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THERAPEUTIC PROPERTIES OF CAPSAICIN: A MEDICINALLY IMPORTANT

BIO-ACTIVE CONSTITUENT OF CHILLI PEPPER
Article in Asian Journal of Pharmaceutical and Clinical Research · July 2022

DOI: 10.22159/ajpcr.2022.v15i7.44405
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Online - 2455-3891
Vol 15, Issue 7, 2022 Print - 0974-2441
Review Article
THERAPEUTIC PROPERTIES OF CAPSAICIN: A MEDICINALLY IMPORTANT BIO-ACTIVE

CONSTITUENT OF CHILLI PEPPER
SANGRAM SINGH1*, MOIN UDDIN2, M. MASROOR A. KHAN1, SARIKA SINGH1, AMAN SOBIA CHISHTI1,
UROOJ HASSAN BHAT1
1
Department of Botany, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. 2Botany Section, Women’s
College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. Email: [email protected]
Received: 12 February 2022, Revised and Accepted: 10 May 2022
ABSTRACT
Plants are the source of numerous pharmaceutically important compounds that have been employed to cure various human ailments since ancient
times. With the assistance of modern chemistry and materials science, such pharmaceutically important compounds have been identified and isolated
to produce new drugs. Alkaloids are one of the most significant classes of naturally occurring secondary-metabolites, which are synthesized and widely
distributed in various parts of plants. They regulate various metabolic activities and induce physiological responses in the human body. Capsaicin is a
naturally occurring alkaloid found in many species of peppers and is attributed to their spicy nature and pungent flavor. This alkaloid is a member of
the Capsaicinoids group, which includes capsaicin, homocapsaicin, homodihydrocapsaicin, dihydrocapsaicin, and nordihydrocapsaicin. Capsaicin has
a wide range of therapeutic potential against various human ailments. In this article, we provide a comprehensive overview of the capsaicin molecule
as well as an examination of its medicinal properties in a variety of human disorders, including pain, various types of cancer, ulcers, diabetes, obesity,
inflammation, cardiovascular diseases, and neurodegenerative diseases.
Keywords: Alkaloids, Capsaicin, Capsaicinoids, Pharmacological, Therapeutic.
© 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ajpcr.2022v15i7.44405. Journal homepage: https://innovareacademics.in/journals/index.php/ajpcr
INTRODUCTION phytochemical from Stephania glabra, has been recognized as an

adenylate cyclase and nitric oxide stimulator, which might minimize the
Plants are the major source of pharmaceutically important active
risk of obesity-related complications and atherosclerosis problems [1].
compounds, with so many medicines derived directly or indirectly
Several plant-derived drugs have been introduced during the last two
from plants. Plants make major contributions to the prevention and
decades. For example, Nitisinone, developed from the natural compound
treatment of diseases, accounting for nearly 25% of pharmaceuticals
Leptospermone (Callistemon citrinus), is used in the treatment of
prescribed worldwide that are derived from plants. 121 such active
tyrosinemia, and the semi-synthetic compound apomorphine, derived
phytochemicals are now in use, with 11% of the WHO’s 252 basic and
from morphine, is used for the treatment of Parkinson’s disease.
essential medicines being derived only from flowering plants [1,2].
Similarly, tiotropium, a derivative of atropine obtained from Atropa
belladonna, is often used in the treatment of cardiovascular disorders.
Plants and plant-derived active constituents have a long track record
In the same way, artemether, an endoperoxide sesquiterpene lactone
of being utilized to cure a wide range of ailments with improved
and semisynthetic compound derived from Artemisinin, is used to treat
patient acceptance and tolerance. At present, about 35,000–70,000
malaria, and Dronabinol and Cannabidiol, obtained from the Cannabis
species of plants have been evaluated for their therapeutic potential.
plant (Cannabis sativa), and capsaicin, obtained from Capsicum annuum,
Morphine was the very first plant-derived natural compound, while
are used as pain relievers [1].
aspirin was the first semi-synthetic pure drug that was introduced and
commercialized for therapeutic use. This increased the identification ALKALOIDS
and isolation of several pharmaceutical active compounds, including
atropine from Atropa belladonna, quinine and quinidine from Cinchona Alkaloids are nitrogen-containing secondary metabolites of plants that
spp., digoxin from Digitalis spp., codeine from Papaver somniferum, and are synthesized and widely distributed in the leaves (Hyoscyamus niger),
vincristine and vinblastine from Catharanthus roseus. The vast majority stem bark (Cinchona officinalis), roots (Rauwolfia serpentina), and fruits
of these drugs cannot yet be commercially manufactured and must, (Strychnos nux-vomica) of some common flowering plant families. Among
therefore, be derived from wild-or cultivated-plants [3]. over 4,000 different plant species, more than 3,000 different types of
alkaloids with diverse therapeutic properties have been identified,
Artemisinin, derived from the Chinese herb Artemisia annua, is used in the which exhibit anti-inflammatory, antitumor, antiviral, antibacterial,
treatment of multidrug-resistant malaria. Silymarin, which is extracted anti-asthmatic, antiarrhythmic, anti-obesity, anti-parasitic, narcotic,
from the seeds of the Silybum marianum plant, is used to treat liver sedative, hypocholesterolemic, cardiovascular, hepatoprotective, and
issues. Paclitaxel, derived from Taxus brevifolia, is used in the treatment nephroprotective effects [4-11]. The consumption of many alkaloids
of a variety of malignancies, including lung, ovarian, and breast cancer. in adequate doses is beneficial for health, while overdoses of alkaloids
These are just a few examples of plant-derived compounds that have been might be poisonous and could even cause death [4,12-19].
synthesized and commercialized as pharmaceuticals in recent years [1].
It is assumed that narcotine was the first plant alkaloid extracted in
Through increased insights into medical science and clinical 1803 by Pierre Sobriquet, a French chemist, in Paris [20], followed by
observations, there is indestructible evidence suggesting that existing morphine in 1806 by Friedrich Wilhelm Adam Sertürner, a German
plant-derived compounds are finding new applications. For example, pharmacist [21]. The term “alkaloid” (like alkali) was first used by
forskolin, an alkaloid derived from Coleus forskohlii and an active W. Meitner in 1819 for substances that behaved like alkali [22]. It is
Singh et al.
Asian J Pharm Clin Res, Vol 15, Issue 7, 2022, 47-58
because the majority of plant alkaloids are weak bases, with a few ranges from 0.1 to 4.25 mg/g of chili tissue (Fig. 2) [37]. Capsicum
exceptions, such as theobromine and theophylline (amphoteric) [23]. frutescens, Capsicum annuum, and Capsicumchinese were found to
carry 0.22–20 mg of total Capsaicinoids per gram of dry weight of
Although alkaloids consist of one or more carbon rings and a nitrogen peppers [38,39]. The chili plant is thought to produce such compounds
atom with a variable location on the ring, their chemical structure varies as defense compounds against fungi, bacteria, and herbivores [40].
greatly among alkaloids as well as plant families [24]. The majority of
alkaloids are non-volatile, crystalline, bitter and colorless in their pure The culinary and medicinal history of Capsicum dates back to
form, the exceptions being nicotine, pilocarpine and coniin (liquid), 7000 BC [41]. People in hot climates have long been using capsicum to
colchicine and berberine (yellow), and canadine (orange) [25]. manage extreme heat by improving heat-dissipation regulation through
capsaicin-induced skin vasodilation and perspiration [42]. Coughing,
CAPSAICIN dry mouth, bronchitis, gastric ulcers, backaches, cholera, gout, hydration,
rheumatism, cramping, dysentery, dyspepsia, and dentistry are all folk
Capsaicin is responsible for the distinctive pungent taste of chili; it is
medical uses for capsicum [43,44]. Despite its widespread use, little was
a naturally occurring vanilloid alkaloid found in adequate amounts
known about the biological action of capsaicin until recently, when its
in the placental tissue and, to a lesser extent, in the seeds and fruit
unique actions on sensory neurons were discovered [27].
pericarp of chilies [26]. Capsaicin’s spicy nature is due to its vanillyl
moiety, which is also responsible for its detrimental consequences
Capsaicin’s therapeutic effects were first discovered in the 19th century,
when used therapeutically [27]. Capsaicin is a highly volatile,
when it was widely used by Westerners to ease itchy or scorching feelings
hydrophobic, odorless, and colorless alkaloid with a molecular weight
in the extremities [45]. Buchheim (1873) and Hőgyes (1878) were
of 305.4 kDa and a melting point of 62–65°C. Capsaicin has a vanillyl
among the first observers to detect the increased gastric-juice secretion
(methyl catechol) head group and an aliphatic tail that are linked by a
in addition to the incinerated feeling generated by capsicol (partially
centralized amide bond (Fig. 1) [28].
purified capsaicin) when it came into contact with mucosal membranes,
confirming the compound’s early pharmacological properties [46,47].
In 1816, Christian Friedrich Bucholz [de] (1770–1818) first extracted
With the advancement in capsaicin research, a transient receptor potential
the impurity compound from the genus Capsicum and named it
(cation) channel of the vanilloid receptor family, subtype 1 (TRPV1),
“capsaicin” after the name of the genus Capsicum. [26]. Capsaicin was
was identified as the capsaicin receptor [48]. TRPV1 is composed of
extracted almost in pure form by John Clough Thresh (1850-1932), who
six transmembrane domains. It has a short, pore-forming hydrophobic
nomenclated it as “capsaicin” in 1876 [29-31]. However, Karl Micko
stretch between the fifth and sixth transmembrane domains. TRPV1 is
extracted the pure form of capsaicin in 1898 [32,33]. Nelson in 1919
composed of six transmembrane domains. It has a short, pore-forming
first determined the chemical composition and also partially described
hydrophobic stretch between the fifth and sixth transmembrane domains.
the chemical structure of capsaicin [33]. Ernst Spath and Stephen F.
TRPV1 is activated by noxious heat (above 43 degrees Celsius), acid
Darling chemically synthesized capsaicin for the first time in 1930 [34].
(pH 5.9), voltage, and a variety of lipids. Capsaicin activates TRPV1, which
results in cation influx and a variety of physiological responses [49].
Uh Kosuge and Inagaki (Japanese pharmacists) identified and
extracted similar chemical compounds in pepper and named them
TRPV1 is a non-selective, ligand-gated cation channel that acts as an
Capsaicinoids [35,36]. The capsaicin content of different chilies
integrator of a variety of stimuli such as vanilloids, voltage, uncomfortable
is determined using the liquid chromatography technique, which
heat, endogenous lipids, protons, cations, and various inflammatory
mediators. Capsaicin is a highly and prototypical exogenous activator
of TRPV1. The TRPV1 discovery brought about a rebirth of faith in
capsaicin’s therapeutic potential [50,51]. The proposed mechanisms,
which involve TRP1 activation, confirm capsaicin’s analgesic effect as
well as its effect on thermoregulation. Capsaicinoids’ positive effects
in the treatment of obesity, hypertension, diabetes, cardiovascular
disease, gastro-protective, or anti-cancer activity have been evaluated
and partially or entirely established based on these processes [52].
Capsaicin-containing ointments and creams have been used in

medication for decades to treat prolonged chronic body pain. When
Fig. 1: Chemical structure of capsaicin
applied topically, capsaicin is effective in the treatment of allergies,
strep, sore muscles, osteoporosis ailments, diabetes mellitus, and
other pain problems when applied topically. Topical capsaicin is sold
under the trade names Menthacin, Zostrix, and Capzasin-P by a number
of pharmaceutical industries [44]. Authorization of capsaicin as a
medicine has extended its therapeutic value. In 2009, the European
Union and the Food and Drug Administration authorized the use of an
8% capsaicin patches (Qutenza or NGX-4010) for the treatment of acute
and chronic pain.
The EU authorized the use of Qutenza for pain problems such as post-
herpetic neuralgia (PHN), peripheral neuropathic pain (PNP), and HIV-
associated distal sensory polyneuropathy (HIV-DSP) [53,54], whereas
in the United States, the FDA has only approved its usage for PHN [55].
Such investigations have clearly demonstrated capsaicin as a potent
therapeutic agent. Nonetheless, the use of capsaicin in a variety of other
clinical conditions has yet to be investigated [56,57].
PHARMACOLOGICAL POTENTIAL
Fig. 2: Capsaicin content of different chillies by liquid Capsaicin has a wide range of therapeutic applications and uses in
chromatography technique resolving a variety of human disorders due to its analgesic, anti-cancer,
48
Singh et al.
anti-obesity, anti-inflammatory, and anti-oxidant characteristics preventive role in ischemia-induced retinal injuries through endogenous
(Fig. 3) [58]. release of somatostatin (a growth hormone inhibitor) Capsaicin
inhibits the production of LPS-induced pro-inflammatory cytokines
Anti-inflammatory action such as IL-1, IL-6, and TNF- in a time- and dose-dependent manner
Several studies have shown that capsaicin, Capsaicinoids, and capsanoid by upregulating LXRs (ligand-activated transcription factors of the
compounds of chili peppers exhibit anti-inflammatory activity [59]. Studies nuclear receptor superfamily). It indicates that LXRs have the potential
on animal inflammation models have revealed that the anti-inflammatory to facilitate capsaicin-mediated activation of PPARs (ligand-activated
effects of capsaicin were accompanied by the inhibition of inflammatory
transcription factors of the nuclear hormone-receptor superfamily),
cytokines (TNF-, IL-1, and IL-6) and a transcription factor (NFκB) in
and persuading the suppression of NF-B (transcription factor that
a dose-dependent manner [60]. Capsaicin exerts anti-inflammatory
is essential for inflammatory responses) in the lipopolysaccharide-
responses in mice in lipopolysaccharide-induced inflammation and
induced inflammatory response [64,65].
lipopolysaccharide-stimulated BV 2 microglia cells by reducing the release
of inflammatory cytokines such as TNF-, IL-1, and IL-6 through inhibiting
Capsaicin appears to have anti-inflammatory effects on the gastritis of
the nuclear factor-kappa B (NF-kB) and microtubule-associated protein
gerbils (Mongolian rodents) induced by Helicobacter pylori. Further,
kinase signaling pathways. (Fig. 4) [61,62].
capsaicin greatly reduced neutrophils inside the antrum and corpus
Capsaicin and Dihydrocapsaicin (a capsaicinoid found in chili peppers) (stomach parts); it also reduced mononuclear cell infiltration and
have anti-inflammatory activity by inhibiting nitric oxide (NO) the presence of heterotopic proliferative glands inside the corpus.
production and activation of heme oxygenase1 in LPS-stimulated Capsaicin also inhibited TNF (tumor necrosis factor-) mRNA expression
RAW264.7 macrophages; it also has an anti-inflammatory and and phospho‐IκB‐α production in the antrum. These observations
suggest that capsaicin may be useful in the prevention and treatment
of Helicobacter pylori-related stomach malignancies too [66].
From the above discussion, one might conclude that capsaicin is

a promising therapeutic agent that might be used to develop novel
drugs for both the treatment and prevention of neuro-inflammatory
disorders [62]. Even though this chemical has been used for years to
treat inflammatory problems, its therapeutic relevance to preventing
or treating inflammatory diseases requires further investigation [60].
Anti-cancer actions
According to the World Health Organization (WHO), cancer is a serious
and substantial public health concern, and it is the second greatest
cause of death worldwide [67]. The correlation between nutritional
deficiencies and cancer is obvious. Eating a balanced diet and lifestyle
improvement are major factors that can assist in reducing the cancer risk
factor. Aloe vera, berries, curcuma, tea, tomatoes, citrus fruits, olive oil,
and honey are examples of foods containing bioactive constituents that
can influence the beginning as well as the progression of carcinogenesis
through their significant impact on cell proliferation, apoptosis, and
metastatic mechanisms [68-70]. Therefore, in the public and private
health-care systems of the common population, taking initiatives to
Fig. 3: Various pharmacological and physiological potential of minimize smoking, improving diets, and enhancing physical exercise
capsaicin should be of higher priority [71].
Fig. 4: Anti-neuroinflammatory responses of capsaicin
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Singh et al.
Both in vitro and in vivo studies have reported that capsaicin has a adenocarcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma,
positive effect on the proliferation of cancer cells by inhibiting cell-cycle and multiple myeloma (Table 1).
progression, autophagy, apoptosis induction, and cellular metabolic
stimulation (Fig. 5), [72-76], in various cancer cell lines, including Capsaicin can be used to treat other types of malignancies, such as
colon cancer, gastric cancer, breast cancer, cutaneous-cell carcinoma, those of the pancreas, prostate gland, tongue, and lungs, and, therefore,
is considered among the potential chemotherapeutic agents [77,78].
Capsaicin has been shown to trigger the death of cancerous cells in
a number of clinical trials, but the exact related mechanisms are still
unconfirmed. However, intracellular events, including the rise of
reactive oxygen species (ROS) and Ca2+, stimulation of transcriptional
regulators (NFB and STATs) and the disruption of the transition
potential of the mitochondrial membrane, along with processes
concerned with AMP-dependent kinase and phagocytosis, have been
well established in this regard [77].
Capsaicin was found to have higher cytotoxicity against cancer cells

than normal ones. It induced cell death and autophagy (a process
that destroys long-lived proteins, damaged organelles, and protein
aggregates) in human melanoma and the OE19 cell line, and results
suggest that it might be a novel candidate-medication for melanoma
treatments [79,80]. Capsaicin and DIM (3, 3’-diindolylmethane, an
active compound in cruciferous vegetables) worked synergistically
to inhibit cell proliferation and induce apoptosis in colorectal cancer
by modulating the transcriptional activity of transcription factors NF-
kB (nuclear factor kappa-B) and p53 (tumor-suppressor protein), as
Fig. 5: Anti-cancer actions of capsaicin through employing well as genes associated with apoptosis (genetically-programmed cell
different pathways death) [81].
Table 1: Capsaicin’ role in different anti-cancer mechanisms
Type of cancer Cell lines Role of capsaicin References

1. Skin cancer A375 and C8161. • Triggered the cell apoptosis and autophagy in melanoma cells. [80]
2. Cholangio carcinoma HuCCT1. • Inhibited the cell migration and invasion via the blockage of Hedgehog- [94]
pathway activation.
3. Breast Cancer MCF-7and MDA-MB-231. • Down-regulated the FBI-1-mediated NF-κB pathway, capsaicin [84]
MCF‐7, BT‐20. significantly inhibited proliferation and induced apoptosis in Breast- [95]
BT‐474, SKBR‐3, MDA cancer cell lines. [96]
MB231. • Inhibited cancer cell growth by inducing apoptosis and Cell cycle arrest
through the mitochondrial pathway.
• Inhibited cell growth and migration by inducing cell‐cycle arrest and
apoptosis through suppression of EGFR and HER‐2 and the activation
of ERK and cyclin D.
4. Liver cancer SMMC-7721. • Induced the apoptosis, generated superoxide and stimulated of both [86]
LM3. JNK and p38 MAPK pathways. [87]
• Capsaicin in combination with sorafenib achieved a markedly stronger
induction of apoptosis by increasing caspase-3, Bax and poly(ADP-
ribose),polymerase activity and inhibiting Bcl-2, and induction of
autophagy by upregulating the levels of beclin-1 and LC3A/B II, and
enhancing P62 degradation.
5. Gastric cancer AGS. • Inhibited the invasion and migration by modulating POU3F2-mediated [92]
SGC‐7901. tNOX down‐regulation. [97]
SW-480. • Inhibited the cell growth by reactivating hMOF and associated [98]
H4K16ac.
• Inhibited the cell growth by reactivating hMOF and associated
H4K16ac.
6. Bladder cancer 5637. • Inhibited the proliferation by induction of cell-cycle arrest, and [99]
5637, T24. apoptosis through inhibition of CDK2, CDK4 and CDK6. [100]
TSGH8301, T24. • Induction of ROS production and mitochondrial membrane [100]
depolarization.
• Induced the autophagy and EMT through Hedgehog signaling pathway
7. Prostate cancer PC‐3, LNCap, DU‐145. • Inhibited the cancer cell migration by down‐regulation of MMP9 [101]
PC‐3. expression through AMPK–NF‐κB signaling pathway. [102]
PC‐3, LNCap, RWPE‐1. • Induced the apoptosis, and disruption of mitochondrial inner Tran’s [103]
membrane potential by ROS generation, and activation of caspase 3,
and inhibited the proliferation through the induction of ER stress and
GADD153/ CHOP up‐regulation.
• Inhibited the cell proliferation by inducing apoptosis through inhibiting
the NF‐κB pathway
50
Singh et al.
Capsaicin caused the death of prostate cancer cells in a time-and cell proliferation in MGC-80 and SGC-7091 GC cell lines, and suggesting
concentration-dependent manner, elevated the levels of the autophagy that Capsaicin has the ability to decrease the proliferation, migration
marker microtubule-associated protein ‘light chain 3-II’ (LC3-II), and and invasion of GC cells through regulation of Tumor-Associated
facilitated the accumulation of p62 (a cargo protein). P62 is a classic NADH Oxidase (tNOX) involving POU Domain Transcription Factor
autophagy receptor (a self-digesting mechanism responsible for the POU3F2 [92]. Capsaicin directly engages with tNOX, resulting in its
elimination of damaged organelles); it is a versatile protein found degradation through the ubiquitin-proteasome and the autophagy-
throughout the cell, where it participates in various signal transduction lysosome systems. In the cells of p53-mutated HSC-3 (human tongue
pathways and the proteasomal destruction of ubiquitinated proteins. squamous carcinoma cell-line), capsaicin triggered both autophagy
It demonstrated that capsaicin-induced non-proliferation of prostate (body’s automatic system to clean out damaged cells), and apoptosis
cancer cells contributed to the underlying capsaicin-mediated anti- (genetically-programmed cell death). Thus, Capsaicin could be used as
carcinogenic mechanism [82]. Capsaicin increased ROS-signaling- a potential therapeutic strategy against oral cancer. It is hoped that this
dependent autophagy in human hepatoma by phosphorylating signal study may lead to new treatments for the disease [93].
transducer and activator of transcription 3 (p-STAT3). This shows that
suppressing autophagy in hepatocellular carcinoma might improve Pain-relieving action
capsaicin-induced apoptosis [83]. Capsaicin has been shown to be effective in the treatment of
certain serious neuropathy problems when administered topically,
Capsaicin reduced proliferation and induced apoptosis in breast cancer intradermally, or orally [104]. When administered intravenously,
cells through down-regulating the FBI-1-mediated NF-B pathway. subcutaneously, or topically, capsaicin significantly improved
The findings suggested that capsaicin could be an effective way of hyperalgesia and pain relief [105]. Capsaicin has been reported to have
targeting the FBI-1, which is involved in anti-proliferation and pro- antinociceptive properties, primarily utilizing the TRPV-1-dependent
apoptosis processes. FBI-1 has been characterized as a proto-oncogenic pathways. Topical administration of high doses of capsaicin is often
protein that represses tumor suppressor ARF gene transcription. used to relieve chronic pain, TRPV1-generated repetitive excitation, and
FBI-1 expression was increased in many cancer tissues; it inhibited epigastric complications in people with irritable bowel syndrome; it
transcription of the Rb gene, a tumor suppressor gene involved in cell relieves dyspepsia by desensitizing nociceptive pathways [106]. Topical
cycle arrest [83,84]. According to a National Cancer Institute study, capsaicin-formulations, administered in high doses, control a wide
capsaicin could have been a potential therapeutic strategy for patients spectrum of peripheral neuropathic pain-implications by countering
with breast cancer [84]. the progressive alterations in the nerve system [107]. Capsaicin
appeared to be effective therapeutic agent to treating moderate pain in
Capsaicin could trigger the generation of ROS in the cells of HCC clinically or radiologically diagnosed osteoarthritis patients [108].
(hepatocellular carcinoma, a liver cancer), destroy the mitochondrial
membrane potential, and stimulate the reactive oxygen scavenger Capsaicin provides effective long-term pain relief and reductions in
“n-acetyl cysteine” (N-acetyl-cysteine, or NAC), resulting in the area and intensity of pain in adult patients with chronic pain,
increased apoptosis of human HCC-cells [85]. According to Bu inducing a faster onset of analgesia and exerting significantly fewer
et al. 2015 [86], capsaicin induced the cell-death of HCC and SMMC- systemic adverse-effects compared to conventional therapy [109].
7721 (a hepatocellular cancer cell line) through ROS generation and Besides providing significant pain relief, it has also been shown to
activation of the JNK (Jun N-terminal kinase) and p38 MAPK (p38 remove tiredness and depression, improving sleep and overall quality
mitogen-activated protein kinase) pathways. Dai et al. (2018) [87] of life [110]. Noncompliance is avoided using a single application
found that capsaicin and sorafenib not only increased the activity of capsaicin. However, because of the strong burning sensation it
of key apoptosis-inducing proteins such as caspase 3, Bax, and poly generates, it must be used under strict supervision and after a local
(ADP-ribose) polymerases (PARPs), but also inhibited the anti- anesthetic injection. Since all capsaicin effects on TRPV1 are reversible,
apoptotic protein Bcl 2 (B cell lymphoma-2) by upregulating the levels it is recommended that the application be repeated after 12 weeks [110].
of autophagy-related genes (Be The treatment increased the induction
of apoptosis by promoting the degradation of the specific autophagy The European Medicines Agency (EMA) has currently approved a high-
protein p62; it could also prevent cancer-cell invasion and metastasis dose of 8% capsaicin-patch for the treatment of postherpetic neuralgia
by up-regulating E-cadherin and by down-regulating N-cadherin, (a painful condition that affects the nerve fibers and skin), associated
vimentin, MMP-2, and MMP-9. pain, HIV-related distal sensory neuropathy, and diabetic neuropathy.
The intensity of pain diminishes dramatically after 1, 2, or 3 weeks of
Capsaicin suppressed bladder cancer cell development by inhibiting capsaicin treatment [111]. By selectively ablation of potential vanilloid
tNOX (tumor-associated NADH oxidase) and SIRT1 (Sirtuin1), subtype 1 TRPV1+ afferent terminals, a single focused injection
suppressing the proliferation, pausing the migration, and delaying the of capsaicin produces long-lasting analgesia for neuropathic pain.
cell-cycle progression in cancer cells [88]. Capsaicin also improves cell Capsaicin can be used to treat chronic pain as a stand-alone treatment
migration in bladder cancer cells by increasing cortactin and -catenin or in conjunction with other drugs. Furthermore, capsaicin should
acetylation, inhibiting and promoting the inhibition of SIRT1, MMP-2, be a viable treatment option for psychiatric patients suffering from
and MMP-9 [88,89]. Capsaicin inhibited the metastasis (reformation persistent pain [112].
of cancer-tissue in different body-parts) of papillary thyroid-cancer
cell-line (B-CPAP). By activating TRPV1 and significantly inhibiting the Action against obesity and weight control
cancer-related proteins MMP-2 (matrix metalloproteinase-2) and MMP-9 Obesity is becoming more common as a result of modern lifestyles in
(matrix metalloproteinase-9), it was demonstrated that targeting TRPV1 both developed and developing countries. Obesity is a condition in
activities might be a viable strategy for the treatment of cancer [90]. which the body-fat level of a person gets increased to the point of health
risk. Obesity is defined as having a body weight of 20% more than the
Through the AMP-activated protein kinase (an energy sensor that average and serves as a portent for various health problems, particularly
regulates cellular metabolism), the combination therapy of docetaxel cardiovascular disease, diabetes mellitus, cancer, hypogonadism, and
(an antineoplastic agent) and capsaicin suppressed the cancer growth osteoarthritis [113].
in the cells of LNCap and PC3 (cultured cancer cell-lines), which
suggests a clinically significant approach to the treatment of prostate Capsaicin has been shown to exert an anti-obesity effect in a variety
cancer [91]. Capsaicin has been shown to reactivate low-expressed of ways, including thermogenesis (dissipation of energy through heat
epigenetic regulatory enzymes in GC cells (human males absent on the production), satiety (overeating), fat oxidation, and increased energy
first, hMOF), stimulate protein expression, and catalyze the enzyme expenditure. It can reduce energy intake, inhibit adipogenesis, decrease
activity regarding the acetylation of histone H4K16, thus limiting the GC pancreatic and lipoprotein lipase activity, increase lipolysis in adipose
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Singh et al.
expression of the proteins, namely, PPAR (peroxisome proliferator-

activated receptor), C/EBP (CCAAT/enhancer binding proteins),
and leptin, whilst it elevated the adiponectin protein content, thus
accelerating apoptosis and inhibiting fat accumulation in the 3T3-L1
cell-line concerned with preadipocytes and adipocytes. As a result of
capsaicin administration, TRPV-1 expression was reduced in adipose
tissue, adiponectin expression was increased in adipose tissue, and
PPAR and PGC-1 expression were enhanced in the liver [132]. Capsaicin
has been shown to enhance browning in white adipocytes by activating
the PPAR/3-AR signaling pathway. Thus, capsaicin may be worth
considering as a treatment option for obesity (Fig. 6) [133].
Conclusively, these investigations revealed that capsaicin might help

induce weight loss by reducing adipogenesis and regulating gene
functions related to lipid metabolism.
Action against diabetes

Diabetes is a metabolic disorder in which the body’s natural ability
to regulate blood sugar levels is either inept or impaired, resulting
in an inefficient or inappropriate response to the insulin hormone.
Chili and its constituent, capsaicin, have been shown to have an anti-
diabetic response through a number of different mechanisms, such as
those inhibiting the activities of polysaccharide hydrolyzing-enzymes
α-amylase and α-glucosidase [134,135], regulating body weight, and
exerting hypolipidemic effects [136].
Fig. 6: General underplaying mechanism of anti-obesity activity of In fact, capsaicin-mediated TRPV1 stimulation led to improved insulin
capsaicin through thermogenesis, lipolysis, adipogenesis, energy sensitivity in liver cells, suppression of inflammatory response,
expenditure regulation of glucose homeostasis, increased insulin sensitivity
in peripheral tissues, stimulation of secretion of glucagon-like
tissue, inhibit adipocyte differentiation, and change adipokine release peptide-1 (GLP1), improved, glucose metabolism, β-cell security from
from adipose tissues. (Fig. 6) [114-122]. apoptosis, significant decline of fasting glucose and insulin levels,
and adipocytokine-gene expression [49], resulting in the production
Capsaicin’s role as an anti-obesity drug has been established in of adipocytokine, which is involved in various processes, including
several laboratories and clinical studies. Further, intake of capsaicin- inflammation, fibrosis, and thermogenesis.
containing diets is correlated with the minimum risk of obesity in
overweight or obese patients [123]. Enhanced fat-oxidation may Gestational diabetes mellitus (GDM) is a condition in which placental-
contribute to increased energy expenditure, and an increase in oxygen secreted hormones make a person unable to use insulin, causing blood-
consumption may be advantageous for weight loss [124]. In a double- sugar levels to rise rather than simply being assimilated by the cells.
blind, randomized and placebo-controlled study, it was observed that This may have a significant impact on the long-term health of females
capsaicin reduced body weight by 0.9 kg when overweight or obese as well as their descendants. Ladies with GDM experience pregnancy-
adults were treated with 6 mg/day capsinoids for 12 weeks [125]. related health problems too, such as hypertension and obstructed
Another randomized double-blind study showed that participants labor. Capsaicin-containing supplements were found to significantly
within the age-group of 30–65 years and with a BMI (body-mass index) improve postprandial hyperglycemia, hyperinsulinemia, and fasting
greater than 23 kg/m2, who were given capsinoids (10 mg/kg/day) for lipid metabolic alterations in women with gestational diabetes [137].
4 weeks, safely lost their weight through increased VO2 max (a measure Capsaicin might reduce glucose tolerance by suppressing inflammatory
of the maximum amount of oxygen one can utilize during exercise), responses in adipocytes (fat-storing cells) in obese patients.
resting energy expenditure, and fat oxidation [126]. Consumption of capsaicin in the daily diet prevented the obesity
brought about by induced sugar intolerance and by increased oxidation
Brawn adipose tissues (BAT) are believed to play a significant role in of fatty acids in the adipose and liver tissues, which are significant
cold-induced non-shivering thermoregulation in order to control the peripheral sites that influence insulin resistance [132].
temperature of the body, which is expected to be an effective treatment
for obesity-associated metabolic ailments in human beings [127]. As per Action against cardiovascular diseases
Saito and Yoneshiro 2013 [128], capsaicin increased energy expenditure Capsaicin has a protective impact on the cardiovascular system through
by activating the BAT in almost the same manner as cold temperatures reducing blood pressure, mitigating coronary disease (damaged blood
do, leading to increased energy expenditure through non-shivering vessels), and preventing myocardial infarction (heart attack), which is
thermogenesis (an increase in metabolic heat production, above associated with its anti-oxidative potential [138]. In studies, it has been
the basal metabolism, which is not associated with muscle activity). demonstrated that dietary capsaicin reduces the risk of atherosclerosis
In an 8-week clinical experiment employing obese people, 9 mg of (buildup of plaque inside arteries), hypertension, cardiac hypertrophy
capsaicin elevated the BAT activity and increased thermogenesis. The (abnormally large heart), and stroke (reduced blood supply to
findings imply that dietary capsaicin consumption may contribute the brain) [139]. Regular consumption of chili by heart patients for four
to weight control by decreasing energy intake and by triggering BAT weeks is believed to enhance the resistance of plasma lipoproteins against
activation [129]. Adipogenesis (differentiation of pre-adipocytes into oxidation as a result of capsaicin’s antioxidant activity (Fig. 7) [140].
adipocytes and the fat-storing cells) is the fundamental and distinctive
mechanism of the accumulation of fatty adipose tissue [130,131]. Capsaicin inhibits platelet aggregation through TRPV1-dependent
or -independent pathways [141-143]. It travels across the platelet
Hence, reduced adipogenesis and lipogenesis (synthesis of fatty acids plasma membranes, altering membrane fluidity [131], thereby eliciting
and triglycerides) may potentially contribute to a reduction in obesity. Ca2+ discharge from intracellular platelet reserves and, consequently,
Hsu and Yen 2007 [130] determined that capsaicin suppressed the inducing the ADP and platelet activation triggered by thrombin (the
52
Singh et al.
investigations suggests that the disorder may be associated with

inflammatory responses, which include microglial activation,
infiltration of peripheral immune cells, specifically macrophages, and
impairment of the blood-brain barrier (a network of blood vessels
and tissue, made up of closely-spaced cells that helps keep harmful
substances from reaching the brain) [154,155].
Both experimental as well as clinical evidence indicates that activated

glia (non-neuron cells of the central nervous system) potentially produce
NADPH oxidase-derived ROS and perhaps even myeloperoxidase-
derived reactive nitrogen species (RNS), both of which trigger oxidative
damage of DA neurons (dopaminergic neurons of the mid-brain)
(Fig. 8), [156-158]. TRPV1 (a receptor protein), which is stimulated by
capsaicin, appears to be widely expressed in the brain, predominantly in
DA neurons, along with glial cells (microglia and astrocytes) throughout
the SN (substantia nigra, a mid-brain dopaminergic nucleus having a
role in motor movements).
Recent investigations have proved that TRPV1 might be a potential

therapeutic approach to treat Parkinson’s disease [159]. For example,
TRPV1 protects DA neurons in the SN of a mouse lesioned by the ions of
such drugs as MPP (1-methyl-4-phenylpridium) and MPTP (1-methyl-4-
Fig. 7: Role of capsaicin in cardio metabolic disease management phenyl-1, 2, 3, 6-tetrahydropyridine), or by 6-OHDA (6-hydroxydopamine,
a neurotoxin) through suppressing glial-induced oxidative damage and
coagulation factor that stops bleeding). Atherosclerosis has been systemic inflammation [160-162]. Nam et al. (2015) [163] observed
associated with the initiation and progression of atherosclerosis, that capsaicin-induced activation of astrocytic TRPV1 resulted in the
whereas capsaicin has been shown to delay the onset of such oxidation production of ciliary neurotrophic factor (CNTF), which inhibited
and/or slow its rate, leading to a rise in LDL resistance to oxidation [133]. the neurodegeneration that might prove a novel therapeutic target
Capsaicin decreases atherosclerosis (build-up of plaque inside arteries) for the treatment of Parkinson’s disease. Capsaicin contributed to
through accelerating ATP-binding cassette transporter A1 (ABCA1) the reduction of pro-inflammatory mediators and prevented the
and diminishing the expression of LDL-related protein 1 (LRP1) in the degeneration of nigral dopaminergic neurons in the LPS-lesioned SN.
aorta (main artery taking blood from the heart to the rest of the body)
through TRPV1 stimulation (Fig. 7) [145]. Further, capsaicin transitioned the pro-inflammatory M1 microglia/
macrophage population to an anti-inflammatory M2 state, resulting
The presence of capsaicin-sensitive sensory nerves in the in dopamine neuron survival. As a result, TRPV1 activation by
cardiovascular system aids in the regulation of cardiovascular function capsaicin is anticipated to have therapeutic promise in the treatment
by releasing CGRP (calcitonin gene-related peptide) via TRPV1 and of neurodegenerative disorders such as Parkinson’s disease [164]. In
SP (substance P, a neuropeptide) [146,147]. According to Yang et al. MPP+-lesioned rats, delayed capsaicin treatment resulted in partial
(2010) [148], dietary capsaicin had positive therapeutic effects on functional recovery by increasing the activity of the nigral tyrosine
hyperlipidemia and atherosclerosis by reducing oxidative stress and hydroxylase (TH) enzyme, the striatal levels of nigrostriatal dopamine
endothelial dysfunction through activation of endothelial TRPV1 and (DA), and its metabolites, utilizing the ciliary neurotrophic factor
nitric oxide (NO)-dependent pathways, which might be a unique way (CNTF), endogenously derived from CAP-activated astrocytes via
to prevent cardiovascular disease. Another study found that capsaicin TRPV1 [165]. Abdel et al. explored the effects of capsaicin on epileptic
had an effect on the endothelial nitric oxide synthase (eNOS) pathway seizures, neuronal damage, and oxidative damage using a rat model
as well as CGRP-mediated endothelium-dependent and -independent of status epilepticus generated by intramuscular administrations
mesenteric artery relaxation [83]. of pentylenetetrazole (PTZ) drug. They revealed that capsaicin or
phenytoin reduced the neuronal damage when applied at 2 mg/kg
Karale et al., 2020 [150], revealed that capsaicin played a potential role and that capsaicin/phenytoin entirely protected the neuronal damage
in cardio toxicity induced by doxorubicin (DOX) through suppressing by lowering the MDA (malondialdehyde) and nitric oxide levels in the
serum markers and oxidative stress in heart tissues. Another study brain, and by decreasing the activity of GSH (reduced glutathione) and
confirmed that capsaicin could minimize mitochondrial dysfunction PON-1 (human-serum paraoxonase) (Fig. 8) [166]. These findings
and was able to protect cardiomyocytes (cells that generate the demonstrate that capsaicin might be effective for the treatment of DA
contractile force in the intact heart) against anoxia/re-oxygenation abnormalities associated with Parkinson’s disease.
(A/R)-induced damage and apoptosis [150]. Capsaicin stimulated
autophagy by increasing the expression of the 14-3-3 protein, Capsaicin and/or resveratrol (a polyphenol that acts as an antioxidant)
decreasing inflammatory responses caused by oxidative damage, protected mouse cerebral cortical neurons from glutamate-induced
restoring mitochondrial function, and protecting cardiomyocytes from neurotoxicity; glutamate significantly reduced cell viability, whereas
lipopolysaccharide (LPS)-induced destruction [151]. These findings capsaicin and/or resveratrol administration significantly increased
indicate that capsaicin might be effective agent in the prevention of cell viability by decreasing glutamine-induced ROS production and
cardiovascular disorders such as atherosclerosis and coronary heart apoptotic neurotoxicity [167]. Capsaicin supplementation was crucial
disease. in rescuing DA neurons, promoting striatal DA functions, and refining
cognitive and behavioral recovery in treated animals by lowering the
Role of capsaicin in Parkinson’s disease generation of pro-inflammatory cytokines as well as ROS/RNS from
Parkinson’s disease (PD) is a neurodegenerative disorder characterized activated microglia-derived NADPH-oxidase.
by the cumulative destruction of dopamine neurons in the substantia
nigra pars compacta (a portion of the mid-brain) and the degradation This suggests that capsaicin and its analogues might be potential
of DA fibers inside the striatum (a brain portion involved in voluntary therapeutic agents for the treatment of Parkinson’s disease and other
movements) [152]. Although the etiology of Parkinson’s disease is neurodegenerative syndromes characterized by chronic inflammation
unknown [153], information from both human-and other animal- and microglial activation-induced oxidative damage [160].
53
Singh et al.
Fig. 8: (A). A possible etiology of Parkinson’s disease. (B). General mechanism associated with possible role of capsaicin in Parkinson’s
disease management
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THERAPEUTIC PROPERTIES OF CAPSAICIN: A MEDICINALLY IMPORTANT

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THERAPEUTIC PROPERTIES OF CAPSAICIN: A MEDICINALLY IMPORTANT BIO-ACTIVE

Keywords: Alkaloids, Capsaicin, Capsaicinoids, Pharmacological, Therapeutic.

INTRODUCTION phytochemical from Stephania glabra, has been recognized as an

Capsaicin-containing ointments and creams have been used in

From the above discussion, one might conclude that capsaicin is

Fig. 4: Anti-neuroinflammatory responses of capsaicin

Capsaicin was found to have higher cytotoxicity against cancer cells

Table 1: Capsaicin’ role in different anti-cancer mechanisms

Type of cancer Cell lines Role of capsaicin References

expression of the proteins, namely, PPAR (peroxisome proliferator-

Conclusively, these investigations revealed that capsaicin might help

Action against diabetes

investigations suggests that the disorder may be associated with

Both experimental as well as clinical evidence indicates that activated

Recent investigations have proved that TRPV1 might be a potential

According to Liu et al. [168], an imbalance between the expression of REFERENCES

5995(00)80004-6 s10886-005-9017-4, PMID 16572297

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