Discussion
Effect of atorvastatin or glucosamine sulfate on
osteoarthritic rats :
The histopathological examination of non-treated OA rats showed several
osteoarthritic changes that are following Bagi et al., 2015;
Marino-Martinez et al., 2019. Surgically-induced models
of OA largely mimic the human OA histopathologically (Kuyinu et al.,
2016).
Glucosamine treated group showed improvement of histopathological
changes that occurred in the non-treated OA group in agreement with Wen
et al., 2010 and Waly et al., 2017. Atorvastatin treated
group showed a significant improvement of the histopathological score
with an improved microscopic picture of the examined knee joint
specimens to be almost near normal. These results are in agreement with
Pathak, Lingaraju, et al., 2015 and Gaballah et al.,
2015.
A significant increase in the maximum angle of knee extension in the
osteoarthritic group, as a sign of joint stiffness, is in agreement with
previous studies (Choi et al., 2015; Phan et al., 2015). The joint
stiffness that occurs in OA mainly results from a chronic inflammatory
process that progresses and leads to fibrosis and then dysfunction of
the joint (Kim et al., 2012). Glucosamine and atorvastatin treated
groups showed significant correction of the joint stiffness found in the
non-treated osteoarthritic group. This improvement of the joint
stiffness is assumed to be due to their anti-inflammatory effect that
reducing the joint fibrosis.
In the present study, surgical induction of OA was associated with a
significant increase in IL-1 β in agreement with previous studies by
(Wei et al., 2018; Castrogiovanni et al., 2019). IL-1β
alters the homeostatic balance of chondrocytes as it suppresses anabolic
activity, and it decreases the expression of type II collagen and
aggrecan and it inhibits glucuronosyltransferase which plays an
important role in glycosaminoglycan biosynthesis. Also, it stimulates
articular cartilage breakdown by increasing the expression of MMPs,
chondrocyte apoptosis, and increasing the production of inflammatory
mediators and reactive oxygen species (ROS)(Kapoor et al., 2011;
Mobasheri and Batt, 2016).
The increase in IL-1β in OA rats was associated with a significant
increase in serum level of MMP-13 following Ali et al., 2017;
Castrogiovanni et al., 2019. Under normal conditions,
there is a dynamic equilibrium between the synthesis and the degradation
of the
extracellular
matrix component in osteoarthritic
states, a disruption of matrix equilibrium leads to apoptosis of
chondrocytes and
cartilage
degradation (Maldonado and Nam, 2013). MMPs are the most important
proteinases responsible for extracellular matrix degradation. MMPs are
activated by abnormal environmental insults, including high-magnitude
mechanical stress,
inflammatory
mediators (Shiomi et al., 2010).
The increase of IL-1β following the induction of OA was significantly
reduced by glucosamine. This finding was in line with Shahine &
Elhadidi, 2014. Glucosamine is assumed to decrease the serum level of
IL-1β as it decreases interleukin 1-induced gene expression (Rovati et
al., 2012). Glucosamine also limited the rise of MMP-13 produced by the
induction of OA. This effect is in agreement with studies of (Rovati et
al., 2012; Gibson et al., 2014).
Atorvastatin treated group in this study showed a significant reduction
in the rise of IL-1 β in agreement with Barsante et al., 2005;
Simopoulou et al., 2010. This decrease in IL-1 β level
with atorvastatin is due to inhibition of production of isoprenoid
derivatives that results in inhibition of NF-κB that regulates
transcription of many inflammatory mediators including the IL-1 β and
mutagenic signaling pathway (Baker et al., 2011).
Administration of atorvastatin to OA rats showed a significant reduction
in the rise of MMP-13. Simopoulou et al., 2010 suggested that
atorvastatin may have possible chondroprotective effects, mainly by
decreasing cartilage degradation protein MMP13. Pathak et al., 2015b
noticed that atorvastatin significantly inhibited the IL-1β-induced
increased production of MMP-13 in an in-vitro OA model.
The effect of statins on MMPs may be due to inhibition of mevalonate
synthesis which in turn plays an essential role in the regulation of
several cellular mechanisms, including cytoskeletal dynamics and
endocytic/exocytic transport. They are involved in MMP secretion, as
well as transcription and synthesis of inflammatory cytokines and
reactive oxygen species (Kavalipati et al., 2015).
Levels of reduced GSH in the erythrocyte lysate of osteoarthritic rats
were reduced suggesting increased oxidative stress following Cifuentes
et al., 2010; Regan et al., 2008. Increased ROS in OA is mainly
associated with the reduction of the cartilage mass due to both
inhibiting synthesis of cartilage matrix and inducing cartilage matrix
breakdown (Henrotin et al., 2005). The glucosamine
treated group in this study showed a significant elevation of the
reduced GSH. Glucosamine was shown to possess antioxidant capacity
(Katoh et al., 2017; Dai et al., 2018).
Atorvastatin treated group in this study showed a significant elevation
of the decreased GSH. A similar antioxidant effect of atorvastatin has
been reported by Pathak, Balaganur, et al., 2015 and
Gaballah et al., 2015, who noticed that the GSH levels
were restored to the normal by atorvastatin in an experimental model of
osteoarthritis. The antioxidant effect of atorvastatin
could be due to either increased biosynthesis of GSH or reduced
oxidative stress. A recent study by (Hosseinzadeh et al., 2019) declared
that atorvastatin enhanced the mRNA expression of antioxidant enzymes
including glutathione peroxidase in cultured chondrocytes. Atorvastatin
mitigated the production of ROS by endothelial cells by inhibiting NADPH
oxidase activity via Rho-dependent mechanisms. Moreover, atorvastatin
binds to erythrocyte membrane phospholipids or to lipoprotein fractions
to prevent the diffusion of free radicals generated under oxidative
stress (Bellosta et al., 2000).
Direct assessment of the anti-inflammatory and analgesic
effects: It was found that sub-plantar injection of carrageenan
produced a significant increase in paw thickness measured after 1, 2,
3, 4, 24h. These results came in agreement with Sadeghi et al., 2014
and Antonisamy et al., 2017. The carrageenan-treated group also showed
a significant decrease in the nociceptive threshold that was parallel
with Kuedo et al., 2016; Marius et al., 2018. The
indomethacin treated group showed a significant reduction of the
increased paw thickness produced by carrageenan in agreement with
Uzkeser et al., 2012 and Okhuarobo and Ozolua, 2017. It also showed a
significant analgesic effect in agreement with Kuedo et al., 2016;
Uzkeser et al., 2012. Indomethacin was used in the present study as a
well-known analgesic anti-inflammatory standard drug to which the
tested drugs are compared.
Glucosamine pretreated group showed a significant reduction in the
increased paw edema. Setnikar et al., 1991 showed that glucosamine
protected against the edema provoked by carrageenan, In contrast, Singh
et al., 2007 noticed that glucosamine caused a non-significant decrease
of paw edema after carrageenan injection. Glucosamine produced a
significant correction of carrageenan-induced hyper nociceptive response
in parallel to Wen et al., 2010. Antinociceptive effect of glucosamine
may be due to its anti-inflammatory effect; suppressing the raised IL-1,
ROS, and neutrophil functions.
Atorvastatin pretreated group produced a significant reduction of
carrageenan-induced paw edema following Jaiswal and Sontakke,
2012. atorvastatin treated group showed significant
inhibition of the hyper nociceptive response following
Santodomingo-Garzon et al., 2006 and Kamel et al., 2016
Atorvastatin inhibition of carrageenan-induced rat paw edema may be due
to inhibition of prostaglandins and other inflammatory mediators such as
IFN- γ, TNF-α, IL-1, and IL-6. Atorvastatin inhibits
leukocyte-endothelial adhesion, reduces the levels of inducible nitric
oxide synthase and inhibits the production of monocyte chemotactic
protein-1. These anti-inflammatory effects are due to the inhibition of
NF-kB that regulates the transcription of many inflammatory mediators
and mutagenic signaling pathways (Baker et al., 2011).
Statins also activate anti-inflammatory transcription factors known as
peroxisome proliferator-activated receptors (PPARs) that interfere with
NF-kB transcriptional activity (Cernuda-Morollón et al., 2002).
Moreover, atorvastatin pretreatment showed correction of
carrageenan-induced hyper nociception by inhibiting the production of
proinflammatory mediators and deceased PGE2 sensitization action on
nociceptors (Santodomingo-Garzon et al., 2006).
The pleiotropic effects of atorvastatin; including anti-inflammatory,
analgesic, anti-catabolic, and antioxidant effects are assumed to have a
beneficial role in the improvement of OA. The measurement of IL-1b and
mmp-13 were performed to assess the anti-inflammatory and anticatabolic
effects of atorvastatin. Besides, GSH assessment is used to detect the
antioxidant effect of atorvastatin. Inflammation, oxidative stress are
claimed to have a role in the catabolic state that occurs in OA. These
pleiotropic effects are assumed to have a beneficial role in the
improvement of OA. Also, it is reported that the expression of genes
regulating cholesterol efflux is impaired in human OA chondrocytes,
resulting in a toxic accumulation of lipid droplets in the chondrocyte
that has a critical role in the development of OA (Tsezou et al., 2010).
Atorvastatin has an anti-atheromatous effect that reduces structural
deterioration of OA joints by improving the blood flow as the reduced
blood flow in the small vessels in the subchondral bone may deteriorate
the cartilage homeostasis and cause OA changes (Hoeven et al., 2013).
Besides, atorvastatin is assumed to have an anabolic effect that is
protective against cartilage damage (Karasawa, 2010). Atorvastatin may
also inhibit osteoclasts activation by preventing mevalonate production,
which leads to the loss of prenylation of small Ras and Rho GTPases and,
consequently, disruption of downstream intracellular signaling pathways
in osteoclasts (Hughes et al., 2007).
Conclusion :
The present study could present
atorvastatin as a new useful
potential DMOAD worse clinical trial for the treatment of OA.
Accordingly, atorvastatin may be a promising DMOAD for treatment of OA
especially in elderly patients suffering from hyperlipidemia,
atherosclerosis.
Limitation of the studyOther markers which are assumed to be involved in the pathogenesis of
OA have to be assessed. An assessment of other statins as a drug group
has similar effects on OA like atorvastatin or not. Investigate the
significance of atorvastatin cholesterol-lowering and
anti-atheromatous action in correction subchondral bone ischemia.
Also, an electron microscope examination of the affected joints may be
of value to get a more precise evaluation.
References
A. Gaballa, N. Risk, A. Elhawary, E. Farrage, and E.G. (2015). Potential
prophylactic effect of oral versus intraarticular atorvastatin in
experimental model of osteoarthritis. Mansoura Med. J. 44 :
145–168.
Ali, S.M., Okda, A.A.K., Dessouky, I.S., Hewedy, W.A., Zahran, N.M., and
Alamrani, B.A. (2017). l -Carnitine ameliorates knee lesions in
mono-iodoacetate induced osteoarthritis in rats . Alexandria J. Med.53 : 61–66.
Antonisamy, P., Dhanasekaran, M., Kim, H.-R., Jo, S.-G., Agastian, P.,
and Kwon, K.-B. (2017). Anti-inflammatory and analgesic activity of
ononitol monohydrate isolated from Cassia tora L. in animal models.
Saudi J. Biol. Sci. 24 : 1933–1938.
Bagi, C.M., Zakur, D.E., Berryman, E., Andresen, C.J., and Wilkie, D.
(2015). Correlation between muCT imaging, histology and functional
capacity of the osteoarthritic knee in the rat model of osteoarthritis.
J. Transl. Med. 13 : 276.
Baker, J.F., Walsh, P., and Mulhall, K.J. (2011). Statins: a potential
role in the management of osteoarthritis? Joint. Bone. Spine 78 :
31–34.
Barsante, M.M., Roffe, E., Yokoro, C.M., Tafuri, W.L., Souza, D.G.,
Pinho, V., et al. (2005). Anti-inflammatory and analgesic effects of
atorvastatin in a rat model of adjuvant-induced arthritis. Eur. J.
Pharmacol. 516 : 282–289.
Bellosta, S., Ferri, N., Bernini, F., Paoletti, R., and Corsini, A.
(2000). Non-lipid-related effects of statins. Ann. Med. 32 :
164–176.
Beutler, E., Duron, O., and Kelly, B.M. (1963). Improved method for the
determination of blood glutathione. J. Lab. Clin. Med. 61 :
882–888.
Castrogiovanni, P., Rosa, M. Di, Ravalli, S., Castorina, A.,
Guglielmino, C., Imbesi, R., et al. (2019). Moderate Physical Activity
as a Prevention Method for Knee Osteoarthritis and the Role of
Synoviocytes as Biological Key. Int. J. Mol. Sci. 20 :.
Cernuda-Morollón, E., Rodríguez-Pascual, F., Klatt, P., Lamas, S., and
Pérez-Sala, D. (2002). PPAR Agonists Amplify iNOS Expression While
Inhibiting NF-κB: Implications for Mesangial Cell Activation by
Cytokines. J. Am. Soc. Nephrol. 13 : 2223 LP – 2231.
Choi, J.-S., Shin, H.-S., Kim, K.Y., Ku, S.K., Choi, I.S., and Kim, J.W.
(2015). Effect of Polycalcium, a mixture of Polycan and calcium
lactate-gluconate in a 1:9 weight ratio, on rats with surgery-induced
osteoarthritis. Exp. Ther. Med. 9 : 1780–1790.
Cifuentes, D.J., Rocha, L.G., Silva, L.A., Brito, A.C., Rueff-Barroso,
C.R., Porto, L.C., et al. (2010). Decrease in oxidative stress and
histological changes induced by physical exercise calibrated in rats
with osteoarthritis induced by monosodium iodoacetate. Osteoarthr.
Cartil. 18 : 1088–1095.
Dai, W., Qi, C., and Wang, S. (2018). Synergistic effect of glucosamine
and vitamin E against experimental rheumatoid arthritis in neonatal
rats. Biomed. Pharmacother. 105 : 835–840.
Dong, H., Sun, H., Magal, E., Ding, X., Kumar, G.N., Chen, J.J., et al.
(2008). Inflammatory pain in the rabbit: a new, efficient method for
measuring mechanical hyperalgesia in the hind paw. J. Neurosci. Methods168 : 76–87.
Gediz, E.I., Nacitarhan, C., Minareci, E., and Sadan, G. (2015).
Antinociceptive Effect of Vardenafil on Carrageenan-Induced Hyperalgesia
in Rat: involvement of Nitric Oxide/Cyclic Guanosine
Monophosphate/Calcium Channels Pathway. Iran. J. Pharm. Res. IJPR14 : 1137–1143.
Ghaisas, M.M., Dandawate, P.R., Zawar, S.A., Ahire, Y.S., and Gandhi,
S.P. (2010). Antioxidant, antinociceptive and anti-inflammatory
activities of atorvastatin and rosuvastatin in various experimental
models. Inflammopharmacology 18 : 169–177.
Gibson, M., Li, H., Coburn, J., Moroni, L., Nahas, Z., Bingham, C. 3rd,
et al. (2014). Intra-articular delivery of glucosamine for treatment of
experimental osteoarthritis created by a medial meniscectomy in a rat
model. J. Orthop. Res. 32 : 302–309.
Henrotin, Y., Kurz, B., and Aigner, T. (2005). Oxygen and reactive
oxygen species in cartilage degradation: friends or foes? Osteoarthr.
Cartil. 13 : 643–654.
Hoeven, T.A., Kavousi, M., Clockaerts, S., Kerkhof, H.J.M., Meurs, J.B.
van, Franco, O., et al. (2013). Association of atherosclerosis with
presence and progression of osteoarthritis: the Rotterdam Study. Ann.
Rheum. Dis. 72 : 646–651.
Hosseinzadeh, A., Bahrampour Juybari, K., Kamarul, T., and Sharifi, A.M.
(2019). Protective effects of atorvastatin on high glucose-induced
oxidative stress and mitochondrial apoptotic signaling pathways in
cultured chondrocytes. J. Physiol. Biochem. 75 : 153–162.
Hughes, A., Rogers, M.J., Idris, A.I., and Crockett, J.C. (2007). A
comparison between the effects of hydrophobic and hydrophilic statins on
osteoclast function in vitro and ovariectomy-induced bone loss in vivo.
Calcif. Tissue Int. 81 : 403–413.
Jaiswal, S.R., and Sontakke, S.D. (2012). Experimental evaluation of
analgesic and anti-inflammatory activity of simvastatin and
atorvastatin. Indian J. Pharmacol. 44 : 475–479.
Janusz, M.J., Bendele, A.M., Brown, K.K., Taiwo, Y.O., Hsieh, L., and
Heitmeyer, S.A. (2002). Induction of osteoarthritis in the rat by
surgical tear of the meniscus: Inhibition of joint damage by a matrix
metalloproteinase inhibitor. Osteoarthr. Cartil. 10 : 785–791.
Johnson, V.L., and Hunter, D.J. (2014). The epidemiology of
osteoarthritis. Best Pract. Res. Clin. Rheumatol. 28 : 5–15.
Kamel, E., Elsaid, A., Gumaa, E., and Sheweal, A.E. El (2016). Statins
attenuate hyperalgesia and inflammation in experimentally induced acute
and neuropathic pain in rats. Ain-Shams J. Anaesthesiol. 9 : 440.
Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J.-P., and
Fahmi, H. (2011). Role of proinflammatory cytokines in the
pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7 :
33–42.
Karasawa, K.Y. and R. (2010). Statin prevents chondrocyte aging and
degeneration of articular cartilage in osteoarthritis ( OA ). Aging
(Albany. NY). 2 : 990–998.
Katoh, A., Kai, H., Harada, H., Niiyama, H., and Ikeda, H. (2017). Oral
Administration of Glucosamine Improves Vascular Endothelial Function by
Modulating Intracellular Redox State. Int. Heart J. 58 : 926–932.
Kavalipati, N., Shah, J., Ramakrishan, A., and Vasnawala, H. (2015).
Pleiotropic effects of statins. Indian J. Endocrinol. Metab. 19 :
554–562.
Khan, H.M., Ashraf, M., Hashmi, A.S., Ahmad, M.U.D., and Anjum, A.A.
(2013). Papain induced progressive degenerative changes in articular
cartilage of rat femorotibial joint and its histopathological grading.
J. Anim. Plant Sci. 23 : 350–358.
Kim, J.-W., Cho, H.-R., and Ku, S.-K. (2012). Efficacy test of Polycan,
a beta-glucan originated from Aureobasidium pullulans SM-2001, on
anterior cruciate ligament transection and partial medial
meniscectomy-induced-osteoarthritis rats. J. Microbiol. Biotechnol.22 : 274–282.
Kuedo, Z., Sangsuriyawong, A., Klaypradit, W., Tipmanee, V., and
Chonpathompikunlert, P. (2016). Effects of Astaxanthin from Litopenaeus
Vannamei on Carrageenan-Induced Edema and Pain Behavior in Mice.
Molecules 21 : 382.
Kuyinu, E.L., Narayanan, G., Nair, L.S., and Laurencin, C.T. (2016).
Animal models of osteoarthritis: Classification, update, and measurement
of outcomes. J. Orthop. Surg. Res. 11 : 1–27.
Maldonado, M., and Nam, J. (2013). The role of changes in extracellular
matrix of cartilage in the presence of inflammation on the pathology of
osteoarthritis. Biomed Res. Int. 2013 : 284873.
Marino-Martinez, I.A., Martinez-Castro, A.G., Pena-Martinez, V.M.,
Acosta-Olivo, C.A., Vilchez-Cavazos, F., Guzman-Lopez, A., et al.
(2019). Human amniotic membrane intra-articular injection prevents
cartilage damage in an osteoarthritis model. Exp. Ther. Med. 17 :
11–16.
Marius, M., Jabeen, A., Gilbert, A., Simjee, S.U., Desire, B.T.F., and
Dastagir, N. (2018). NO-cGMP-K channel-dependent anti-nociceptive
activities of methanol stem bark extract of Piptadeniastrum africanum
(Mimosaceae) on rats. Asian Pac. J. Trop. Biomed. 8 : 150–159.
Mobasheri, A., and Batt, M. (2016). An update on the pathophysiology of
osteoarthritis. Ann. Phys. Rehabil. Med. 59 : 333–339.
Okhuarobo, A., and Ozolua, R. (2017). Analgesic and anti-inflammatory
effects of the aqueous leaf extract of Dichrostachys cinerea.
Pathak, N.N., Balaganur, V., Lingaraju, M.C., Kant, V., Kumar, D.,
Kumar, D., et al. (2015a). Effect of atorvastatin, a HMG-CoA reductase
inhibitor in monosodium iodoacetate-induced osteoarthritic pain:
implication for osteoarthritis therapy. Pharmacol. Rep. 67 :
513–519.
Pathak, N.N., Lingaraju, M.C., Balaganur, V., Kant, V., More, A.S.,
Kumar, D., et al. (2015b). Anti-inflammatory and chondroprotective
effects of atorvastatin in a cartilage explant model of osteoarthritis.
Inflamm. Res. 64 : 161–169.
Phan, D.Q., Silka, M.J., Lan, Y.-T., and Chang, R.-K.R. (2015).
Comparison of formulas for calculation of the corrected QT interval in
infants and young children. J. Pediatr. 166 : 960–962.
Regan, E.A., Bowler, R.P., and Crapo, J.D. (2008). Joint fluid
antioxidants are decreased in osteoarthritic joints compared to joints
with macroscopically intact cartilage and subacute injury. Osteoarthr.
Cartil. 16 : 515–521.
Rezende, M.U. de, Gurgel, H.M. de C., Vilaca Junior, P.R., Kuroba, R.K.,
Lopes, A.S.S., Phillipi, R.Z., et al. (2006). Diacerhein versus
glucosamine in a rat model of osteoarthritis. Clinics (Sao Paulo).61 : 461–466.
Rovati, L.C., Girolami, F., and Persiani, S. (2012). Crystalline
glucosamine sulfate in the management of knee osteoarthritis: efficacy,
safety, and pharmacokinetic properties. Ther. Adv. Musculoskelet. Dis.4 : 167–180.
Sadeghi, H., Hajhashemi, V., Minaiyan, M., Movahedian, A., and Talebi,
A. (2013). Further studies on anti-inflammatory activity of maprotiline
in carrageenan-induced paw edema in rat. Int. Immunopharmacol.15 : 505–510.
Sadeghi, H., Mostafazadeh, M., Sadeghi, H., Naderian, M., Barmak, M.J.,
Talebianpoor, M.S., et al. (2014). In vivo anti-inflammatory properties
of aerial parts of Nasturtium officinale. Pharm. Biol. 52 :
169–174.
Santodomingo-Garzon, T., Cunha, T.M., Verri, W.A.J., Valerio, D.A.R.,
Parada, C.A., Poole, S., et al. (2006). Atorvastatin inhibits
inflammatory hypernociception. Br. J. Pharmacol. 149 : 14–22.
Schmitz, N., Laverty, S., Kraus, V.B., and Aigner, T. (2010). Basic
methods in histopathology of joint tissues. Osteoarthr. Cartil. 18
Suppl 3 : S113-6.
Setnikar, I., Cereda, R., Pacini, M.A., and Revel, L. (1991).
Antireactive properties of glucosamine sulfate. Arzneimittelforschung.41 : 157–161.
Shahine, E.M., and Elhadidi, A.S. (2014). Efficacy of glucosamine
sulfate in lowering serum level of interleukin-1β in symptomatic primary
knee osteoarthritis: Clinical and laboratory study. Alexandria J. Med.50 : 159–163.
Shiomi, T., Lemaitre, V., D’Armiento, J., and Okada, Y. (2010). Matrix
metalloproteinases, a disintegrin and metalloproteinases, and a
disintegrin and metalloproteinases with thrombospondin motifs in
non-neoplastic diseases. Pathol. Int. 60 : 477–496.
Simopoulou, T., Malizos, K.N., Poultsides, L., and Tsezou, A. (2010).
Protective effect of atorvastatin in cultured osteoarthritic
chondrocytes. J. Orthop. Res. 28 : 110–115.
Singh, S., Khajuria, A., Taneja, S.C., Khajuria, R.K., Singh, J., and
Qazi, G.N. (2007). Boswellic acids and glucosamine show synergistic
effect in preclinical anti-inflammatory study in rats. Bioorg. Med.
Chem. Lett. 17 : 3706–3711.
Solanki, H.K., Shah, D.A., Maheriya, P.M., and Patel, C.A. (2015).
Evaluation of anti-inflammatory activity of probiotic on
carrageenan-induced paw edema in Wistar rats. Int. J. Biol. Macromol.72 : 1277–1282.
Tsezou, A., Iliopoulos, D., Malizos, K.N., and Simopoulou, T. (2010).
Impaired expression of genes regulating cholesterol efflux in human
osteoarthritic chondrocytes. J. Orthop. Res. 28 : 1033–1039.
Uzkeser, H., Cadirci, E., Halici, Z., Odabasoglu, F., Polat, B., Yuksel,
T.N., et al. (2012). Anti-inflammatory and antinociceptive effects of
salbutamol on acute and chronic models of inflammation in rats:
involvement of an antioxidant mechanism. Mediators Inflamm. 2012 :
438912.
Waly, N.E., Refaiy, A., and Aborehab, N.M. (2017). IL-10 and TGF-beta:
Roles in chondroprotective effects of Glucosamine in experimental
Osteoarthritis? Pathophysiol. Off. J. Int. Soc. Pathophysiol. 24 :
45–49.
Wei, Y., Jia, J., Jin, X., Tong, W., and Tian, H. (2018). Resveratrol
ameliorates inflammatory damage and protects against osteoarthritis in a
rat model of osteoarthritis. Mol. Med. Rep. 17 : 1493–1498.
Wen, Z.-H., Tang, C.-C., Chang, Y.-C., Huang, S.-Y., Hsieh, S.-P., Lee,
C.-H., et al. (2010). Glucosamine sulfate reduces experimental
osteoarthritis and nociception in rats: association with changes of
mitogen-activated protein kinase in chondrocytes. Osteoarthr. Cartil.18 : 1192–1202.
Winter, C.A., Risley, E.A., and Nuss, G.W. (1962). Carrageenin-induced
edema in hind paw of the rat as an assay for antiiflammatory drugs.
Proc. Soc. Exp. Biol. Med. 111 : 544–547.