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CHAPTER 10
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Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
MD. ADIL SHAHARYAR, CHOWDHURY MOBASWAR HOSSAIN, SANMOY KARMAKAR
1

1,2
MAHFOOZUR RAHMAN,3 KUMAR ANAND,
1
IMRAN KAZMI,4 and
2
2

2
Department of Pharmaceutical Technology, Jadavpur University,
 
3


Sam Higginbottom Institute of Agriculture, Technology, and Sciences,
 
4

Saharanpur, Uttar Pradesh, India
ABSTRACT
Cardiovascular disease has been a source of morbidity and mortality in the world. The American Heart Association states that though the mortality has decreased yet the burden and impact are still threatening. Molecules from the plants have been a boon for mankind. These gifted molecules from nature have been a source of cure for various diseases, the cardiovascular disease being one of them. Many molecules have been investigated and rosmarinic acid obtained from various plants being one of them. Rosmarinic acid, till now, has received less attention in terms of its cardiovascular potential from the scientific community. This book chapter deals with the cardiovascular disease-modifying activities of rosmarinic
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acid and sheds light for carrying out research in this domain. This book chapter has covered the attenuation or inhibition of AMI, arrhythmia, hypertension (HTN), etc., by Rosmarinic acid. For studying the effect of rosmarinic acid on cardiovascular disease, various protocols have been mentioned. After this discussion Rosmarinic, acid turns out to be a strong candidate having promising results in the management of cardiovascular diseases (CVDs).

Heart and its ailments find a special place in the contemporary scientific circle. Cardiovascular disease is a menace to the society. According to the American Heart Association, the mortality rate has declined but the impact and burden of the disease remain unchanged. The mortality rate in 2006 from cardiovascular disease was 262.5 per 100,000 (International Classification of disease 10, 100–199). The value was a higher for white males. For white males 306.6 per 100,000 and for black males 422.8 per 100,000. In the case of females, it was lower 215.5 and 298.2 per 100,000 for white and black females respectively. A 2006 report of AHA foregrounded the fact that 2300 Americans die per day of cardiovascular disease. One of every six deaths in the US is due to CHD. Every 6 deaths in the US are due to CHD. Each year around 95,000 people experience a new or recurrent stroke. According to a survey conducted by the National Health and Nutrition Examination (NHANES) 2003–2006 points out
that 33.6% of US adults ≥ 20 years of age have hypertension (HTN). The data
of cardiovascular disease affecting people presents a disturbing picture, which needs immediate attention (Jones et al., 2010).
Plant extracts have always been useful and exploited by mankind for the treatment of various diseases since ancient civilization. Rosmarinic acid is one such molecule extracted from various plants having a cardiovascular effect.

Rosmarinic acid oil found in Perilla frutescens (Lee et al., 2013) from which glucoside of rosmarinic acid (rosmarinic acid-3-O-glucoside) is obtained (Makino et al., 2001). Rosemary (Al Sereiti et al., 1999) (Rosmarinus offi- cinalis Linn.), Sage which is a spice herb Mint (Ellis et al., 1970), Thyme (Dapkevicius et al., 2002), Basil (rosmarinic acid and related phenolics in hairy root cultures of Ocimum basilicum) and the Ayurvedic medicine Holy Basil (Hakkim et al., 2007), Melissa officinalis (Labiatae) at 2.2–5.5%,
231 Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
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Orthosiphon stamineus (Malahubban et al., 2013), Clerodendranthus spicatus (Thunberg) (Zheng et al., 2012), Verbascumxantho phoeniceum
(Scrophulariaceae) (Georgiev et al., 2012), and Heliotropium foertherianum (Boraginaceae) (Braidy et al., 2013).

The phenylpropanopid pathway uses 4-coumaroyl CoA. Thus, 4-coumaroyl CoA acts as a hydroxycinnamoyl donor. The hydroxy cinnamoyl acceptor is synthesized from the Shikimic acid pathway.
From chemical and biological point of view, rosmarinic acid is synthe­sized from an ester of caffeic acid (CAA) with 3,4-dihydroxyphenyllactic acid and 4-coumaroyl-4’-hydroxyphenyllactate respectively. Rosmarinate is synthesized with the help of rosmarinate synthase which utilizes caffeoyl­CoA and 3,4-dihydroxyphenyllactic acid to produce the same (Petersen et al., 1988) (Figure 10.1).
The pathway has many enzymes taking part which probably came from the pathway that involves synthesis of chlorogenic and caffeoylshikimic acid (Petersen et al., 2009).
 Biosynthesis of rosmarinic acid. (Source: Reprinted from Wu et al., 2015. © Elsevier.)

Two eminent Italian scientists namely M. L. Scarpatti and G. Oriente are cred­ited with the isolation of rosmarinic acid from the plant Rosemary (Rosmarinus
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officinalis). The Iupacname of the rosmarinic acid is (2R)-3- (3,4-dihy-
droxyphenyl)-2-[ (E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl]oxypropanoic
acid (pubchem.ncbi.nlm.nih.gov) (Figure 10.2).
 Rosmarinic acid. Source: PubChem URL:
It is a powder with red-orange color having slight solubility in water and soluble in almost all the organic solvent (Petersen et al., 2003).
 
Labiatae family of the plant kingdom has been tremendously exploited as traditional medicine for conditions like depression, strengthening of fragile blood vessels, memory enhancement, weakness, circulation improvement, exhaustion (Wang et al., 2004), infection, inflammation (Vieira, 2010),
https://pubchem.ncbi.nlm.nih.gov.
233 Rosmarinic Acid: A Boon in the Management of Cardiovascular Disease
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gastritis, and indigestion (Hajimehdipoor et al., 2010). Researchers have shown that rosmarinic acid possesses anti-oxidant (Zheng et al., 2001), anti­inflammatory (Al-Sereiti et al., 1999), anti-allergic (Ito et al., 1998), anti­depression (Takeda et al., 2002), anti-hyperglycemic (Kumar et al., 2010) and antimicrobial (Nascimento, 2009; Jain, 2010; Zomorodian et al., 2011).
An investigation was conducted to nd out the best source of rosmarinic
acid in plants belonging to family Labiatae which predominantly grows in Iran. HPLC was used to ascertain the RA contents in 29 plants, using the mobile phase as 0.085% O-phosphoric acid in water: 0.085% O-phosphoric acid in methanol: 0.085% O-phosphoric acid in 2-propanol in gradient mode for 20 min (Table 10.1).
TABLE 10.1 Rosmarinic Acid Content Analysis from Gradient Time Perspective
Water Containing o‑Phosphoric Acid
(%)
10 10 80 0 15 15 70 10 20 20 60 15 20 20 60 20
Methanol Containing o‑Phosphoric Acid
(%)
Isopropyl Alcohol Containing
o-Phosphoric Acid (%)
Time (mins)
Source: Shekarchi et al. (2012).
The separation was best with the above HPLC protocol. C8 and C
columns were compared and the best separation efcacy was obtained by C
18
18
column. HPLC chromatogram of Mentha spicata sample and UV spectrum of RA in 11.16 min obtained from PDA detector. Different genus of the labiata family was analyzed and rosmarinic acid contents were found greatest in Mentha species. From Table 10.2, it is observed all Mentha species contain RA in fairly good concentration (19.3–58.5 mg g
–1
) and M. spicata revealed
the highest rosmarinic acid content (Shekarchi et al., 2012).

The pharmacokinetic parameters of rosmarinic acid, tissue distribution studies, excretion, and metabolism as well as its metabolism in serum are not clear. In a Pharmacokinetic study miltiorrhiza depside salts in a dose of 60 mg/kg S were administered to Sprague Dawley rats were administered and