{"id":49589,"date":"2023-06-30T10:32:43","date_gmt":"2023-06-30T10:32:43","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49589"},"modified":"2023-07-11T06:35:27","modified_gmt":"2023-07-11T06:35:27","slug":"subacute-toxicity-subacute-anti-inflammatory-and-anti-arthritic-activities-of-combination-of-hydroethanolic-extract-of-terminalia-macroptera-and-ximenia-americana-in-vivo","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/subacute-toxicity-subacute-anti-inflammatory-and-anti-arthritic-activities-of-combination-of-hydroethanolic-extract-of-terminalia-macroptera-and-ximenia-americana-in-vivo\/","title":{"rendered":"Subacute Toxicity, Subacute Anti-inflammatory and Anti-arthritic Activities of Combination of Hydroethanolic Extract of Terminalia macroptera and Ximenia americana In-vivo"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Inflammation\nis intended to repair tissue damage. The immune system fights this damage by\ninducing acute inflammation within minutes or longer 1<\/sup>.\nWhen the tissue damage has not recovered, acute inflammation turns into chronic\ninflammation 2<\/sup>.\nInflammation is initiated by a local increase in vessel diameter and high\npermeability, resulting in inflammatory oedema following passage of exudate. Subsequently,\nleukocytes migrate into the damaged tissue and eventually a granuloma is formed\n3<\/sup>.\nThese inflammatory leukocytes have degranulation and superoxide production as\nresponses. These products generate free radicals or reactive oxygen species,\nwhich cause oxidation and attack cell membranes and biomolecules, making them\ndangerous. Oxidative stress is the consequence of the imbalance between\nantioxidants and oxidants, causing alterations in proteins and lipids 3,4<\/sup>. This situation potentiates inflammation,\nespecially in chronic pathologies, which are a public health problem 5<\/sup>.\n<\/p>\n\n\n\n

Drugs\nto treat inflammatory have serious adverse effects or are very expensive. This\nreflects the interest of researchers in therapeutic substances derived from plants\nas a source of molecules to prevent or treat inflammatory diseases 6<\/sup>.<\/p>\n\n\n\n

In West Africa, medicinal plants, accessible, less toxic and effective inflammation could be a possibility alongside conventional medicines 7,8<\/sup>. The Terminalia macroptera<\/em> leaves and Ximenia americana<\/em> roots are indicated in several inflammatory diseases according to traditional medicine. Ethnobotanical studies have revealed that in Burkina Faso, Mali and Guinea, the two plants mentioned above are prescribed against hepatitis, tuberculosis, wounds and inflammations 9\u201311<\/sup>. Both plants have also shown anti-inflammatory activities in vitro<\/em> and anti-inflammatory effects against acute inflammation models. Both plants also showed in vitro<\/em> anti-inflammatory activities and anti-inflammatory effects against acute inflammation models 12,13<\/sup>. The aim of this study was to assess the subacute anti-inflammatory and anti-arthritis effects of the combination. <\/p>\n\n\n\n

Materials and Methods<\/strong><\/p>\n\n\n\n

Plant\nsamples <\/strong><\/p>\n\n\n\n

Terminalia\nmacroptera<\/em>\nleaves and Ximenia americana<\/em> roots were harvested in September 2020 on\nthe hill of an outlying (Sam\u00e9) district of Bamako. The plants were identified\nat the Department of Traditional Medicine and herbarium of each plant was\ndeposited under number 2468; 0027 respectively. The collected samples were\ndried in the drying room of the Department of Traditional Medicine at room\ntemperature and protected from sunlight. They were then pulverized.  <\/p>\n\n\n\n

Extraction\nmethods<\/strong><\/p>\n\n\n\n

On\neach powder, two extraction methods at 10% (m\/v) were performed. Aqueous\ndecoction and hydroethanolic (30:70\nv\/v) maceration were used as described previously 14<\/sup>.\nbriefly, 100 g of powder\nin 1 liter of 70% ethanol macerated for 24 hours and for decoction, 100 g of\npowder in 1 liter of distilled water, boiled for 15 minutes.     <\/p>\n\n\n\n

Experimental\nanimals<\/strong><\/p>\n\n\n\n

Male\nand female wistar rats of 8-10 weeks, from the Department of Traditional\nMedicine were used. Rats were placed in cages at a temperature of 24 \u00b1 2 \u00baC. At 12\/12 h of light and\ndark. All experiments were conducted in accordance with international\nanimal care guidelines 15<\/sup>. All described procedures were reviewed by\nthe Ethics Committee and a protocol approval was issued #Reg. No. 2021 \/ 234 \/\nUSTTB.<\/p>\n\n\n\n

Reagents\nand Medication <\/strong><\/p>\n\n\n\n

The\nfollowing products were used: Carrageenan SIGMA-ALDRICH; Adjuvant Freund\u2019s<\/p>\n\n\n\n

Complete\nSIGMA-ALDRICH, Ellman’s reagent; trichloroacetic acid; thiobarbituric acid;\ndichromate; acetic acid; adrenaline; sodium diclofenac and prednisone. <\/p>\n\n\n\n

Subacute\ntoxicity<\/strong><\/p>\n\n\n\n

Subacute\ntoxicity was performed according to OECD Test Guideline 407 16<\/sup>. 30 rats\nincluding 15 males and 15 non-pregnant nulliparous females aged 8 weeks were\nused. Rats were randomized into 3 homogeneous groups of 5 males and 5 females\neach, treated daily by<\/p>\n\n\n\n

gavage for 28 consecutive days:<\/p>\n\n\n\n

Group 1: neutral\ncontrol, 10 \u00b5l\/g of distilled water was administered; <\/p>\n\n\n\n

Group 2 and group\n3 (satellite): 2000 mg\/kg bw of the combination was administered; <\/p>\n\n\n\n

After 28 days of\ntreatment, the satellite group rats were observed for two weeks without any\nadministration. To monitor for possible reversibility, persistence or late\nonset of toxic effects. On day 29 (two weeks later for the satellite group),\nthe rats were sacrificed and blood was collected from dry and EDTA tubes.\nBiochemical and hematological parameters were measured.<\/p>\n\n\n\n

Carrageenan\ngranuloma inflammation model (air pouch)<\/strong><\/p>\n\n\n\n

The\nmethod previously used by DA et al.<\/em>17<\/sup>\nwas slightly modified for this study. Twenty-five rats randomized into 5 groups\nof 5 for the experiment. They were anaesthetized by injection of ketamine (100\nmg\/kg) intraperitoneally on day 0 and the pouch was created by subcutaneous\nadministration of 10 ml of sterilized air to dorsal surface. On third day, each\nair pouch was re-inflated with 6 ml of sterile air and immediately, 4 ml of 2% carrageenan in 0.9% NaCl\nintroduced. The animals received daily oral treatment for 4 days.<\/p>\n\n\n\n

Group 1: negative\ncontrol, 10 \u00b5l\/g of distilled water was administered;<\/p>\n\n\n\n

Group 2: positive\ncontrol, 50 mg\/kg bw diclofenac was administered;<\/p>\n\n\n\n

Group 3: combination C1: 250 mg\/kg of\nT. macroptera<\/em>\n+ 250 mg\/kg of X. americana<\/em> was administered;<\/p>\n\n\n\n

Group 4:\ncombination C2: 250 mg\/kg of T. macroptera<\/em> + 150 mg\/kg of X. americana<\/em> was\nadministered;<\/p>\n\n\n\n

Group 5:\ncombination C3: 150 mg\/kg of T. macroptera<\/em> + 250 mg\/kg of X. americana<\/em> was\nadministered.<\/p>\n\n\n\n

On 7th<\/sup> day,\nthe rats were sacrificed. The exudate was aspirated, measured and used to\nquantify leukocytes. Granuloma, liver and blood in dry EDTA tubes were collected.\n<\/p>\n\n\n\n

Arthritis\ninduced in rats by Complete Freund’s adjuvant (CFA)<\/strong><\/p>\n\n\n\n

The\nanti-inflammatory activity of the combination against chronic inflammation in\nrats was evaluated according to the method previously described 18<\/sup>.\nThe rats were randomized into 4 different groups of 5 rats (n = 5):<\/p>\n\n\n\n

Group 1 (neutral\ncontrol): no CFA injection and rats received distilled water; <\/p>\n\n\n\n

Group 2 (CFA\ncontrol): CFA injection and rats received distilled water; <\/p>\n\n\n\n

Group 3 (positive\ncontrol): CFA injection and rats received 5 mg\/kg\/day of prednisone; <\/p>\n\n\n\n

Group 4: CFA\ninjection and rats received 500 mg\/kg\/day of combination C1. <\/p>\n\n\n\n

On first day, the\nvolumes of the hind legs were recorded and 100 \u00b5l of CFA was administered\nsubcutaneously to the left hind paw. The animals were treated for the first\ntwelve days. The effect against the primary lesion of the prednisone and the\ncombination was assessed by measuring the volume of the paw injected on the 5th\nday. On the 21st day, the volume of the posterior paws was measured; afterwards\nthe rats were sacrificed, liver and blood were collected to assess biochemical\nand oxidative stress parameters 19,20<\/sup>.\nThe arthritic index was assessed macroscopically. The morphological features of\npolyarthritis were scored from 0 to 4 21<\/sup>.\n<\/p>\n\n\n\n

For primary\nlesions: The percentage inhibition of the injected paw volume versus control\nwas measured on 5th<\/sup> day. Secondary lesions were estimated by the\nincrease in volume of the non-injected paw versus control on the last day of\nthe experiment. The total of the scores corresponds to the arthritis index. <\/p>\n\n\n\n

Preparation\nof serum and liver homogenate <\/strong><\/p>\n\n\n\n

The\nserum of the collected blood was kept in the refrigerator for biochemical\nexaminations. After dissection, the liver was removed and washed immediately\nwith cold 0.9% NaCl. 0.20\ng of ground liver was homogenized in 1 ml of 50 mM Tris-HCl and centrifuged.<\/p>\n\n\n\n

Biochemical\nassays<\/strong><\/p>\n\n\n\n

AST,\nALT, total cholesterol and triglyceride levels were measured according to the\nprocedures described in the commercially available reagent kit.<\/p>\n\n\n\n

Estimation\nof oxidative stress biomarkers<\/strong><\/p>\n\n\n\n

The\nsupernatant was used to determine oxidative stress parameters. Catalase (CAT)\nactivity was determined by the colorimetric method according to Sinha22<\/sup>.<\/em>\nSuperoxide dismutase was estimated to assess the ability to inhibit\nauto-oxidation accord 23<\/sup>.\nThe concentration of malondialdehyde (MDA) was assessed and reduced glutathione\n(GSH) was estimated 24,25<\/sup>.\n <\/p>\n\n\n\n

Statistical\nanalysis<\/strong><\/p>\n\n\n\n

Results are expressed as mean \u00b1 SEM.\nStatistical analysis was performed using one-way ANOVA followed by Tukey’s test\nfor Graph Pad Prism\u00ae version 5.03. Differences were considered statistically\nsignificant, very significant and highly significant when p was <0.05 (*),\n<0.01 (**) and <0.001 (***), respectively.  <\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Sub-acute\ntoxicity<\/strong><\/p>\n\n\n\n

The\nresults focused on biochemical and hematological parameters.<\/p>\n\n\n\n

The\neffects of the combination on hematological constants<\/strong><\/p>\n\n\n\n

Hematological parameters such as white and red blood cells, hemoglobin, platelets and hematocrit showed no significant variation between the different groups (table 1).<\/p>\n\n\n\n

Table 1: Effect of the combination on hematological parameters of different groups of male and female rats.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Hematology parameters<\/strong><\/p>\n<\/td>\n

\n

Control<\/strong><\/p>\n<\/td>\n

\n

Combination 2000 mg\/kg bw<\/strong><\/p>\n<\/td>\n

\n

Satellite<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Males<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

WBC (109<\/sup>\/l)<\/p>\n<\/td>\n

\n

16.52 \u00b1 1.56<\/p>\n<\/td>\n

\n

15.24 \u00b1 2.59<\/p>\n<\/td>\n

\n

15.86 \u00b1 2,06<\/p>\n<\/td>\n<\/tr>\n

\n

RBC (1012<\/sup>\/l)<\/p>\n<\/td>\n

\n

8.32 \u00b1 1.06<\/p>\n<\/td>\n

\n

8.97 \u00b1 0.23<\/p>\n<\/td>\n

\n

8.58 \u00b1 0.31<\/p>\n<\/td>\n<\/tr>\n

\n

HGB (g\/dl)<\/p>\n<\/td>\n

\n

15.07 \u00b1 1.27<\/p>\n<\/td>\n

\n

15.33 \u00b1 0.93<\/p>\n<\/td>\n

\n

14.95 \u00b1 1.02<\/p>\n<\/td>\n<\/tr>\n

\n

PLT (109<\/sup>\/l)<\/p>\n<\/td>\n

\n

844.2 \u00b1 46.08<\/p>\n<\/td>\n

\n

858.4 \u00b1 32.39<\/p>\n<\/td>\n

\n

847 \u00b1 37,85<\/p>\n<\/td>\n<\/tr>\n

\n

HCT (%)<\/p>\n<\/td>\n

\n

44.36 \u00b1 4.24<\/p>\n<\/td>\n

\n

46.72 \u00b1 2.52<\/p>\n<\/td>\n

\n

46.34 \u00b1 3.31<\/p>\n<\/td>\n<\/tr>\n

\n

Females<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

WBC (109<\/sup>\/l)<\/p>\n<\/td>\n

\n

15.84 \u00b1 1.34<\/p>\n<\/td>\n

\n

15,44 \u00b1 4,14<\/p>\n<\/td>\n

\n

16,04 \u00b1 1,87<\/p>\n<\/td>\n<\/tr>\n

\n

RBC (1012<\/sup>\/l)<\/p>\n<\/td>\n

\n

9.08 \u00b1 0.16<\/p>\n<\/td>\n

\n

9,32 \u00b1 0,53<\/p>\n<\/td>\n

\n

9,17 \u00b1 0,58<\/p>\n<\/td>\n<\/tr>\n

\n

HGB (g\/dl)<\/p>\n<\/td>\n

\n

15.59 \u00b1 0.79<\/p>\n<\/td>\n

\n

15,78 \u00b1 1,27<\/p>\n<\/td>\n

\n

15,45 \u00b1 0,36<\/p>\n<\/td>\n<\/tr>\n

\n

PLT (109<\/sup>\/l)<\/p>\n<\/td>\n

\n

858.6 \u00b1 34.77<\/p>\n<\/td>\n

\n

869,2 \u00b1 35,81<\/p>\n<\/td>\n

\n

857,8 \u00b1 27,91<\/p>\n<\/td>\n<\/tr>\n

\n

HCT (%)<\/p>\n<\/td>\n

\n

44.94 \u00b1 1.23<\/p>\n<\/td>\n

\n

46,56 \u00b1 4,18<\/p>\n<\/td>\n

\n

47,88 \u00b1 3,39<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The values are expressed as mean \u00b1 SEM, n = 10. WBC: White blood cells, RBC: Red Blood Cell, HGB: Hemoglobin, PLT: Platelets and HCT: hematocrit.<\/p>\n\n\n\n

Effects of the combination on biochemical parameters<\/strong><\/p>\n\n\n\n

The biochemical profiles of the different groups of rats are presented in table 2. The combination at 2000 mg\/kg induced a significant (p < 0.05) decrease in transaminases and total cholesterol. This decrease disappeared after an additional two weeks observation without administration in the satellite group. However, no variation of kidney markers such as creatinine and urea were observed in neither the combination group or satellite group.  <\/p>\n\n\n\n

Table 2: Effect of the combination on the biochemical parameters of the different groups of male and female rats.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Biochemical parameters<\/strong><\/p>\n<\/td>\n

\n

Control<\/strong><\/p>\n<\/td>\n

\n

Combination 2000 mg\/kg bw<\/strong><\/p>\n<\/td>\n

\n

Satellite<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Males<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Creatinine (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

51.26 \u00b1 2.75<\/p>\n<\/td>\n

\n

54.2 \u00b1 3.07<\/p>\n<\/td>\n

\n

52.86 \u00b1 3.29<\/p>\n<\/td>\n<\/tr>\n

\n

Urea (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

4.38 \u00b1 0.63<\/p>\n<\/td>\n

\n

4.87 \u00b1 0.57<\/p>\n<\/td>\n

\n

4.83 \u00b1 0.63<\/p>\n<\/td>\n<\/tr>\n

\n

Cholesterols (mg\/dl)<\/p>\n<\/td>\n

\n

76.2 \u00b1 2.63<\/p>\n<\/td>\n

\n

70.93 \u00b1 6.21*<\/p>\n<\/td>\n

\n

75.45 \u00b1 4.52<\/p>\n<\/td>\n<\/tr>\n

\n

Triglycerides (mg\/dl)<\/p>\n<\/td>\n

\n

35.94 \u00b1 3.46<\/p>\n<\/td>\n

\n

37.64 \u00b1 3.17<\/p>\n<\/td>\n

\n

36.71 \u00b1 2.8<\/p>\n<\/td>\n<\/tr>\n

\n

AST (U\/l)<\/p>\n<\/td>\n

\n

47.09 \u00b1 1.98<\/p>\n<\/td>\n

\n

43.63 \u00b1 1.64*<\/p>\n<\/td>\n

\n

45.54 \u00b1 1.52<\/p>\n<\/td>\n<\/tr>\n

\n

ALT (U\/l)<\/p>\n<\/td>\n

\n

42.2 \u00b1 1.44<\/p>\n<\/td>\n

\n

40.30 \u00b1 3.16<\/p>\n<\/td>\n

\n

40.72 \u00b1 1.91<\/p>\n<\/td>\n<\/tr>\n

\n

Females<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Creatinine (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

50.48 \u00b1 2.66<\/p>\n<\/td>\n

\n

54.99 \u00b1 2.89<\/p>\n<\/td>\n

\n

51.78 \u00b1 1.38<\/p>\n<\/td>\n<\/tr>\n

\n

Urea (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

4.67 \u00b1 0.89<\/p>\n<\/td>\n

\n

5.18 \u00b1 0.53<\/p>\n<\/td>\n

\n

4.72 \u00b1 1.09<\/p>\n<\/td>\n<\/tr>\n

\n

Cholesterols (mg\/dl)<\/p>\n<\/td>\n

\n

78.89 \u00b1 3.1<\/p>\n<\/td>\n

\n

72.25 \u00b1 3.1*<\/p>\n<\/td>\n

\n

76.27 \u00b1 3.03<\/p>\n<\/td>\n<\/tr>\n

\n

Triglycerides (mg\/dl)<\/p>\n<\/td>\n

\n

36.61 \u00b1 1.35<\/p>\n<\/td>\n

\n

37.5 \u00b1 2.38<\/p>\n<\/td>\n

\n

35.83 \u00b1 1.11<\/p>\n<\/td>\n<\/tr>\n

\n

AST (U\/l)<\/p>\n<\/td>\n

\n

49.3 \u00b1 2<\/p>\n<\/td>\n

\n

46.5 \u00b1 1.37*<\/p>\n<\/td>\n

\n

47.4 \u00b1 1.33<\/p>\n<\/td>\n<\/tr>\n

\n

ALT (U\/l)<\/p>\n<\/td>\n

\n

43.42 \u00b1 1.56<\/p>\n<\/td>\n

\n

41.54 \u00b1 1.77<\/p>\n<\/td>\n

\n

41.37 \u00b1 1.05<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The values are expressed as mean \u00b1 SEM, n = 10. * p < 0.05 when comparing the other groups to the control group. <\/p>\n\n\n\n

Effects of the combination on carrageenan-induced inflammation in the air pouch<\/strong><\/p>\n\n\n\n

Effect\nof the combination on air pouch granuloma  <\/strong><\/p>\n\n\n\n

Figure\n1 shows a significant (p<0.001) decrease in inflammatory granuloma formation\nby all three combinations (C1, C2, C3) compared to the negative control. This\ndecrease was also significant (p<0.001) for dry granuloma weight. Furthermore,\na significant decrease (p<0.05) in the dry granuloma weight of rats in the\ndiclofenac group was observed compared to rats of combination C2 group.<\/p>\n\n\n\n

Effects\nof the combination on exudate volume and leukocyte infiltration in the air\npouch<\/strong><\/p>\n\n\n\n

Inflammation produced a significant (p<0.001) increase in exudate volume and leukocyte infiltration in the negative control group compared to rats in all three combinations (C1, C2, C3) and diclofenac. The volume of exudate and leukocyte infiltration of rats in the diclofenac group did not differ significantly from rats in the combination C1 (Figure 1). <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Effects of the combination and diclofenac on capillary permeability and leukocyte recruitment of air pouch inflammation. A: Effect of the combination on the fresh and dry weight of granuloma tissue;<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Effects of the combination C1 on Arthritis  <\/strong><\/p>\n\n\n\n

 For primary lesions, prednisone 5 mg\/kg and\nthe combination C1 showed significant inhibition (p < 0.05) of oedema\ncompared to the CFA control.<\/p>\n\n\n\n

However, the effect on primary lesions of the combination was inferior to that of prednisone. On the last day of treatment (12th<\/sup> day), prednisone and combination C1 significantly (p < 0.01) inhibited the oedema of the injected paw compared to the negative group. As for secondary lesions, prednisone and combination C1 showed significant (p < 0.05) inhibition of non-injected paw volume compared to CFA control. The percentage inhibition of non-injected paw volume was maximal for the combination C1. Arthritis scores were significantly (P < 0.01) elevated in CFA control compared to combination C1 group.  (Table 3).  <\/p>\n\n\n\n

Table 3: Anti-inflammatory activity of the combination C1 on chronic inflammation by CFA-induced arthritis in rats<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n
\n

Groups<\/strong><\/p>\n<\/td>\n

\n

Increase in paw volume (Mean \u00b1 SEM) (ml)<\/strong><\/p>\n

(% Inhibition within parentheses)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Injected paw<\/strong><\/p>\n<\/td>\n

\n

Uninjected paw<\/strong><\/p>\n<\/td>\n

\n

Arthritis Index<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

 <\/p>\n<\/td>\n

\n

Day 5<\/strong><\/p>\n<\/td>\n

\n

Day 12<\/strong><\/p>\n<\/td>\n

\n

Day 21<\/strong><\/p>\n<\/td>\n

\n

Day 21<\/strong><\/p>\n<\/td>\n

\n

Day 21<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

CFA control<\/p>\n<\/td>\n

\n

3.85 \u00b1 0.9<\/p>\n<\/td>\n

\n

3.17 \u00b1 1<\/p>\n<\/td>\n

\n

1.97 \u00b1 0.7<\/p>\n<\/td>\n

\n

0.44 \u00b1 0.2<\/p>\n<\/td>\n

\n

7.1 \u00b1 0.22<\/p>\n<\/td>\n<\/tr>\n

\n

Prednisone<\/p>\n<\/td>\n

\n

2.41 \u00b1 0.3**<\/p>\n

(33.34%)<\/p>\n<\/td>\n

\n

1.78 \u00b1 0.3**<\/p>\n

(40.21%)<\/p>\n<\/td>\n

\n

0.51 \u00b1 0.3***<\/p>\n

(74.26%)<\/p>\n<\/td>\n

\n

0.15 \u00b1 0.1*<\/p>\n

(64.63%)<\/p>\n<\/td>\n

\n

4.2 \u00b1 0.84***<\/p>\n<\/td>\n<\/tr>\n

\n

Combination C1<\/p>\n<\/td>\n

\n

2.75 \u00b1 0.5*<\/p>\n

(25.64%)<\/p>\n<\/td>\n

\n

1.82 \u00b1 0.1**<\/p>\n

(38.68%)<\/p>\n<\/td>\n

\n

0.55 \u00b1 0.3**<\/p>\n

(71.76%)<\/p>\n<\/td>\n

\n

0.13 \u00b1 0.1*<\/p>\n

(73.47%)<\/p>\n<\/td>\n

\n

4.6 \u00b1 1.14**<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The values are expressed as mean \u00b1 SEM, n = 5. ***p < 0.001, **p < 0.01, *p < 0.05 Significant different when compared CFA to combination C1 and prednisone.<\/p>\n\n\n\n

Effects of the combination C1 on biochemical parameters<\/strong><\/p>\n\n\n\n

The combination C1 significantly reduced serum ALT, AST, creatinine and urea concentrations compared to CFA control. Furthermore, this reduction was not significantly different from the prednisone group. Uric acid concentration was also significantly (p <0.001) reduced by the combination and prednisone. Prednisone produced a significant reduction (p < 0.05) compared to the combination C1 (Table 4).    <\/p>\n\n\n\n

Table 4: Effect of combination C1 on biochemical analysis of CFA-induced arthritis in rats<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n
\n

Biochemical parameters<\/strong><\/p>\n<\/td>\n

\n

CFA control<\/strong><\/p>\n<\/td>\n

\n

Combination C1<\/strong><\/p>\n<\/td>\n

\n

Prednisone<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Creatinine (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

109.7 \u00b1 1.5<\/p>\n<\/td>\n

\n

104.1 \u00b1 0.8*<\/p>\n<\/td>\n

\n

103.3 \u00b1 1.5*<\/p>\n<\/td>\n<\/tr>\n

\n

Urea (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

7.8 \u00b1 0.6<\/p>\n<\/td>\n

\n

5.5 \u00b1 0.6*<\/p>\n<\/td>\n

\n

5.2 \u00b1 0.3**<\/p>\n<\/td>\n<\/tr>\n

\n

Uric acid (\u00b5mol\/l)<\/p>\n<\/td>\n

\n

508.4 \u00b1 2.7<\/p>\n<\/td>\n

\n

372.9 \u00b1 1.21***, #<\/sup><\/p>\n<\/td>\n

\n

302.2 \u00b1 1.5***<\/p>\n<\/td>\n<\/tr>\n

\n

AST (U\/l)<\/p>\n<\/td>\n

\n

93.85 \u00b1 2.4<\/p>\n<\/td>\n

\n

61.4 \u00b1 1.7***<\/p>\n<\/td>\n

\n

67.74 \u00b1 1.2***<\/p>\n<\/td>\n<\/tr>\n

\n

ALT (U\/l)<\/p>\n<\/td>\n

\n

78.6 \u00b1 6.4<\/p>\n<\/td>\n

\n

44.6 \u00b1 1.2***<\/p>\n<\/td>\n

\n

47.1 \u00b1 2.2***<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The values are expressed as mean \u00b1 SEM, n = 5. ***p < 0.001, **p < 0.01, *p < 0.05 and #p < 0.05 Significant different when compared CFA control to treatments and prednisone to combination C1 respectively.<\/p>\n\n\n\n

Effects of the combination C1 on oxidative stress biomarkers<\/strong><\/p>\n\n\n\n

The results showed a significant (P<0.001) elevation in MDA levels, a significant (P<0.001) reduction in GSH levels, SOD and catalase activity in the CFA control compared to the neutral control. The combination C1 and prednisone reversed this trend by causing a significant (P < 0.01) elevation in GSH, SOD and catalase levels and a reduction in MDA level (P < 0.001) compared to CFA control (Figure 2).<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Effects of the combination and prednisone on oxidative stress parameters. The values are expressed as mean \u00b1 SEM, n = 5. *p< 0.05, **p< 0.01, ***p< 0.001 significant difference when compared to negative control group.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

The aim of this study was to assess the\nsubacute anti-inflammatory and anti-arthritis effects of the combination. The\nanti-inflammatory effect was observed by a significant reduction (p<0.05) in\ngranuloma formation, exudate volume and leucocyte infiltration in the air\npouch.  The\nadministration of plant extracts would affect the physiology of many organs\nsuch as the liver and kidneys. It is important to carry out a biochemical\nassessment in a sub-acute toxicity study 26<\/sup>. Biochemical assessments included blood\nlevels of creatinine, urea, transaminases, cholesterols and triglycerides. The\nonly changes observed were in ALT and cholesterol.  The combination induced a significant\ndecrease (p < 0.05) in blood levels of ALT and cholesterol. Similar results\nwere obtained with extracts of Celosia trigyna<\/em> and Eleophorbia\ndrupifera<\/em> leaves in rats 26,27<\/sup>.\nALT and cholesterols are considered to be a more specific indicator of the\nhepatoprotective effect and lipid balance respectively, which would reflect the\nexistence of hepatoprotective properties of the combination. The main\nendogenous markers of renal function are creatinine and urea. Their increases\nor decreases may reflect, respectively, renal failure or muscle atrophy 28<\/sup>.\n Our results showed no significant change\nwith the administration of 2000 mg\/kg of the combination in male and female\nrats. Other authors have found similar results 29<\/sup>.\nSerum AST, ALT, cholesterol and triglyceride levels and urea and creatinine\nlevels were analyzed to identify possible hepatic and renal damage due to\nsub-acute treatment, a critical point for the development of new analgesic or\nanti-inflammatory drugs 30<\/sup>.\nThe results suggest that the combination is not nephro- or hepatotoxic under\nour test conditions.<\/p>\n\n\n\n

In\ninflammatory responses, an acute phase with vasodilatation and high\npermeability,<\/p>\n\n\n\n

subacute phase\nwith cell migration and a chronic phase, where fibrosis of the tissues is noted31<\/sup>.\nSubacute and chronic inflammation models such as air pouch were used to assess\nthe transudative and proliferative components of inflammation 17<\/sup>.\nThe results showed that granuloma formation was inhibited by the combinations.\nThis inhibition followed this order: diclofenac > C1 > C3 > C2.\nDiclofenac showed significant inhibition (p < 0.05) compared to C2. The\nvolume of fluid in the pouch was also significantly reduced by the\ncombinations. C1 showed similar inhibition to diclofenac. <\/p>\n\n\n\n

This reduction in\ngranuloma formation and transudate would demonstrate the power of the extracts\nto inhibit the synthesis of macro-molecules and prevent the formation of\ngranulomatous tissue 17,32<\/sup>.\nThe getting leukocytes to the site of inflammation is an important parameter of\nthe inflammatory response. Leukocyte migration results from an elaborate series\nof events, including cell adhesion and motility 3,33<\/sup>.\nThe combinations inhibited the accumulation of leukocytes in the inflammatory\nfluid of the pouch. The results showed that the combinations especially\ncombination C1 has effects on this carrageenan granuloma air pouch model and\ncould therefore be a potential source of drugs against sub-chronic inflammation.<\/p>\n\n\n\n

Polyarthritis\nis a chronic inflammatory illness that injures the joints and causes deformity,\ndisability and premature death in most patients 34<\/sup>.\n <\/p>\n\n\n\n

The induction of arthritis in rats, previously described 18<\/sup> manifests itself as in humans. This model is frequently used to examine the effect of drugs against polyarthritis. After inoculation into rats, CFA induces polyarthritis in two phases. The acute phase, a maximum after 3 to 5 days, is attributed to the primary lesions, while the chronic phase occurs after 11 to 12 days, attributed to the secondary lesions and recognized by inflammation of the non-injected paw 21<\/sup>. In primary lesions, CFA-injected rats showed a significantly (P<0.05) reduced paw volume with the administration of combination C1.   Arthritis scores were significantly (P < 0.01) elevated in the CFA control compared to combination C1 group. This suggests that the combination has anti-inflammatory properties and the ability to attenuate immune system responses. In the 19th<\/sup> century, Garrod discovered that hyperuricemia was the cause of gout and it is clear that serum uric acid may play a key role in inflammatory responses 35,36<\/sup>. The combinations significantly reduced (P < 0.001) the increase in serum uric acid levels. <\/p>\n\n\n\n

Imbalance\nbetween oxidants and antioxidants induces hepatic damage causing lipid\nalterations that result in increased MDA levels. Antioxidant enzymes such as\nsuperoxide dismutase, catalase and glutathione peroxidase convert reactive\noxygen species into harmless compounds that inhibit lipid peroxidation 37<\/sup>.\nThe induction of arthritis even alters the antioxidant defense system, nearly\ndepleting the vital lines of defense (GSH, SOD and CAT) against reactive oxygen\nspecies 38<\/sup>.\nIncreased serum ALT and AST levels confirm liver damage. These were observed in\nthe CFA control group. These results are in line with the results of previous\nstudies 39\u201341<\/sup>.\nThe combination C1 induced a significant (P < 0.01) increase in catalase\nactivity, SOD and reduced glutathione accompanied by a significant (P < 0.01)\ndecrease in MDA levels compared to CFA control. Similar results were also\nreported by other investigators 42\u201344<\/sup>.\nThese results show that the combination C1 can reduce the deleterious effects\nof oxygen radical accumulation. Combination C1 therapy could be an alternative\nto combat oxidative stress. Previous studies have shown high contents of total\npolyphenols, flavonoids and tannins in the two hydroethanolic extracts of the\ntwo plants that form the combinations 14<\/sup>.\nEffect of the combinations on the two models of inflammation used in this study\ncould be explained by the presence of total polyphenols, more precisely\ntannins, and the capacity of these two hydroethanolic extracts that form the\ncombinations to inhibit pro-inflammatory enzymes. The antioxidant power of the\ncombination is attributed to the flavonoids. 12,13<\/sup>.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Finally, the non-toxicity of the combination after daily administration\nof a dose of 2000 mg\/kg for 28 days. The combination showed potential\naction against sub-acute inflammation and markedly reduced the symptoms of\nCFA-induced arthritis. The combination showed a significant decrease in inflammatory granuloma\nformation, exudate volume and leukocyte infiltration. The combination also\nsignificantly reduced the concentration of uric acid. Furthermore, the\ncombination significantly prevented oxidative stress in arthritic rats. We can therefore conclude that\nthe subacute anti-inflammatory and anti-arthritic activities of the combination\nare found to be very encouraging. Some compounds, including polyphenols and flavonoids were\nmeasured in the extracts forming the combination, which are known to have\nanti-inflammatory effects 13<\/sup>.Certainly,\na clinical study is essential and highly recommended to validate the\ncombination at 250 mg\/kg\nof T. macroptera<\/em> + 250 mg\/kg of X. americana<\/em> as an\nalternative treatment for inflammation.<\/p>\n\n\n\n

Acknowledgment<\/strong><\/p>\n\n\n\n

The authors would like to thank the teams of the drug development laboratory, of Training, Research and Expertise Centre in Medicine Sciences, Joseph Ki-ZERBO University, Burkina Faso and the Point G University Hospital Center as well as the Department of Traditional Medicine of Bamako, Mali, for their support to this study.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors declare that there are no conflicts of interest. <\/p>\n\n\n\n

Funding<\/strong> Sources<\/strong><\/p>\n\n\n\n

There are no funding sources<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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