Anti-arthritic effects and toxicity of the essential oils of turmeric (Curcuma longa L.)

Abstract

Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids and the less well-studied essential oils. Having previously identified potent anti-arthritic effects of the curcuminoids in turmeric extracts in an animal model of rheumatoid arthritis (RA), studies were undertaken to determine whether the turmeric essential oils (TEO) were also joint protective using the same experimental model. Crude or refined TEO extracts dramatically inhibited joint swelling (90-100% inhibition) in female rats with streptococcal cell wall (SCW)-induced arthritis when extracts were administered via intraperitoneal injection to maximize uniform delivery. However, this anti-arthritic effect was accompanied by significant morbidity and mortality. Oral administration of a 20-fold higher dose TEO was nontoxic, but only mildly joint-protective (20% inhibition). These results do not support the isolated use of TEO for arthritis treatment but, instead, identify potential safety concerns in vertebrates exposed to TEO.

Figure 1

Effects of ip turmeric essential oil (TEO) extracts on joint inflammation. Female Lewis rats were injected on day 0 with vehicle or streptococcal cell wall (SCW, 25 ug/g body weight) to induce arthritis. Joint swelling in limbs was assessed at indicated times and expressed as mean arthritic index (AI) (scale 0-3/limb for total possible score of 16/animal) with statistical significance determined by analysis of variance with post hoc testing or Mann Whitney (n = 4-7 animals/group). A. Intraperitoneal treatment with crude or refined TEO (normalized to 56 mg refined TEO/g) or vehicle was begun 4 days prior to SCW injection and continued daily until 10 days after SCW injection, at which time dosing frequency decreased to 3-5 days per week. * p < 0.05 for refined or crude TEO (vs. vehicle). ** p < 0.10 for refined or crude TEO (vs. vehicle). § p < 0.05 for crude TEO only (vs. vehicle), ¶ p < 0.05 for refined TEO only (vs. vehicle). B. Intraperitoneal treatment with crude TEO (normalized to 56 mg refined TEO/g) or vehicle was delayed until 3 days after SCW injection and continued daily until 10 days after SCW injection, at which time dosing frequency decreased to 3-5 days per week. * p < 0.05 for crude TEO (vs. vehicle).

Figure 2

Dose-dependent inhibition of joint swelling by ip TEO extracts. Female Lewis rats were injected on day 0 with vehicle or streptococcal cell wall (SCW, 25 μg/g body weight) to induce arthritis. Intraperitoneal treatment with crude or refined TEO (with indicated extract doses, beginning as low as 0.28 mg/kg/d, normalized to refined TEO), or with vehicle, was begun 4 days prior to SCW injection and continued daily until 10 days after SCW injection, at which time dosing frequency decreased to 3-5 days per week. Arthritic index was assessed in TEO-treated and vehicle-injected animals and is expressed here as percent inhibition relative to controls (n = 5-30/group) with * p < 0.01 vs. untreated. A. TEO inhibition of initial, transient joint swelling (day 3). B. TEO inhibition of joint swelling during chronic, joint-destructive phase (day 28).

Figure 3

Mortality in Animals Treated with ip TEO. Survival in all animals (SCW or control) treated ip with ≥ 28 mg/mg/d refined (n = 62) or crude TEO (n = 90) vs. vehicle (n = 86) was analyzed by log-rank using Kaplan Meier survival curves. Mortality was significantly (p < 0.0001) increased in animals treated ip with either crude or refined TEO extract as compared with vehicle.

Figure 4

Hepatotoxicity and anemia associated with ip vs. oral TEO. A. Effects of ip treatment (≥ 26 mg/kg/d) with crude TEO (n = 32) or refined TEO (n = 54) vs. vehicle alone (n = 48) on serum levels of alanine aminotransferase (ALT) were determined in SCW or control animals surviving 23-32 days of treatment. Means are not statistically different by ANOVA. B. Effects of ip treatment with crude TEO (n = 18) or refined TEO (n = 37) vs. vehicle alone (n = 29) on hemacrit (HCT) were determined in control animals surviving 23-32 days of treatment. p < 0.001, crude vs. vehicle. p <0.01, refined vs. vehicle. C. Effects of oral treatment (> 560 mg/kg/d) with crude TEO (n = 34) or refined TEO (n = 5) vs. vehicle alone (n = 23) on serum levels of alanine aminotransferase (ALT) were determined in SCW or control animals surviving 28-32 days of treatment. p <0.01, refined vs. vehicle. D. Effects of oral treatment (> 560 mg/kg/d) with crude TEO (n = 11) or refined TEO (n = 5) vs. vehicle alone (n = 6) on HCT were determined in control animals surviving 28-32 days of treatment. p <0.01, crude vs. vehicle.

Figure 5

Time course of adverse effects of ip treatment with refined TEO on liver and hematopoetic parameters. In normal female Lewis rats, the effect of daily ip treatment with 28 mg/kg/d refined TEO vs. vehicle was determined over a 23-day period. Animals (n = 3 vehicle and n = 4 TEO) were sacrificed at the indicated times for assessment of hematologic parameters (hematocrit [HCT], total white blood cell [WBC], and platelet [PLT] counts) and liver function (serum levels of alanine aminotransferase) as well as gross necropsy which was notable for peritonitis, beginning as early as day 8. Results are presented as mean ± SEM.

Figure 6

Effects of oral crude TEO extract on joint inflammation. Female Lewis rats were injected on day 0 with vehicle or streptococcal cell wall (SCW, 25 μg/g body weight) to induce arthritis. Joint swelling in limbs was assessed at indicated times and expressed as mean arthritic index (AI) (scale 0-3/limb for total possible score of 16/animal) (n = 4-8 animals/group). A. Oral treatment with crude TEO (normalized to 560 mg refined TEO/kg/d) or vehicle was begun 4 days prior to SCW injection and continued daily until 10 days after SCW injection, at which time dosing frequency decreased to 5 days per week. * p < 0.05 for crude TEO (vs. vehicle). B. Oral treatment with crude TEO (normalized to 560 mg refined TEO/kg/d) or vehicle was delayed until 3 days after SCW injection and continued daily until 10 days after SCW injection, at which time dosing frequency decreased to 5 days per week.