What is Cisplatin?
Cisplatin is a “chemotherapeutic agent” which can bind with DNA covalently with the purine base mainly guanine in a cross link that leads to transcription inhibition, arrest cell cycle and causes apoptotic effect27. Cisplatin is responsible of production of reactive oxygen species28 Absorption of cisplatin into the nucleus DNA, binding two adjacent guanines in the same DNA strand causing an inhibition of DNA synthesis and death of the cell 29. In addition, Programmed cell death or apoptosis has been associated with several anticancer drugs administration, including cisplatin. This active form of cell death is characterized by morphological alternation such as cell shrinkage, vacuolization, chromatin condensation and fragmentation of DNA, which often requires the formation of new proteins called caspases30.
In our study, Cisplatin appeared to affect the histological pattern of the pulp tissue. The histological examination of the pulp that injection with a single dose of Cisplatein revealed a fatty degeneration and vacuolization of some areas of odontoblastic layer and in other areas showed crowding in odontoblasts. Osteodentine was an idiopathic calcification inside pulp tissues some areas showed hyaline degeneration. These changes were thought to be due to the mechanism of action of cisplatin that aim for cell death. Fibrosis of pulpal connective tissue with chronic inflammatory cells which in coincides with previous study on the kidney that noticed that there was an increase the chronic inflammatory cells and fibrosis induced by injection with Cisplatin31,. A study of Jiang et al. demonstrated that the DNA-damaging agent cisplatin lowered the contractile function of thoracic aortas; and caused direct vessel wall damage and cytotoxicity towards smooth muscle cells32. This study agreed with our result that showed multiple dilated blood vessels of different sizes engorged with blood appeared with areas of vacuolization in pulp tissue core were recorded in this study.
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L-carnitine is an essential amine in skeletal muscle metabolism as it is important in fatty acid metabolism, it regulates caspases activity and expression. As mentioned, caspases are essential in apoptosis33 . In the present study, the normal appearance of pulp tissue in the third group which received L-carnitine before Cisplatin injection indicated that LCarnitine has anti-oxidant and anti-inflammatory role which protects the cells from the devastating effect of Cisplatin34 . Furthermore, L-Carnitine antagonizes the induced fibrosis which Cisplatin can triggers35 . Marilyn et al. reported that L Carnitine cause vasodilation of human subcutaneous arteries, an effect that appeared mostly mediated by endothelial production of prostaglandins, but also appeared to have a modest smooth muscle cell component at higher concentrations. Therefore, the beneficial cardiovascular effects of this compound may related to vasodilation and improve the blood flow36. Marilyn results agreed with our result as group III that received single dose of L carnitine before cisplatein showed dilatation in blood vessels of the pulp core.
Induction of apoptosis using Bax protein which is one member of Bcl2 family. Bax protein is one of best anti-apoptotic regulators which can regulate the apoptotic factors release from mitochondria37 . Bax protein present in the cytoplasm of healthy cells. If the cell is subjected to chemotherapeutic agent as Cisplatin, the Bax protein is moved to the mitochondria by the help of caspases38 . Chemotherapeutic agents as Cisplatin trigger and increase Bax protein overexpression which has apoptotic effect on cancer cells, this indicated through our results as Bax imunohistochemical localization in pulpal tissue of group II showed high significant difference comparing to control group that suggested increase the apoptotic changes in cells. These results are in consistence with the results of a study performed on inner ear as Bax expression was evident after injection with Cisplatin39.
Immunohistochemical examination of group receive L-Carnitine revealed no significant difference in Bax immunoreactivity compared with control group which may suggest the protective role of L carnitine against the distructive effect of cisplatein. Cisplatin administration upregulates chemokine’s and cytokines secreted by many leukocytes and which responsible for tumour necrosing factor ? release40.
Immunohistochemical examination of tissues for TNF-? revealed a significant increase in TNF-? expression in pulp tissues after Cisplatin injection when compared to control. Whereas, no significant expression appeared for TNF-? in tissues when L-Carnitine was injected before Cisplatin. These results suggested that Cisplatin injection increases the TNF-? which is responsible for necrosis of tissues and that L-Carnitine has antagonistic effect on release of TNF-? which implies the protective effects of L-Carnitine on pulp tissues. These results are in agreement with the results of study performed on kidneys that showed Cisplatin cause nephrotoxicity which is induced by increase TNF-? produced from many leukocytes and immune cells41
In conclusion, Cisplatin has a devastating effect on pulp tissues via both the apoptotic and necrotic pathways. It is obvious from the results of the study the protective effect of L-carnitine against the cytotoxicity of Cisplatin as L-Carnitine acts as anti-oxidant and anti-inflammatory moreover it prevents fibrosis of pulp tissues if injected before Cisplatin.