Garlic and Its Role in Arthritis Management

Abstract

Garlic is a proven potential natural remedy for arthritis. The advancement of medical
science and research has made it possible to exploit its various components for the targeted administration of this wonder drug. Making nanoformulations of garlic compounds will help further the easy use and bioavailability for arthritis patients. Also, preclinical and clinical studies should be conducted to elucidate garlic’s beneficial and risk effects withrespect to arthritis.

Full text

CHAPTER 14
Garlic and Its Role in Arthritis
Management
Shalini Pareek*, Meenal Dixit*, Sumit Govil*, Indrani Jadhav*, Divya
Shrivastava*, Maryam Vahedi
†
, Prakash S. Bisen*
,‡
*
School of Life Sciences, Jaipur National University, Jaipur, India
†
Department of Horticultural Science, Faculty of Agricultural Science and Engineering, University of Tehran, Tehran, Iran
‡
Research and Development Division, Tropilite Foods Pvt Ltd, Gwalior, India
1. INTRODUCTION
In the era of development and globalization, human beings are paying less attention to
their routine lifestyles, leading to various medical cases. The most prevalent and common
of all are the musculoskeletal diseases that lead to various forms of joint and bone diseases,
collectively termed arthritis. Arthritis is now not only prevalent in elderly people but also
in younger generations. Research is ongoing to detect the mechanism and cure for the
deadly and painful disease leading to joint destruction.
In rheumatoid arthritis, the lining layer becomes thick and the inflammatory cells
infilter into the sublining portion. Fibroblasts give the appearance of transformed cells
in this lining layer as a result of the influence of the proto-oncogenes of the cell cycle.
Cytokines such as IL-1, IL-10, IL-4, and TNF-αthat are present in the synovium pro-
duce inflammation and joint-destroying enzymes such as serine protease, matrix metal-
loproteinase, etc. Research has been done to target these enzymes and inflammatory
factors and suppress their activity as a cure for arthritis.
1
The role of transient receptor potential receptors—especially the transient receptor
potential vanilloid 1 and the transient receptor potential ankyrin 1 channels, commonly
known as TRPV1 and TRPA1—are reported to play an important role in inducing pain
and inflammation in arthritis.
2, 3
The functional dependence of TRPs on COX-2 path-
way sensitization in arthritis has been described.
4
Arthritis is reported to have a natural cure with the help of various natural herbs. One
of the best reported is garlic. Garlic is a pungent wonder drug in the treatment of various
major diseases such as cardiac diseases, cancer, high cholesterol, aging, arthritis, viral
fevers such as dengue, etc.
5–11
Aged garlic is reported to have immunomodulatory func-
tions in mice bearing Sarcome-180.
12
The role of an important organosulfur compound
in garlic called allicin in treatments for cancer, microbial infections, arthritis, and
245
Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases ©2019 Elsevier Inc.
https://doi.org/10.1016/B978-0-12-813820-5.00014-3 All rights reserved.

cardiovascular diseases has been reviewed by Rahman.
13
The various methods of using
and extracting ajoene from garlic for different diseases were patented by Tatarintsev and
coworkers (US5856363A).
14
In further sections, we will discuss the role of garlic and its compounds as a miraculous
drug with special reference to arthritis.
2. GARLIC—A NATURAL REMEDY FOR ARTHRITIS
Garlic (Allium sativum) is one of the oldest cultivated herbal and spice plants. It was used in
World War II for the treatment of wounds.
15
The Dietary Supplement Health and Edu-
cation Act of 1994, passed by the US Congress, claimed that garlic possesses various
health supplements. This wonder spice contains various sulfur compounds, protein,
and inorganic elements such as selenium, copper, iron, polyphenols, and various amino
acids
16
(Figure 14.1).
In Charaka Samhita, garlic is reported as a drug for the heart as well as arthritis. On the
other hand, in Historica Naturalis, garlic is reported to be a wonder drug for animal bites,
digestion-related problems, and arthritis.
17
Garlic moxibustion was reported as an effective
treatment in curing patients of gonococcal arthritis.
18
An 86.5% success rate was reported
for arthritis patients in Russia with the administration of alisate, which is a garlic prepara-
tion of a drug.
19
In a survey, garlic has been reported as a natural remedy used by local and
tribal people for the treatment of joints and related diseases.
20
Garlic grounding techniques
play an important role in the yield of chemically effective allicin from fresh garlic. Various
techniques, including bath sonication, probe sonication, microwave extraction and cold
maceration, were used.
21
Microwave radiation was found to be the most effective one.
Garlic soup alone or with the soup of some specific animals such as snakes, sharks, sea
Figure 14.1 Compounds from garlic having antiarthritic and antiinflammatory effects.
246 Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

horses, goats, and chickens is recommended as a natural treatment of arthritis by the
Chinese community.
22
On the other hand, the administration of garlic along with exercise
and meditation has been recommended as a much better treatment than exercise and med-
itation alone for the arthritis patient.
23
Similarly, garlic intake in the form of juice and salad
is suggested in the management of bone diseases and arthritis types.
24
As far as the extraction
procedure is concerned, in comparison to aqueous extracts, methanolic extracts of garlic
were found to be more effective in antiarthritic and antihemolytic activity.
25
The overall
health benefits of garlic are also presented in recent reviews.
26, 27
3. ANTIINFLAMMATORY EFFECTS OF DIETARY GARLIC
The antiinflammatory and immunomodulatory effects of garlic were well reviewed by
Arreola et al.
28
Various sulfur compounds from garlic such as diallyl sulfide, S-allylmercap-
tocysteine, ajoene, etc., are involved in suppressing an important inflammatory factor
called NF-κB.
29, 30
The expression of various inflammatory factors, including nitric oxide,
prostaglandin E
2
, tumor necrosis factor-α, IL-6, and IL-1β, was found to be downregu-
lated as an effect of another sulfur compound Z- and E-ajoene from garlic.
31
Still another
sulfur compound from garlic, alliin, was found to have antiinflammatory properties, evi-
dent by the suppression of activation of various inflammatory compounds.
32
In chondrocyte-like cells, the activity of protease that degrades the matrix decreased as
a result of an organosulfur compound called diallyldisulfide, present in garlic.
33
Diallylsul-
fide from garlic was also reported to inhibit the effect of matrix metalloproteinase and the
tissue inhibitor of metalloproteinase-1 responsible for causing inflammation.
34
The antiinflammatory effect of allicin from garlic was clearly demonstrated by Shin
et al.
35
The fresh raw garlic extract was much more effective than heated raw garlic
extract in reducing the effect of inflammation-inducing cytokines and nitric oxide.
An increase in the activity of the antioxidant Heme oxygenase 1 enzyme was also
observed. The production of TNF-αand IL-6 decreased as an effect of garlic on placental
explants while at higher doses of garlic, a reduction in IL-10 was also observed.
36
The use
of allicin resulted in an enhancement of the expression of chondrocyte cell cycle proteins
D1, CDK4, and CDK 6. As a result, the cell cycle transition from G1 to S phase was
observed.
37
Different onion types and garlic were screened for their free radical scaveng-
ing activity.
38
The highest free radical reducing capacity was observed for garlic.
4. INHIBITORY ROLE OF GARLIC-DERIVED COMPOUNDS IN ARTHRITIS
SIGNALING PATHWAYS
Compounds derived from garlic have been used to specifically target the inflammatory
factors involved in arthritis pathways (Figure 14.2). Thiacremonone (2,4-dihydroxy-2,5-
dimethyl-thiophene-3-one), earlier reported from fungal sps. Acremonium, was isolated
247Garlic and Its Role in Arthritis Management

(A)
(B)
(C)
(D)
(
E
)
34
2
5
OH
O
S
HO
Thiacremonone
Amyloidogenesis
NF-κB
S-Allylmercaptocysteine
Matrix metalloproteinase
Tissue inhibitor of metalloproteinase-1
NF-κBSS
O
NH
Figure 14.2 (A–E) Active compounds from garlic regulating the expression of gene coding for factors or
enzymes involved in arthritis and inflammatory pathways.

from garlic at high temperature (130°C) and pressure.
39, 40
Thiacremonone is known to
have various therapeutic effects such as being anticancerous, antiinflammatory, antiarthri-
tis, etc.
41–43
The sulfhydryl group of thiacremonone binds with the NF-κB molecule and
suppresses its activation, thereby inhibiting the NF-κB signaling pathway of arthritis.
42
Rheumatoid arthritis is characterized by the formation of amyloid bodies, resulting in
a person’s early death.
44
Thiacremonone from garlic has antiamyloidogenesis properties
via NF-κB inhibition.
45
Chondrocytes with IL-1βactivity that resemble osteoarthritis were treated with
S-allylmercaptocysteine, isolated from A. sativum. As a result, an increase in the viability
of chondrocytes and a reduction in type-II collagen degradation was observed due to
the inhibition of the NF-κB pathway. Also, a change in the ratio of matrix metallopro-
teinase and tissue inhibitors of metalloproteinase was induced.
46
Similarly, allicin, another
compound from garlic, was found to significantly reduce the levels of IL-1β-induced
prostaglandins E
2
, nitric oxide, collagenase-3 (MMP-13), NF-κB, and mitogen-activated
and protein-kinase production, thereby acting as a potential compound to alleviate the
effects of osteoarthritis.
18, 47
Ankylosing spondylitis, a type of arthritis, can be ameliorated by the use of allicin from
garlic by inhibiting the production of IL-6, IL-8, and TNF-αwhile downregulating the
expression of the HLA-B27 gene present in all patients suffering from the disease.
48
Alli-
cin is also reported to enhance the transition of a cell cycle from one phase to another.
The enhancement in the expression of chondrocyte cell cycle proteins D1, CDK4, and
CDK 6 was reported by the use of allicin, as a result of which an early transition from G1
to S phase and a decrease in the G1/G0 phase of the cell cycle was observed.
37
Prostaglandins are the inflammatory compounds that occur during arthritis via the
cyclooxygenase pathway by expression of COX-1 and COX-2 genes. These COX genes
were found to be upregulated by monosodium urate crystals and IL-1β, involved in the
development of joint arthritis. On the other hand, they are downregulated by the admin-
istration of diallyl sulfide from garlic.
31
Compounds from garlic such as uracil, S-allyl cys-
teine, and caffeine were also reported to inhibit the activity of the NF-κB and COX-2
genes involved in arthritis signaling pathways.
41
The improvement in the degradation of
IL-1β-induced arthritis in cartilage and chondrocytes by downregulating the expression
of matrix metalloproteinase-1, -3, and -13 with the help of garlic-derived diallylsulfide has
been reported.
49
The inhibitory effect of various concentrations of diallyldisulfide was
observed on the IL-1β-induced stress and cell death in cultured chondrocytes.
50
The
application of diallyldisulfide increased the expression of various antioxidant enzymes
such as glutathione transferase, heme oxygenase, catalase, and peroxidase while reducing
the expression of various inflammation and cell death causing factors such as caspases 3,
IL-1β-induced reactive oxygen species, and the phosphorylation of c-Jun N-terminal
kinase and P58 protein.
50
249Garlic and Its Role in Arthritis Management

The use of selenium to reduce the effect of rheumatic diseases has been demonstrated
by Peretz and his colleagues.
51
The antiarthritic activity of garlic oil was enhanced by the
use of boron when administered to mice with formaldehyde-induced arthritis.
52
A significant reduction in the selenium concentration of plasma and the synovial fluid
of the arthritis patient has been observed.
53
The presence of selano compounds in garlic
and onion with the help of the EC/HPLC-APCI-MS-MS technique was reviewed by
Arnault and Auger.
54
Garlic is a proven potential natural remedy for arthritis. The advancement of medical
science and research has made it possible to exploit its various components for the tar-
geted administration of this wonder drug. Making nanoformulations of garlic compounds
will help further the easy use and bioavailability for arthritis patients. Also, preclinical and
clinical studies should be conducted to elucidate garlic’s beneficial and risk effects with
respect to arthritis.
REFERENCES
1. Cunnane G, Hummel KM, Muller-Ladner U, Gay RE, Gay S. Mechanism of joint destruction in rheu-
matoid arthritis. Arch Immunol Ther Exp (Warsz). 1998;46(1):1–7.
2. Brain SD. TRPV1 and TRPA1 channels in inflammatory pain: elucidating mechanisms. Ann N Y Acad
Sci. 2011;1245:36–37.
3. Fernandes ES, Russell FA, Spina D, et al. A distinct role for transient receptor potential ankyrin 1, in
addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory
hyperalgesia and Freund’s complete adjuvant-induced monarthritis. Arthritis Rheum. 2011;63
(3):819–829.
4. Lowin T, Apitz M, Anders S, Straub RH. Anti-inflammatory effects of N-acylethanolamines in rheu-
matoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner.
Arthritis Res Ther. 2015;17:321.
5. Alder R, Lookinland S, Berry JA, Williams M. A systematic review of the effectiveness of garlic as an
anti-hyperlipidemic agent. J Am Acad Nurse Pract. 2003;15:120–129.
6. Durak I, Kavutcu M, Aytac¸B, et al. Effects of garlic extract consumption on blood lipid and oxidant/
antioxidant parameters in humans with high blood cholesterol. J Nutr Biochem. 2004;15:373–377.
7. Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure: a systematic
review and meta-analysis. BMC Cardiovasc Disord. 2008;8:13.
8. Parle M, Kaura S. How to live with rheumatoid arthritis. IJRP. 2012;3:115–121.
9. Fleischauer AT, Arab L. Garlic and cancer: a critical review of the epidemiologic literature. J Nutr.
2001;131:1032S–1040S.
10. Bisen PS, Emerald M. Nutritional and therapeutic potential of garlic and onion (Allium sp.). Curr Nutr
Food Sci. 2016;12:190–199.
11. Hall A, Troupin A, Londono-Renteria B, Colpitts TM. Garlic organosulfur compounds reduce inflam-
mation and oxidative stress during dengue virus infection. Viruses. 2017;159. https://doi.org/10.3390/
v9070159.
12. Kyo E, Uda N, Kasuga S, Itakura Y. Immunomodulatory effects of aged garlic extract. J Nutr.
2001;131:1075S–1079S.
13. Rahman MS. Allicin and other functional active components in garlic: health benefits and bioavailabil-
ity. Int J Food Prop. 2007;10:245–268.
14. Tatarintsev AV, Turgiev AS, Davidson JB. Methods of using ajoene. Patent No. US5856363A.
15. Kashyap P, Baskar SK, Tripathi AK, Sahu R. Rajput DSA brief update on use of garlic as folklore med-
icine: a review. EJPMR. 2016;3:188–193.
250 Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

16. Cardelle-Cobas A, Soria AC, Corzo-Martinez M, Villamiel M. A comprehensive survey of garlic
functionality. In: Pacurar M, Karejci G, eds. Garlic Consumption and Health. Hauppauge, NY: Nova
Science Publishers, Inc.; 2010:1–60.
17. Rivlin RS. Historical perspective on the use of garlic. J Nutr. 2001;131:951S–954S.
18. Wang L, Pan H-T, Wang B, Liu Y, Fei K, Han W-F. Allicin reduces IL-1β-induced inflammatory cyto-
kines via attenuating the NF-κB and MMP3 activation in human osteoarthritis chondrocytes model. Int
J Clin Exp Pathol. 2016;9:10320–10326.
19. Denisov LN, Andrianova IV, Timofeeva SS. Garlic effectiveness in rheumatoid arthritis. Ter Arkh.
1999;71:55–58.
20. Singh H, Krishna G, Baske PK. Plants used in the treatment of joint diseases (rheumatism, arthritis, gout
and lumbago) in Mayurbhanj district of Odisha, India. Rep Opin. 2010;2:22–26.
21. Bose S, Laha B, Banerjee S. Anti-inflammatory activity of isolated allicin from garlic with post-acoustic
waves and microwave radiation. J Adv Pharm Edu Res. 2013;3:512–515.
22. Mahomoodally MF, Muthoorah LD. An ethnopharmacological survey of natural remedies used by the
Chinese community in Mauritius. Asian Pac J Trop Biomed. 2014;4:S387–S399.
23. Hussein NA, Sharara GM. Effect of combined garlic therapy and comprehensive rehabilitation program
versus comprehensive rehabilitation program alone on control of clinical manifestations and quality of
life of knee osteoarthritis patients. Int J Phys Med Rehabil. 2015;3:282.
24. Tyagi DK, Kumar S, Joshi N. Role of different juices in the management of osteoarthritis, rheumatoid
arthritis and backache—a review. J Ayurveda Integr Med Sci. 2017;2:162–166.
25. Johri S, Khan N, Tiwari S, Shakyawar L. Assessment of secondary metabolites: in vitro antiarthritic and
antihemolytic potential of various extracts of garlic. J Herb Drugs. 2016;7:45–50.
26. Bayan L, Koulivand PH, Gorji A. Garlic: a review of potential therapeutic effects. Avicenna J Phytomed.
2014;4:1–14.
27. Tripathi A. Garlic: a natural wonder drug. Res Rev J Pharmacogn. 2017;4:41–44.
28. Arreola R, Quintero-Fabia
´nS,Lo
´pez-Roa RI, et al. Immunomodulation and anti-inflammatory effects
of garlic compounds. J Immunol Res. 2015;https://doi.org/10.1155/2015/401630.
29. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-
derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2004;1030:434–441.
30. Keiss HP, Dirsch VM, Hartung T, et al. Garlic (Allium sativum L.) modulates cytokine expression in
lipopolysaccharide-activated human blood thereby inhibiting NF-kappaB activity. J Nutr.
2003;133:2171–2175.
31. Lee HS, Lee CH, Tsai HC, Salter DM. Inhibition of cyclooxygenase 2 expression by diallyl sul-
fide on joint inflammation induced by urate crystal and IL-1beta. Osteoarthritis Cartilage.
2009;17:91–99.
32. Shi L, Lin Q, Li X, et al. Alliin, a garlic organosulfur compound, ameliorates gut inflammation through
MAPK-NF-κB/AP-1/STAT-1 inactivation and PPAR-γactivation. Mol Nutr Food Res. 2017;61.
https://doi.org/10.1002/mnfr.201601013.
33. Williams FM, Skinner J, Spector TD, et al. Dietary garlic and hip osteoarthritis: evidence of a protective
effect and putative mechanism of action. BMC Musculoskelet Disord. 2010;8:280.
34. Meyer K, Ueberham E, Gebhardt R. Influence of organosulphur compounds from garlic on the secre-
tion of matrix metalloproteinases and their inhibitor TIMP-1 by cultured HUVEC cells. Cell Biol
Toxicol. 2004;20:253–260.
35. Shin JH, Ryu JH, Kang MJ, Hwang CR, Han J, Kang D. Short-term heating reduces the
anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and
pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages. Food Chem
Toxicol. 2013;58:545–551.
36. Makris A, Thornton CE, Xu B, Hennessy A. Garlic increases IL-10 and inhibits TNFalpha and IL-6
production in endotoxin-stimulated human placental explants. Placenta. 2005;26:828–834.
37. Li T, Shi HY, Hua YX, et al. Effects of allicin on the proliferation and cell cycle of chondrocytes. Int
J Clin Exp Pathol. 2015;8:12525–12532.
38. Benkeblia N. Free-radical scavenging capacity and antioxidant properties of some selected onions
(Allium cepa L.) and garlic (Allium sativum L.) extracts. Braz Arch Biol Technol. 2005;48:753–759.
251
Garlic and Its Role in Arthritis Management

39. Woo KS, Hwang IG, Kim HY, Lee SH, Jeong HS. Physiological activities of thiacremonone produced
in high temperature and high pressure treated garlic. Prev Nutr Food Sci. 2016;21:68–72.
40. Hwang IG, Woo KS, Kim DJ, et al. Isolation and identification of an antioxidant substance from heated
garlic (Allium sativum L.). Food Sci Biotechnol. 2007;16:963–966.
41. Kim SR, Jung YR, An HJ, et al. Anti-wrinkle and anti-inflammatory effects of active garlic components
and the inhibition of MMPs via NF-κB signaling. PLoS ONE. 2013;8:e73877.
42. Ban JO, Oh JH, Kim TM, et al. Anti-inflammatory and arthritic effects of thiacremonone, a novel sulfur
compound isolated from garlic via inhibition of NF-κB. Arthritis Res Ther. 2009;11:R145.
43. Ban JO, Lee HS, Jeong HS, et al. Thiacremonone augments chemotherapeutic agent-induced growth
inhibition in human colon cancer cells through inactivation of nuclear factor-κB. Mol Cancer Res.
2009;7:870–879.
44. Husby G. Amyloidosis and rheumatoid arthritis. Clin Exp Rheumatol. 1985;3:173–180.
45. Lin GH, Lee YJ, Choi DY, et al. Anti-amyloidogenic effect of thiacremonone through anti-inflamation
in vitro and in vivo models. J Alzheimers Dis. 2012;29:659–676.
46. Yang G, Li S, Li B, et al. Protective effects of garlic-derived S-allylmercaptocysteine on IL-1β-
stimulated chondrocytes by regulation of MMPs/TIMP-1 ratio and type II collagen expression via sup-
pression of NF-κB pathway. Biomed Res Int. 2017;https://doi.org/10.1155/2017/8686207.
47. Li H-Z, Wan J-Y, Zhang L, Luo F-L, Zhang Z, Zhou Q-X. Effect of allicin on adjuvant arthritis rats.
Chin Pharmacol Bull. 2007;07 [in Chinese].
48. Gu X, Wu H, Fu P. Allicin attenuates inflammation and suppresses HLA-B27 protein expression in
ankylosing spondylitis mice. Biomed Res Int. 2013; https://doi.org/10.1155/2013/171573.
49. Chen WP, Tang JL, Bao JP, et al. Effects of diallyl sulphide in chondrocyte and cartilage in experimental
osteoarthritis in rabbit. Phytother Res. 2011;25:351–356.
50. Hosseinzadeh A, Jafari D, Kamarul T, Bagheri A, Sharifi AM. Evaluating the protective effects and
mechanisms of diallyl disulfide on interlukin-1β-induced oxidative stress and mitochondrial apoptotic
signaling pathways in cultured chondrocytes. J Cell Biochem. 2017;118:1879–1888.
51. Peretz AM, Ne
`ve JD, Famaey JP. Selenium in rheumatic diseases. Semin Arthritis Rheum.
1991;20:305–316.
52. Shah SA, Vohora SB. Boron enhances anti-arthritic effects of garlic oil. Fitoterapia. 1990;61:121–126.
53. Yazar M, Sarban S, Kocyigit A, Isikan UE. Synovial fluid and plasma selenium, copper, zinc, and iron
concentrations in patients with rheumatoid arthritis and osteoarthritis. Biol Trace Elem Res.
2005;106:123–132.
54. Arnault I, Auger J. Seleno-compounds in garlic and onion. J Chromatogr A. 2006;21:23–30.
252 Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases