This study investigated the impact of ethanol leaf extract of Buchholzia coriacea (ELEBC) on biochemical dysregulations due to rheumatoid arthritis induction in rats. First, we investigated the chemical composition of the leaves of Buchholzia coriacea to ascertain whether it has relevant bioactive components. The result of quantitative Vitamin, Phytochemical and Mineral analysis of Buchholzia coriacea leaves (BCL) revealed that BCL has important compounds in varying concentrations, which could have impacted the positive ameliorative trend observed in the in vivo studies. There were high levels of Vitamin C, B1, and B2 in the extract in addition to high levels of phenols, flavonoids, alkaloids, and terpenoids. Iron was highest in the mineral constituents present in ELEBC. The above bioactive compounds are known to have various physiological potentials ranging from antioxidant to anti-inflammatory potentials respectively.
Furthermore, the result from the in vivo studies revealed that administration of ELEBC at varied doses of 200, 400 and 800 mg/kg displayed anti-rheumatoid arthritis potentials in the albino rats. The ELEBC reduced the inflamed paw volumes and also led to significant elevations in lowered body weight of the arthritic rats. Rheumatoid arthritis further caused some biochemical abnormalities and rats administered with varied doses of ELEBC displayed a reversal of these deleterious abnormalities. This indicates that ELEBC has ameliorating potentials in the rheumatoid arthritis-induced liver, renal and hematological dysfunctions.
Rheumatoid arthritis is a disease that involves many body organs like the liver, heart, and kidney (39). Some functions of the liver include the metabolism of drugs, detoxification, synthesis, and storage of some vital biomolecules. The liver is an essential modulatory organ whose roles during autoimmune and other chronic inflammatory diseases are indispensable (40). Hepato-protective effects of medicinal plants are reported in our earlier studies (41). Severe rheumatoid arthritis is marked by the over-production of autoantibodies, inflammatory cytokine release, and immune complex deposition (42). RA, like other inflammation disorders, can lead to changes in the hematopoietic system (43). Thus, the assessment of hematologic indices could be helpful in evaluating disease severity or the extent of recovery of arthritic patients.
RA being a systemic disorder can also affect kidney adversely (44). Creatinine and uric acid are well-known markers of glomerular filtration rate (GFR). Elevated creatinine and uric acid levels could be due to lowered capacity of nephrons culminating in a decrease in the kidney’s filtering capacity and subsequent accumulation of waste products within the system (44). In this study, some of the biochemical markers of the liver (ALT, AST, ALP, total protein, albumin, total and conjugated bilirubin), hematological (Hb, PCV, RBC, WBC, and ESR) and renal (creatinine and uric acid) functions were investigated. Our study revealed a bifold increase in paw size of the arthritic rats. Tang et al. (44)) made a similar observation. We observed a reduced paw size after administering standard drugs and various doses of ELEBC to rats. Previous studies have also documented the paw size-reducing properties of some medicinal plants in arthritic rats (32).
Edema is a key attribute of acute inflammation and hence always monitored when examining anti-inflammatory potential of any compound (45). Manifestation of inflammation causes vasodilation and increased blood flow culminating in increased heat and redness. Inflamed rat paws heighten extra vascular protein infiltration and subsequent edema. Extravascular protein infiltration is aided by enhanced vascular permeability of blood vessels, culminating in the discharge of plasma proteins and fluids into the tissue, and consequent edema and swelling. It has been reported that hind paw swelling at the site of injection of Freund’s adjuvant connotes inflammation which is the initial presentation of RA (46).
Markedly, at the first week of induction of RA, there was an obvious reduction in body weight. This trend was however reversed when the animals received the standard drug and various doses of ELEBC. A continuous reduction of weight was noticed in rats that received no drug or ELEBC. This result conforms to the study of other authors (47). Perhaps this reduction in body weights of the rats may be owing to elevated leptin amount as suggested by Mariam et al. (48). Leptin is a hormone made by fat cells which subdue hunger and also influences the immune system. An increase in leptin level can lead to the generation of pro-inflammatory cytokines culminating in chronic inflammation if not arrested (48). The presence of other inflammatory mediators can also lead to increased leptin levels (48).
It is pertinent to note that raised concentration of pro-inflammatory cytokines could impair energy metabolism and also enhance muscle protein breakdown. Enhanced catabolism accelerates resting energy expenditure leading to weight loss and reduced lean body mass (49). The increase in body weight in rats that received standard drug and extract could be attributed to the decline of the inflammatory cytokines coupled with a decline in protein and muscle breakdown. Inflammation can also cause a reduction in the absorption ability of the intestine(49). According to Zhang et al. (50), the absorption power of the intestine was restored when anti-inflammatory drugs were administered and weight gain was observed. Therefore, the observed significant gain in body weight of rats treated with standard drug and extract could be due to enhanced absorption capacity of the intestine.
Additionally, our results showed high activities of liver enzymes (ALT, AST, and ALP) as well as raised total and conjugated bilirubin in arthritic rats while lowered albumin level was observed. Administration of indomethacin and samples to rats reversed this trend in a time and dose-dependent approach except for AST activity which had no change on the administration of ELEBC. Usually, AST and ALT are domiciled in the liver. However, when hepatocellular integrity is impaired, these enzymes leak into the general circulation (51). The fact that AST activity remained unchanged after standard drug and sample administration shows that the samples produced no harmful effect on the liver of rats nor did it ameliorate the high activity of AST seen as a consequence of induction of arthritis.
Administration of standard drug and ELEBC to arthritic rats significantly lowered the raised ALP level. ALP is commonly present in the liver, bile, and other organs. Increased activity of ALP could portend biliary obstruction, gallstone, and other liver diseases. ALP activity can also rise when there is a bone disease where osteoblastic activity is enhanced (52).
Adjuvant administration caused a significant increase in uric acid and creatinine concentrations. Treatment did not cause any alteration in uric acid level even at dose 800 mg/kg in the arthritic rats. More so, treatment with standard drug, and ELEBC yielded no effect on creatinine level on days 10 and 17. However, ELEBC treatment produced highest reduction on creatinine level on days 24 and 31 of the investigation. Plasma creatinine is an established marker of glomerular filtration rate (GFR). Elevated creatinine and uric acid concentration could signify impairment in filtering capacity of kidney and this could result to pileup of unwanted products within various systems (53). Perhaps, the observed non-alteration in uric acid and creatinine concentrations in treated groups portends that the administration of ELEBC probably did not alter renal function indices.
Furthermore, concentrations of Hb, PCV, and RBCs in rats were significantly reduced on induction with rheumatoid arthritis. Interestingly, the administration of standard drugs and varied doses of ELEBC reversed this trend. Several authors have also reported marked improvement in Hb, PCV, and RBCs in rats administered with medicinal plant extracts (54–56). Anemia is a very recurrent feature observed in RA patients. The commonest one is anemia of chronic disease (57). It is mostly a result of chronic blood loss from gastritis (induced by NSAIDS), peptic ulcer, or gastroesophageal reflux. The reduction in the Hb concentration could have been caused by the reduced lifespan of RBCs and impaired iron absorption and utilization (58). Inflammatory mediators released during anemia in RA patients can induce excess production of hepcidin. Hepcidin is a hormone that regulates iron metabolism. It hinders iron exportation from cells by reducing the activity of ferroportin (59, 60).
WBCs are biological soldiers recruited against foreign attacks. Induction of RA resulted in a rise in WBC counts. The stimulation of the immune system by the adjuvant could have led to the generation of WBCs. Reduction in WBC levels was remarkable during treatment. This is suggestive of the immune system suppressing effect and consequent WBCs lowering the ability of the samples. We also observed that induction of RA caused a significant increase in the erythrocyte sedimentation rate in the arthritic rats, which suggests an increase in inflammation. This result corroborates the findings of previous authors(32). During periods of RA, cytokines like TNF-α, IL-6, and IL-1β play contribute to disease severity. Lymphocytes are affiliated with arthritic diseases since their signaling could elicit autoimmunity. Lymphocyte activation could result in chronic inflammation, damage to structure and function (39, 61)