الفهرس 
Introduction and Aim of The WorkOnly 14 pages are availabe for public view
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Abstract
In this study, we investigated the neuroprotective role of trimetazidine (TMZ) and taurine (TAU) against paclitaxel-induced peripheral neuropathy (PIPN) and the possible mechanisms underlying this effect. In addition, the impact of these combination on the anticancer effect of PTX was also evaluated.
Induction of PIPN was achieved via intraperitoneal administration of 4 doses of paclitaxel (PTX) (4.5 mg/kg, every other day, cumulative dose of 18 mg/kg). Mice were divided into two separate sets for evaluation of neuroprotection of TMZ and TAU as following:
Set 1: Evaluation of neuroprotective effect of TMZ
Control group: Mice treated with intraperitoneal injection of vehicle (ethanol/tween 80/saline equivalent to ethanol (0.03 ml/Kg), 4 doses, every other day).
TMZ group: Mice treated with TMZ (5 mg/kg, i.p, daily for 8 days) .
PTX group: Mice treated with paclitaxel (4.5 mg/kg, i.p, 4 doses given every other day).
PTX + TMZ group: Mice treated with a combination of paclitaxel (4.5 mg/kg, i.p, 4 doses given every other day) and TMZ (5 mg/kg, i.p, daily for 8 days) injected 30 minutes after PTX.
Set 2: Evaluation of neuroprotective effect of taurine
Control group: Mice treated with intraperitoneal injection of vehicle (ethanol/tween 80/saline equivalent to ethanol (0.03 ml/Kg), 4 doses, every other day).
TAU group: Mice treated with taurine (100 mg/kg, oral, daily for 8 days).
PTX group: Mice treated with paclitaxel (4.5 mg/kg, i.p, 4 doses given every other day).
PTX + TAU group: Mice treated with a combination of paclitaxel (4.5 mg/kg, i.p, 4 doses given every other day) and taurine (100 mg/kg, oral, daily for 8 days) injected 30 minutes after PTX.
Assessment of neuropathy has been done over the days (8-11), animals were sacrificed and sciatic nerve and dorsal root ganglia were collected.
For evaluation of possible interference of the suggested treatments with the anticancer effect of PTX, solid Ehrlich carcinoma (SEC) was induced in male mice via subcutaneous injection of 0.2 ml of Ehrlich ascites carcinoma cell suspension (2 × 106/ml) into the right thigh. Fourteen days after inoculation of Ehrlich cells, tumor dimensions were measured. Then, mice which developed palpable tumor were randomly allocated into experimental groups which received the same treatment as the experimental groups of neuropathy. During treatments, tumor volume was measured every other day. Then after treatment cessation, animals were sacrificed and samples of tumor tissues were harvested for histological assessment.
To fulfil the aim of this study, The neuroprotective effect of these treatments has been assessed via different behavioral tests which evaluates sensory and motor functions. Both stimulus-induced tests such as tail flick test and von Frey test as well as pain suppressed behaviors such as nesting behaviors were evaluated. Then the role of TLR4 receptors was evaluated throughout the TLR4/p38/NF-kβ and IL-1β and IL-10. Moreover, the possible role of cell senescent markers Klotho and HSP27 were also evaluated. The present study demonstrated the following results;
• Administration of PTX (4.5 mg/kg, every other day, cumulative dose of 18 mg/kg) to Swiss albino male mice successfully induced PIPN as verified by behavioral tests and histopathological changes observed in H&E-stained sections. Cotreatment with either TMZ or taurine prevented the behavioral changes associated with neuropathy and significantly inhibited the histological changes associated with the neurotoxic effect of PTX.
• Paclitaxel resulted in over expression of TLR4, p38 and NF-kβ. In addition, PTX increased the concentration of IL-1β in both DRG and sciatic nerve. These proteins were significantly suppressed via co treatment with either TMZ or TAU.
• Paclitaxel treated animals showed a lower expression of Klotho, and HSP27 as well as the concentration of IL-10. All markers were partially preserved in animals cotreated with either TMZ or TAU.
• Paclitaxel administered to solid Ehrlich carcinoma-bearing mice resulted in reduction of the tumor volume compared to vehicle treatment. On one hand, cotreatment of PTX with TMZ had no effect on the tumor suppressing effect of PTX. On the other hand, cotreatment with taurine enhanced the anticancer effect of PTX.
In conclusion, both trimetazidine and taurine exerted a neuroprotective effect against PIPN without interfering with its anticancer effect. TMZ and taurine interfered with PTX induced overexpression of TLR4/p38/NF-Kβ and inflammatory IL-1β. The study suggests a possible role of klotho and HSP27 in the neuroprotective effect of these treatments.