretreated with standard Terminalia arjuna
tablets (250 mg/kg body weight), HAMO (200 mg/kg, 400mg/kg body weight) have
significantly (p<0.001, p<0.05) decreased the levels of MDA, whereas, the
levels of catalase and GSH significantly (p<0.001, p<0.05) increased in
pretreated groups in comparison to disease control (Table 3).
Effect of hydroalcoholic extract of Moringa oleifera on
histopathology of heart:
In vehicle control (Figure 5A) no abnormalities were
detected. Moderately multifocal, mild to moderate degree necrosis and loss of
sarcoplasm with minimal to mild degree mononuclear cell infiltration was
observed in disease control. Prominent changes in endocardium and papillary
muscles were also seen (Figure 5B). Although histological damage decreased in
treatment groups in comparison to disease control. In standard treatment Terminalia
arjuna tablets (250mg/kg) sporadic foci of minimal degree and mononuclear
cell infiltration in the myocardium was seen (Figure 5C). Mildly multifocal,
mild degree necrosis and loss of sarcoplasm with mild degree mononuclear cell
infiltration was observed in HAMO (200mg/kg) (Figure 5D). The HAMO (400mg/kg)
group has shown minimal multifocal, mild degree of necrosis and loss of
sarcoplasm with minimal degree mononuclear cell infiltration (Figure 5E).
Figure 5: Histology of ischemic heart by
hematoxylin-eosin stain; A) Vehicle control, B) Disease control, C) Standard
treatment Terminalia Arjuna tablets (250 mg/kg), D) Low dose HAMO (200
mg/kg), E) High dose HAMO (400 mg/kg)
DISCUSSION:
The present study revealed that Moringa oleifera
seeds can act as cardioprotective by attenuating Isoproterenol induced acute
myocardial infarction.
Our data demonstrated that HAMO mainly contains
flavonoids, phenols and tannins which could be responsible to produce
cardioprotective effect. MO seeds mainly contains flavonoids like kaempferol,
quercetin, moringin, ß-sitosterol 11. Quercetin has ability to act
as cardioprotective due to its antioxidant and antiplatelet properties25.
Kaempferol improves cardiac function and structure by preventing apoptosis,
oxidative damage, inflammation, fibrosis, calcium regulation, and other heart
diseases26–28.
In current investigation, HAMO exerted
cardioprotective action by reducing the levels of serum lipids, cardiac marker
enzymes and lipid peroxidation and by restoring endogenous antioxidant enzymes.
In ECG, the present study revealed elevation in ST segment, increased heart
rate and low QRS complex in disease control, which are diagnostic features of
acute myocardial infarction which occurs due to auto oxidation 29–31.
Alterations to the ECG, including an elevation of the ST segment were prevented
in treatment with Terminalia arjuna tablets and HAMO, 33,32.
The lipids affect the composition, structure, and
stability of cellular membranes, which significantly impacts development of
atherosclerosis and other cardiovascular diseases [34]. It was found
that disease control had high levels of serum TC, TG and LDL-C and low level of
HDL-C[35]. HDL-C facilitates the transfer of cholesterol from
peripheral tissue to the liver, where it is catabolized and expelled from the
body, and inhibits the uptake of LDL-C by the arterial wall 36.
While administration of Terminalia arjuna tablets and HAMO in treatment
groups restored normal lipid levels.
Cardiac markers like CK-MB, LDH, ALT and AST. CK-MB
isoenzyme activity is mostly seen in cardiac tissues makes it a valuable marker
for the early detection of MI [37]. When cell membranes become more
permeable or break, cytosolic enzymes such as CK-MB, LDH, AST, and ALT leaks
into the blood stream. The concentrations of these cellular enzymes in the
serum are reflection of changes to plasma membrane permeability and proportional
to necrosis of cell, in response to β-adrenergic stimulation [38–40].
Pretreatment with of Terminalia arjuna tablets and HAMO reduced the
elevated levels, indicating that HAMO restricts leakage of these enzymes and
maintains cell permeability.
The physiological balance between the free radical
production and body's anti-oxidative defence mechanism is altered in ISO
induced MI, leading to myocardial oxidative stress 41. In this study
the endogenous antioxidants GSH and catalase activity decreased in disease
control in comparison to vehicle control. Pretreatment with of Terminalia arjuna
tablets and HAMO improved the activity of endogenous antioxidants. The levels
of MDA were increased in disease control as it is ending product of lipid
peroxidation45. Heart tissue appears to be more vulnerable to
oxidative damage due to increased lipid peroxidation as the first stage of the
pathophysiology in MI. The MDA levels were significantly decreased in treatment
groups.
Histopathology of heart tissue of vehicle control
illustrated no changes in myocardial cell integrity. Disease group has shown
moderate necrosis and loss of sarcoplasm. Whereas, pretreatment with HAMO
(400mg/kg) has shown similar results to that of standard. Minimal degree of
mononuclear cell infiltration was observed in standard whereas, minimally
multifocal with minimal degree of mononuclear cell infiltration was seen in
HAMO (400mg/kg).
CONCLUSION:
The ECG, biochemical and histopathology findings
confirm HAMO has cardioprotective activity. This could be due to antioxidant
activity caused by polyphenols, flavonoids present in the MO seeds. We conclude
that MO seeds can be used as cardioprotective by preventing myocardium damage
caused by oxidative stress. Although the exact mechanism is not known. Further
studies should be carried out to understand the exact mechanism.
ACKNOWLEDGEMENT:
The authors are grateful to The Principal, Dr.
Vilasrao Kadam of Bharati Vidyapeeth’s College of Pharmacy, C.B.D Belapur for
providing facilities to carry out the present work.
ETHICS COMMITTEE APPROVAL:
The protocol was approved by Institutional Animal
Ethics Committee (IAEC), Bharati Vidyapeeth’s College of Pharmacy
(BVCP/IAEC/09/2022).
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