الفهرس 
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Abstract
Cisplatin is a platinum chemotherapeutic agent that is used in a variety of malignancies; however, the severe nephrotoxicity following cisplatin treatment is the dose-limiting adverse reaction. Despite its toxicity, cisplatin remains to be one of the most commonly used chemotherapy drugs due to its therapeutic efficacy. Indeed, several mechanisms have been proposed for cisplatin-induced nephrotoxicity, including mitochondrial dysfunction, direct DNA damage, activation of caspase, formation of reactive oxygen species, effects on the endoplasmic reticulum, and increased lipid peroxidation. Nevertheless, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In spite of using protective measures, successive cisplatin dosing results in progressive and irreversible nephrotoxicity. Therefore, searching for new signaling pathways involved in the nephrotoxicity induced by cisplatin may represent a promising alternative.
Aim of the Work:
The aim of the current study was to investigate the potential nephroprotective effect of wogonin, O-methylated flavone found in Scutellaria baicalensis against cisplatin-induced nephrotoxicity in rats. Also, the possible mechanisms underlying this effect will be explored; particularly its effects on oxidative stress, inflammation, PPAR-γ pathway and Wnt/beta-catenin pathway signaling.
The present study was divided into two parts:
First, a preliminary study was designed to assess the potential wogonin nephroprotective dose in a model of cisplatin-induced nephrotoxicity in rats. In this study, sixty rats were randomly divided into six groups (n=10) and treated as follows:
• group (I): served as the control group and the rats were given saline (0.9 %), i.p, which was used as a vehicle for wogonin, daily for 12 consecutive days.
• group (II): served as the diseased group and the rats were given the vehicle only for 7 days and then on the 8th day, cisplatin was injected as a single dose (7mg/kg, i.p.).
• Groups (III), (IV) and (V): the rats were given wogonin at doses of (10, 20 and 40 mg/kg), respectively. Wogonin was dissolved in saline and given i.p once daily for 7 consecutive days followed by a single i.p injection of cisplatin (7mg/kg) on the 8th day. Then, this was followed by i.p injection of wogonin daily till the 12th day.
• group (VI): the rats were given wogonin at dose of 40 mg/kg dissolved in saline once daily for 12 consecutive days.
The following parameters were assessed:
1. Nephrotoxicity indices:
• Percentage of dead rats
• Body weight
• Relative Kidney weight
• Blood urea nitrogen (BUN)
• Serum creatinine (SCr)
2. Histopathological examination of the kidney tissues taken from the different treatment groups (hematoxylin and eosin staining).
Based on data obtained from the previous step, the optimal nephroprotective dose of wogonin was found to be 40 mg/kg, since it significantly reduced the kidney index, mortality rate, SCr and BUN levels, as compared to the cisplatin group. Also, the weight of the wogonin pre-treated rats was preserved. Besides, this dose significantly ameliorated the histopathological damage induced by cisplatin. Thus, wogonin was used at a dose of 40 mg/kg was used to study the possible mechanisms underlying this effect.
Second, the possible mechanisms underlying this effect were explored; particularly its effects on oxidative stress, inflammation, apoptosis and PPAR-γ pathway signaling and its interaction with Wnt/β-catenin pathway. To assess this goal, Forty rats were randomly divided into four groups (ten rats per each group), and treated for 12 days as follows:
• group (I): served as the control group and the rats were given saline (0.9%), i.p., which was used as a vehicle for wogonin, daily for 12 consecutive days.
• group (II): served as the diseased group and the rats were given the vehicle only for 7 days and then on the 8th day, cisplatin was injected as a single dose (7mg/kg, i.p.).
• Groups (III): the rats were given wogonin at dose of 40 mg/kg dissolved in saline and given i.p. once daily for 7 consecutive days followed by a single i.p injection of cisplatin (7mg/kg) on the 8th day. Then, this was followed by i.p injection of wogonin daily till the 12th day.
• group (IV): the rats were given wogonin at dose of 40 mg /kg dissolved in saline i.p. once daily for 12 consecutive days.
The following parameters were assessed:
1. Oxidative stress markers
• Reduced glutathione (GSH) in kidney tissues.
• Malondialdehyde levels (MDA) in kidney tissues.
2. Anti-oxidant enzymes: Catalase activity in kidney tissues.
3. Inflammatory markers:
• Tumor necrosis factor-alpha (TNF- α) levels in kidney tissues.
• Interleukin- 1 beta (IL-1β) levels in kidney tissues.
• Nuclear factor kappa-B (NF-κB) levels in kidney tissues.
4. Apoptotic Marker: assessment of the active form of caspase-3 activity in kidney tissues.
5. Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ).
6. Wnt/β-catenin pathway markers:
• Wnt levels in kidney tissues.
• β-catenin levels in kidney tissue.
The findings of the mechanistic study can be summarized as follows:
1. Cisplatin prompted a noteworthy reduction of GSH and the activity of the anti-oxidant enzyme (catalase) as well as a rise in the lipid peroxidation level in the renal tissues. These impacts were together notably ameliorated with wogonin pre-treatment.
2. Cisplatin-injected group showed a noticeable augment in the pro-inflammatory cytokines such as IL-1β, TNF-α and NF-κB; also these impacts were reversed in the wogonin-pre-treated rats.
3. Cisplatin-treated animals showed a marked apoptosis. This result was reversed by the reduced, where the levels of the active caspases-3 were reduced in the wogonin-pre-treated rats.
4. The group given cisplatin demonstrated a significant reduction in PPAR-γ expression and an elevation in Wnt/β-catenin pathway markers, while wogonin pre-treatment nearly normalized their levels in the renal tissues.
Taken together, our study showed that wogonin conferred a marked nephroprotection against cisplatin-triggered renal injury in vivo in rats. The mechanisms underlying this nephroprotective effect can be partly attributed to counteracting cisplatin-induced oxidative stress. This was determined by the significant rise in GSH and CAT levels as well as the reduction in lipid peroxidation. Also, wogonin showed a potential anti-inflammatory activity, that was manifested by reducing pro-inflammatory mediators; IL-1β, TNF-α, and NF-κB. Moreover, the suppressing effect of cisplatin on PPAR-γ was attenuated by wogonin pretreatment. Furthermore, the apoptotic cell death was significantly reduced by wogonin via diminishing caspase-3 enzymatic activity. Additionally, this study shed the light on the possible role of Wnt/β-catenin pathway in cisplatin nephrotoxicity, where wogonin pre-treatment markedly attenuated the activation of this pathway. This effect may be partly involved in the protective effect provided by wogonin. Collectively, these findings provide a new avenue for using wogonin to improve the therapeutic outcome of cisplatin in vivo.