BACKGROUND
6-shogaol  is one of the major biologically active compounds found in the rhizome of zingiber officinale/ginger  <cit> .
this compound was previously reported to have antipyretic and analgesic effects in addition to inhibitory effect on lipoxygenase activity  <cit> .
its presence in ginger may also contribute to the anti-inflammatory effects associated with the use of powdered ginger  <cit> .
to confirm this contribution, 6-shogaol was used in this study as an isolated single compound to determine whether it has anti-inflammatory properties and to demonstrate these properties in an animal model of chronic inflammation.
many of the animal models used in investigations of chronic inflammation produce polyarthritis after injection of complete freund's adjuvant  or other pro-inflammatory agents at the base of the rat tail  <cit>  or in a single foot pad of the rat  <cit>  or a single knee joint of the rat  <cit> .
the polyarthritis developed in these animal models was reported to be dose-dependent such that large doses of the pro-inflammatory agent were more likely to produce inflammation at multiple sites  <cit>  including the corresponding contralateral sites to the injection sites  <cit> .
this type of symmetrical development of polyarthritis in the animal models is similar to human rheumatoid arthritis, osteoarthritis and psoriasis  <cit> , but the mechanisms underlying the inflammatory response at the contralateral sites are still unclear.
there is however, evidence of neurological involvement in the development of inflammation at the contralateral site as reported in a review by shenker et al  <cit> .
substance p  and calcitonin gene-related peptide  were identified as neuropeptides that may be involved in development of contralateral inflammation  <cit> .
these are pro-inflammatory neuropeptides that increase mobilization of leukocytes from the blood and loss of fluid from the circulation .
the mechanisms of these effects at the contralateral sites may be different from the mechanism induced by the pro-inflammatory agent at the primary injection site.
consequently, experimental data obtained in the polyarthritic model would be complex and difficult to interpret.
to avoid this complexity and to minimise the influence of contralateral inflammation, a monoarthritic model was used to investigate the anti-inflammatory potential of 6-shogaol.
the inflammation produced in this monoarthritic model is localized at the site of induction and according to butler et al  <cit> , it is stable for chronic studies.
our model was developed with the use of a low potency commercial preparation of cfa  to induce chronic inflammation in the knees of sprague dawley rats over a period of  <dig> days.
the mycobacterium content of cfa was reported in several studies to be the inducing agent of chronic inflammation through stimulation of the immune response  <cit> .
the resulting pathological features include swelling of the joint due to edema, leukocyte migration into the joint and various degrees of cartilage degradation  <cit> .
sfikakis and tsokos  <cit>  reported that leukocyte migration was facilitated by adhesion molecules in the blood.
an example of this type of molecule was identified as soluble vascular cell adhesion molecule- <dig> , and it was reported to be produced in increased concentration in the blood of patients with chronic inflammatory diseases such as rheumatoid arthritis  <cit> .
these features of chronic inflammation were reproduced in the cfa monoarthritic model used in this study and they provided the basis for evaluating the anti-inflammatory potential of 6-shogaol.
RESULTS
effect of 6-shogaol on edema production in cfa treated rats
in a control group of rats that received peanut oil  daily for  <dig> days, a single injection of cfa  in the synovial cavity of the right knee of each rat produced swelling of the knee due to edema.
maximum swelling of the knee was reached within  <dig> days of cfa injection and it was measured as a mean increase in knee circumference of  <dig>  ±  <dig>  mm .
this magnitude of swelling was maintained up to the end of the  <dig> day investigation period .
a comparatively lower magnitude of unsustained swelling was produced within  <dig> days of cfa injection in the 6-shogaol  treated rats.
maximum swelling in this group of rats, obtained after  <dig> doses of 6-shogaol, was measured as a mean increase in knee circumference of  <dig>  ±  <dig>  mm which was significantly lower  than in the control group, and it was progressively reduced after day  <dig> to reach a minimum of  <dig>  ±  <dig>  mm on day  <dig> .
qualitatively similar progressive reduction in mean increase in knee circumference from  <dig>  ±  <dig>  mm to  <dig>  ±  <dig>  mm  was produced after three doses of the standard anti-inflammatory drug indomethacin .
but at the beginning of the treatment, indomethacin did not inhibit the swelling after  <dig> doses, consequently the maximum swelling, measured as a mean increase in knee circumference of  <dig>  ±  <dig>  mm was significantly larger  than in the control and 6-shogaol treated group of rats .
this exacerbation of the edematous swelling by indomethacin on day  <dig> was reduced from  <dig>  ±  <dig>  mm to  <dig>  ±  <dig>  mm, when equimolar montelukast , a cysteinyl leukotriene receptor antagonist, was given in combination with indomethacin from day zero to day three of the treatment period.
effect of 6-shogaol on leukocyte infiltration into the synovial cavity of cfa treated rats
total leukocyte concentration in the fluid of the synovial cavity was determined on day  <dig> when 6-shogaol and indomethacin was most effective in reducing swelling of the knee due to edema production.
figure  <dig> shows that total leukocyte count on this day in the 6-shogaol and indomethacin treated groups of rats was significantly lower , n = 6) than the count in the peanut oil treated control group of rats in which maximum swelling of the knee was still present.
differential counts of the infiltrated leukocytes show  that the 6-shogaol treated group of rats also had significantly lower counts compared to the peanut oil controls for lymphocytes  and monocytes/macrophages .
indomethacin treatment also resulted in significantly lower counts  for lymphocytes  and monocytes/macrophages .
effect of 6-shogaol on vcam- <dig> concentration in the blood of cfa treated rats
soluble vcam- <dig> concentration in the blood was determined on day  <dig> when 6-shogaol was most effective in reducing swelling of the knee due to edema production.
in the peanut oil treated control group,  <dig>  ±  <dig>  ng/ml of soluble vcam- <dig> was detected in the blood compared to  <dig>  ±  <dig>  ng/ml detected in the blood of the 6-shogaol treated group of rats .
these concentrations of soluble vcam- <dig> are significantly different , and it is interesting to note that the lower concentration of soluble vcam- <dig> in the 6-shogaol treated group of rats was associated with significantly lower infiltration of leukocytes  into the synovial cavity compared to the controls .
also, the relationship between these two variables showed a strong positive correlation  in which the magnitude of leukocyte infiltration was dependent on the concentration of soluble vcam- <dig> produced in the blood.
effect of 6-shogaol on femoral cartilage morphology of cfa treated rats
after  <dig> days of exposure of the two groups of rats to a single cfa injection in the synovial cavity of the knee of each rat and daily oral doses of either peanut oil  or 6-shogaol, histological sections of the knee joint were prepared.
figure  <dig> shows a representative histological section of the knee joint with significant cartilage damage that was produced in the peanut oil treated control group of rats.
but no such damage of the cartilage was detected in the 6-shogaol treated group of rats .
in fact, the treatment with 6-shogaol was associated with preservation of the morphological integrity of the cartilage lining the femur as shown in the representative micrograph .
discussion
within  <dig> days of injecting  <dig>  ml  complete freund's adjuvant  into the synovial cavity of the right knees of three groups of rats, localized edematous swelling to a maximum magnitude was produced as the first sign of inflammatory response.
the volume of fluid injected in the knee was discounted from this response by using the knee circumference taken thirty minutes after the injection as the baseline from which the magnitude of edematous swelling was calculated.
the time course of maximum edema production after cfa injection was similar to that observed in the study reported by yu et al  <cit> .
however, the maximum swelling produced in our study was smaller.
this difference in magnitude of the response was most likely due to a difference in potency of the commercial cfa preparation used in our study.
support for this suggestion is based on our use of a larger amount  of the commercial cfa compared to the  <dig> μg prepared and used by yu et al  <cit>  for induction of monoarthritis in the knee.
also, in other studies with the cfa model  <cit>  amounts above  <dig> μg usually produce polyarthritis which was not obtained in our study; therefore our commercial preparation must have been of a lower potency.
during the initial phase of the inflammatory response, swelling of the knee was greatest on day  <dig> in the indomethacin treated group compared to the peanut oil treated control group of rats.
but, in the 6-shogaol treated group of rats, the magnitude of swelling was significantly lower compared to either of the preceding groups of rats.
this difference in the early response to indomethacin treatment compared to its usual anti-inflammatory effect, appeared to have resulted from increased production of pro-inflammatory cysteinyl leukotrienes whose effect was inhibited in this study by the receptor antagonist, montelukast  <cit> .
this pro-inflammatory effect was also obtained with the use of other non-steroidal anti-inflammatory drugs .
aspirin, for example, was reported to increase the production of cysteinyl leukotrienes and precipitate an asthmatic attack in susceptible subjects  <cit> .
the underlying mechanism of the nsaids effect was postulated as resulting from an increase in production of leukotrienes from the common arachidonic acid substrate following inhibition of cyclooxygenase and production of prostaglandins by aspirin and indomethacin  <cit> .
after the early inflammatory response on day  <dig>  indomethacin and 6-shogaol progressively reduced the edematous swelling of the knee to a level close to the pretreatment value by day  <dig>  in contrast, maximum swelling of the knee in the peanut oil treated controls was maintained up to the end of the investigational period on day  <dig>  these results suggest that in this model of inflammation, 6-shogaol  reduced edematous swelling of the knee with similar effectiveness as an equivalent human daily dose of indomethacin   <cit> , which is a standard anti-inflammatory drug  <cit> .
note that although enterohepatic cycling was previously reported by oberbauer et al  <cit>  as contributing to delayed onset of indomethacin therapeutic effect, this action may have only contributed a minor effect compared to the cysteinyl leukotriene involvement in the early exaggeration of the cfa inflammatory response observed in our study.
the effectiveness of 6-shogaol and indomethacin in reducing the cfa-induced edematous swelling of the knee was associated with significant reduction of total leukocyte migration as well as lymphocytes and monocytes/macrophages migration from the blood into the synovial cavity.
these inflammatory cells are major contributors to the initiation and maintenance of the immune response  <cit> , and their concentrations were significantly greater in the peanut oil treated controls compared to either the 6-shogaol or indomethacin treated group of rats in this study.
regulation of migration of these cells from the blood was reported to be facilitated by adhesive interactions with the vascular endothelium  <cit> .
soluble vascular cell adhesion molecule, type- <dig>  was identified as a major mediator of the adhesive interactions  <cit> .
in our study, the 6-shogaol treated group of rats had significantly lower concentration of soluble vcam- <dig> in the blood and leukocyte infiltration into the synovial cavity compared to the peanut oil treated control group.
the relationship of these two variables showed strong positive correlation in which the magnitude of leukocyte infiltration into the synovial cavity was dependent on the concentration of soluble vcam- <dig> produced in the blood.
it is also interesting to note that whereas low infiltration of inflammatory cells in the synovial cavity of the 6-shogaol treated rats was not associated with damage to the cartilage, greater infiltration of inflammatory cells obtained in the peanut oil treated controls was associated with damage to the cartilage in these rats.
this type of damage in human arthritic joints was previously reported to result from cellular output of toxic agents such as nitric oxide and its oxidizing product, peroxynitrite which was detected by the presence of protein nitrotyrosine marker in synovial tissues of rheumatoid and osteoarthritic patients  <cit> .
free radicals were also reported to be involved in producing damage to the arthritic joint.
examples include malondialdehyde  which was detected in high concentration in the blood of arthritic patients  <cit> , and products of hydrogen peroxide  which were associated with adjuvant arthritis in rats <cit> .
in a more recent study of extracts from two species of ginger  on human synoviocytes, the investigators reported that the extracts decreased tnfα induced production of macrophage chemotactic factor  and interferon-γ activated protein  as well as their respective mrna  <cit> .
in another study of crude and fractionated extracts of zingiber officinale on monocyte production of tnfα and pge <dig>  the investigators reported that both the crude and fractionated extracts reduced production of these agents.
however, although the shogaol-rich extract inhibited the production of pge <dig> from the cells, they had no effect on the induction of cox- <dig> enzyme  <cit> .
the implication of these results is that compounds such as 6-shogaol derived from ginger has the potential to inhibit the production of tissue damaging agents such as tnfα as well as chemotactic factors that would attract inflammatory cells to areas of joint inflammation.
when these results obtained by phan et al  <cit>  and lantz et al  <cit>  are considered together with our findings, there is strong support for anti-inflammatory properties for 6-shogaol and other compounds derived from ginger.
6-shogaol was particularly effective in our study in reducing cfa induced chronic inflammation in the knee joint of rats.
its effectiveness was reflected as reduction of edematous swelling of the joint, mononuclear cell infiltration that was dependent on soluble vcam- <dig> concentration in the blood and prevention of cartilage damage.
CONCLUSIONS
it is concluded from the results of this study that 6-shogaol reduced cfa induced chronic inflammatory response in the knee joint of rats and protected the femoral cartilage from damage.
these findings suggest that 6-shogaol has useful anti-inflammatory properties that can be exploited.

 6-shogaol is one of the major biologically active compounds found in the rhizome of zingiber officinale/ginger. this compound was previously reported to have antipyretic and analgesic effects in addition to inhibitory effect on lipoxygenase activity. its presence in ginger may also contribute to the anti-inflammatory effects associated with the use of powdered ginger. to confirm this contribution, 6-shogaol was used in this study as an isolated single compound to determine whether it has anti-inflammatory properties and to demonstrate these properties in an animal model of chronic inflammation. many of the animal models used in investigations of chronic inflammation produce polyarthritis after injection of complete freund's adjuvant or other pro-inflammatory agents at the base of the rat tail or in a single foot pad of the rat or a single knee joint of the rat. the polyarthritis developed in these animal models was reported to be dose-dependent such that large doses of the pro-inflammatory agent were more likely to produce inflammation at multiple sites including the corresponding contralateral sites to the injection sites. this type of symmetrical development of polyarthritis in the animal models is similar to human rheumatoid arthritis, osteoarthritis and psoriasis, but the mechanisms underlying the inflammatory response at the contralateral sites are still unclear. there is however, evidence of neurological involvement in the development of inflammation at the contralateral site as reported in a review by shenker et al. substance p and calcitonin gene-related peptide were identified as neuropeptides that may be involved in development of contralateral inflammation. these are pro-inflammatory neuropeptides that increase mobilization of leukocytes from the blood and loss of fluid from the circulation. the mechanisms of these effects at the contralateral sites may be different from the mechanism induced by the pro-inflammatory agent at the primary injection site. consequently, experimental data obtained in the polyarthritic model would be complex and difficult to interpret. to avoid this complexity and to minimise the influence of contralateral inflammation, a monoarthritic model was used to investigate the anti-inflammatory potential of 6-shogaol. the inflammation produced in this monoarthritic model is localized at the site of induction and according to butler et al, it is stable for chronic studies. our model was developed with the use of a low potency commercial preparation of cfa to induce chronic inflammation in the knees of sprague dawley rats over a period of days. the mycobacterium content of cfa was reported in several studies to be the inducing agent of chronic inflammation through stimulation of the immune response. the resulting pathological features include swelling of the joint due to edema, leukocyte migration into the joint and various degrees of cartilage degradation. sfikakis and tsokos reported that leukocyte migration was facilitated by adhesion molecules in the blood. an example of this type of molecule was identified as soluble vascular cell adhesion molecule-, and it was reported to be produced in increased concentration in the blood of patients with chronic inflammatory diseases such as rheumatoid arthritis. these features of chronic inflammation were reproduced in the cfa monoarthritic model used in this study and they provided the basis for evaluating the anti-inflammatory potential of 6-shogaol.  effect of 6-shogaol on edema production in cfa treated rats in a control group of rats that received peanut oil daily for days, a single injection of cfa in the synovial cavity of the right knee of each rat produced swelling of the knee due to edema. maximum swelling of the knee was reached within days of cfa injection and it was measured as a mean increase in knee circumference of ± mm. this magnitude of swelling was maintained up to the end of the day investigation period. a comparatively lower magnitude of unsustained swelling was produced within days of cfa injection in the 6-shogaol treated rats. maximum swelling in this group of rats, obtained after doses of 6-shogaol, was measured as a mean increase in knee circumference of ± mm which was significantly lower than in the control group, and it was progressively reduced after day to reach a minimum of ± mm on day. qualitatively similar progressive reduction in mean increase in knee circumference from ± mm to ± mm was produced after three doses of the standard anti-inflammatory drug indomethacin. but at the beginning of the treatment, indomethacin did not inhibit the swelling after doses, consequently the maximum swelling, measured as a mean increase in knee circumference of ± mm was significantly larger than in the control and 6-shogaol treated group of rats. this exacerbation of the edematous swelling by indomethacin on day was reduced from ± mm to ± mm, when equimolar montelukast, a cysteinyl leukotriene receptor antagonist, was given in combination with indomethacin from day zero to day three of the treatment period. effect of 6-shogaol on leukocyte infiltration into the synovial cavity of cfa treated rats total leukocyte concentration in the fluid of the synovial cavity was determined on day when 6-shogaol and indomethacin was most effective in reducing swelling of the knee due to edema production. figure shows that total leukocyte count on this day in the 6-shogaol and indomethacin treated groups of rats was significantly lower, n = 6) than the count in the peanut oil treated control group of rats in which maximum swelling of the knee was still present. differential counts of the infiltrated leukocytes show that the 6-shogaol treated group of rats also had significantly lower counts compared to the peanut oil controls for lymphocytes and monocytes/macrophages. indomethacin treatment also resulted in significantly lower counts for lymphocytes and monocytes/macrophages. effect of 6-shogaol on vcam- concentration in the blood of cfa treated rats soluble vcam- concentration in the blood was determined on day when 6-shogaol was most effective in reducing swelling of the knee due to edema production. in the peanut oil treated control group, ± ng/ml of soluble vcam- was detected in the blood compared to ± ng/ml detected in the blood of the 6-shogaol treated group of rats. these concentrations of soluble vcam- are significantly different, and it is interesting to note that the lower concentration of soluble vcam- in the 6-shogaol treated group of rats was associated with significantly lower infiltration of leukocytes into the synovial cavity compared to the controls. also, the relationship between these two variables showed a strong positive correlation in which the magnitude of leukocyte infiltration was dependent on the concentration of soluble vcam- produced in the blood. effect of 6-shogaol on femoral cartilage morphology of cfa treated rats after days of exposure of the two groups of rats to a single cfa injection in the synovial cavity of the knee of each rat and daily oral doses of either peanut oil or 6-shogaol, histological sections of the knee joint were prepared. figure shows a representative histological section of the knee joint with significant cartilage damage that was produced in the peanut oil treated control group of rats. but no such damage of the cartilage was detected in the 6-shogaol treated group of rats. in fact, the treatment with 6-shogaol was associated with preservation of the morphological integrity of the cartilage lining the femur as shown in the representative micrograph. discussion within days of injecting ml complete freund's adjuvant into the synovial cavity of the right knees of three groups of rats, localized edematous swelling to a maximum magnitude was produced as the first sign of inflammatory response. the volume of fluid injected in the knee was discounted from this response by using the knee circumference taken thirty minutes after the injection as the baseline from which the magnitude of edematous swelling was calculated. the time course of maximum edema production after cfa injection was similar to that observed in the study reported by yu et al. however, the maximum swelling produced in our study was smaller. this difference in magnitude of the response was most likely due to a difference in potency of the commercial cfa preparation used in our study. support for this suggestion is based on our use of a larger amount of the commercial cfa compared to the μg prepared and used by yu et al for induction of monoarthritis in the knee. also, in other studies with the cfa model amounts above μg usually produce polyarthritis which was not obtained in our study; therefore our commercial preparation must have been of a lower potency. during the initial phase of the inflammatory response, swelling of the knee was greatest on day in the indomethacin treated group compared to the peanut oil treated control group of rats. but, in the 6-shogaol treated group of rats, the magnitude of swelling was significantly lower compared to either of the preceding groups of rats. this difference in the early response to indomethacin treatment compared to its usual anti-inflammatory effect, appeared to have resulted from increased production of pro-inflammatory cysteinyl leukotrienes whose effect was inhibited in this study by the receptor antagonist, montelukast. this pro-inflammatory effect was also obtained with the use of other non-steroidal anti-inflammatory drugs. aspirin, for example, was reported to increase the production of cysteinyl leukotrienes and precipitate an asthmatic attack in susceptible subjects. the underlying mechanism of the nsaids effect was postulated as resulting from an increase in production of leukotrienes from the common arachidonic acid substrate following inhibition of cyclooxygenase and production of prostaglandins by aspirin and indomethacin. after the early inflammatory response on day indomethacin and 6-shogaol progressively reduced the edematous swelling of the knee to a level close to the pretreatment value by day in contrast, maximum swelling of the knee in the peanut oil treated controls was maintained up to the end of the investigational period on day these results suggest that in this model of inflammation, 6-shogaol reduced edematous swelling of the knee with similar effectiveness as an equivalent human daily dose of indomethacin, which is a standard anti-inflammatory drug. note that although enterohepatic cycling was previously reported by oberbauer et al as contributing to delayed onset of indomethacin therapeutic effect, this action may have only contributed a minor effect compared to the cysteinyl leukotriene involvement in the early exaggeration of the cfa inflammatory response observed in our study. the effectiveness of 6-shogaol and indomethacin in reducing the cfa-induced edematous swelling of the knee was associated with significant reduction of total leukocyte migration as well as lymphocytes and monocytes/macrophages migration from the blood into the synovial cavity. these inflammatory cells are major contributors to the initiation and maintenance of the immune response, and their concentrations were significantly greater in the peanut oil treated controls compared to either the 6-shogaol or indomethacin treated group of rats in this study. regulation of migration of these cells from the blood was reported to be facilitated by adhesive interactions with the vascular endothelium. soluble vascular cell adhesion molecule, type- was identified as a major mediator of the adhesive interactions. in our study, the 6-shogaol treated group of rats had significantly lower concentration of soluble vcam- in the blood and leukocyte infiltration into the synovial cavity compared to the peanut oil treated control group. the relationship of these two variables showed strong positive correlation in which the magnitude of leukocyte infiltration into the synovial cavity was dependent on the concentration of soluble vcam- produced in the blood. it is also interesting to note that whereas low infiltration of inflammatory cells in the synovial cavity of the 6-shogaol treated rats was not associated with damage to the cartilage, greater infiltration of inflammatory cells obtained in the peanut oil treated controls was associated with damage to the cartilage in these rats. this type of damage in human arthritic joints was previously reported to result from cellular output of toxic agents such as nitric oxide and its oxidizing product, peroxynitrite which was detected by the presence of protein nitrotyrosine marker in synovial tissues of rheumatoid and osteoarthritic patients. free radicals were also reported to be involved in producing damage to the arthritic joint. examples include malondialdehyde which was detected in high concentration in the blood of arthritic patients, and products of hydrogen peroxide which were associated with adjuvant arthritis in rats. in a more recent study of extracts from two species of ginger on human synoviocytes, the investigators reported that the extracts decreased tnfα induced production of macrophage chemotactic factor and interferon-γ activated protein as well as their respective mrna. in another study of crude and fractionated extracts of zingiber officinale on monocyte production of tnfα and pge the investigators reported that both the crude and fractionated extracts reduced production of these agents. however, although the shogaol-rich extract inhibited the production of pge from the cells, they had no effect on the induction of cox- enzyme. the implication of these results is that compounds such as 6-shogaol derived from ginger has the potential to inhibit the production of tissue damaging agents such as tnfα as well as chemotactic factors that would attract inflammatory cells to areas of joint inflammation. when these results obtained by phan et al and lantz et al are considered together with our findings, there is strong support for anti-inflammatory properties for 6-shogaol and other compounds derived from ginger. 6-shogaol was particularly effective in our study in reducing cfa induced chronic inflammation in the knee joint of rats. its effectiveness was reflected as reduction of edematous swelling of the joint, mononuclear cell infiltration that was dependent on soluble vcam- concentration in the blood and prevention of cartilage damage.  it is concluded from the results of this study that 6-shogaol reduced cfa induced chronic inflammatory response in the knee joint of rats and protected the femoral cartilage from damage. these findings suggest that 6-shogaol has useful anti-inflammatory properties that can be exploited. 
confirmation of this contribution was sought in this study in sprague- dawley rats treated with a single injection of a commercial preparation of complete freund's adjuvant to induce monoarthritis in the right knee over a period of days. from these results, it is concluded that 6-shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a cfa monoarthritic model of the knee joint of rats. 6-shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. there was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats. this exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. during this development of arthritis, each rat received a daily oral dose of either peanut oil or 6-shogaol. also, 6-shogaol and indomethacin were most effective in reducing swelling of the knees on day when the controls still had maximum swelling. the effect of 6-shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule- in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. within days of cfa injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period.
 6-shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. confirmation of this contribution was sought in this study in sprague- dawley rats treated with a single injection of a commercial preparation of complete freund's adjuvant to induce monoarthritis in the right knee over a period of days. during this development of arthritis, each rat received a daily oral dose of either peanut oil or 6-shogaol.  within days of cfa injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period. but, in the 6-shogaol treated group, significantly lower magnitudes of unsustained swelling of the knees were produced during the investigation period. unsustained swelling of the knees was also produced after days of treatment with indomethacin as a standard anti-inflammatory drug, but during the first days of drug treatment swelling of the knees was significantly larger than either the controls or the 6-shogaol treated group of rats. this exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. also, 6-shogaol and indomethacin were most effective in reducing swelling of the knees on day when the controls still had maximum swelling. the effect of 6-shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule- in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. there was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats.  from these results, it is concluded that 6-shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a cfa monoarthritic model of the knee joint of rats. 