الفهرس 
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Abstract
SUMMARY AND CONCLUSION
During the past 30 years, dramatic improvements have been observed in cancer therapeutics, leaving a growing number of cancer survivors (Tong et al., 2020). Unfortunately, the survivors are often plagued with several side effects attributed to chemotherapy, negatively affecting their quality of life (Ahles and Saykin, 2007). The most compromising side effect is chemotherapy-induced cognitive impairment (CICI), characterized by reduced memory, learning, and processing speed during and after the chemotherapy treatment course (Ferguson and Ahles, 2003; Noha M. Mounier et al., 2020). Cisplatin (CP), cis-diamine-dichloro platinum (II), is commonly used against a variety of solid tumors, including those of the ovary, testis, and lung (Desoize and Madoulet, 2002).
Recent studies have focused on glucagon-like peptide-1 (GLP-1), an incretin hormone, for its potential to stimulate insulin secretion (Jones et al., 2018). GLP-1 arose as a promising protector against several neurodegenerative diseases in various experimental models (During et al., 2003; Hlscher, 2012; Safar, 2015). The dipeptide peptidase-4 enzyme (DPP-4) degrades GLP-1, decreasing its half-life (Jin et al., 2010). DPP-4 inhibitors (gliptins), an important family of oral glucose-lowering medications, raise GLP-1 levels (Darsalia et al., 2015). GLP-1 binding to its receptors (GLP-1R) induces phosphorylation of PI3k/Akt, which activates various signaling pathways leading to cellular proliferation, inhibition of oxidative stress, and apoptosis (Athauda and Foltynie, 2016; Zhou et al., 2016).
Vildagliptin (vilda) is one of the FDA-approved, powerful, selective DPP-4 inhibitors used in diabetes mellitus (II) (Lauster et al., 2007). Recent research has shown that vilda is neuroprotective against Parkinsonism and Alzheimer’s disease (Ma et al., 2018; Safar, 2015; Rasha R. Yossef et al., 2020). However, vilda’s neuroprotective effect against chemotherapy-induced chemo brain has yet to be explored.
Thus, the current study assessed vilda’s possible protective role against CP-induced neurotoxicity in rats and its underlying mechanism, focusing on oxidative stress, AMPK/Akt/CREB, and apoptotic pathways.
The study design included 4 different parts:
1. Screening the neurotoxic dose of cisplatin:
A preliminary study was conducted in which rats were randomly divided into 4 groups (8 animals per group) and treated as follows: control, CP 2mg/kg once weekly for 4 weeks, CP 2mg/kg twice weekly for 2 weeks and CP 5mg/kg once weekly for 4 weeks.
The assessed parameters:
Behavioral test; passive avoidance test.
Histological examination: Hematoxylin and Eosin (H & E).
2. Screening the neuroprotective dose of vildagliptin:
A preliminary study was conducted in which rats were randomly divided into 4 groups (8 animals per group) and treated as follows: control, CP 5 mg/kg once weekly for 4 weeks, CP + vilda (5 mg/kg) for 4 weeks and CP + vilda 10 mg/kg once weekly for 4 weeks.
The assessed parameters:
Behavioral test; passive avoidance test.
Histological examination: Hematoxylin and Eosin (H & E).
3. The mechanistic study
Rats were randomly divided into four groups (15 animals per group) and treated as follows: vilda was given at dose (10 mg/kg P.O) once daily for 30 consecutive days and a dose of CP 5 mg/kg i.p. was given on once weekly for 4 weeks.
The assessed parameters:
1. Assessment of oxidative stress markers:
- Thiobarbituric acid reactive species (TBARS) measured as malondialdehyde (MDA)
- Reduced Glutathione (GSH)
- Superoxide dismutase (SOD)
2. Assessment of Acetylcholine Esterase concentration
3. Assessment of apoptotic markers
- Bax
- Bcl-2
- Caspase-3
4. Assessment of neuroinflammatory marker glial fibrillary acidic protein (GFAP)
5. Assessment of neurotrophic and proliferation markers:
- Brain-derived neurotrophic factor (BDNF)
- proliferative cell nuclear antigen (PCNA)
6. Assessment GLP-1 Pathway:
- pAMPK
- pAKT
- pCREB
7. Histopathological examination using H&E stain and toulidine blue staining.
4. Evaluation of the effect of Vildagliptin on cisplatin cytotoxicity:
To investigate the possible modulatory effect of vilda on CP cytotoxicity, the sensitivity of Human hepatocellular carcinoma (HepG-2) and Prostate carcinoma (PC-3) cell lines to CP, vilda, and their combination was determined by the MTT assay.
The findings of the present study can be summarized as follows:
1. The neuroprotection effect of vildagliptin was confirmed by the ability to restore the histopathological damage caused by cisplatin. Moreover, the neuroprotection effect was confirmed by increasing the percentage of viable neurons in the toluidine blue staining.
2. Vildagliptin restores the normal behavior of rats in the Morris water maze, Y-maze, and Passive avoidance.
3. Vildagliptin significantly counteracted the oxidative stress damage induced by cisplatin by decreasing MDA and increasing GSH and SOD activity.
4. Vildagliptin exhibited an anti-apoptotic effect by; i) lowering Bax and Caspase -3 concentration, ii) increasing the percentage area of Bcl-2 immunoreactivity.
5. Vildagliptin has neurotrophic activity by; i) enhancing the P percentage area of PCNA immunoreactivity, ii) increasing the hippocampal concentration of BDNF.
6. Vildagliptin has an anti-inflammatory effect manifested by decreasing the percentage of GFAP immunoreactivity.
7. The underline mechanism of vildagliptin in the protection of cisplatin