الفهرس 
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHYOnly 14 pages are availabe for public view
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Abstract
PN is one of the most common adverse drug reactions of cancer chemotherapy which occurs in about 19–85% of patients receiving cancer chemotherapy. The exact pathophysiology of OXL-induced PN has not been established, including Ion channel dysfunction, transporter-mediated uptake of OXL, nuclear DNA damage, oxidative stress secondary to mitochondrial damage, activation of the immune system and neuroinflammation, glia activation, neurotransmitters alterations, axonal degeneration, and DRG neurons apoptosis. OXL is a third-generation platinum-based anticancer drug that is widely used for the treatment of CRC. It mainly affects DNA synthesis by causing cross-links in DNA. Currently, there are no established therapies to prevent CIPN.
LOS is a non-peptide orally active selective AT1 receptor antagonist which was initially developed to treat high blood pressure. It has a neuroprotective effect through anti-inflammatory properties with a reduction of axonal degeneration. To our knowledge, there are no studies that assessed LOS as a preventive agent for OXL-induced PN. DPZ is a highly selective, reversible, and non-competitive AChE inhibitor rationally developed for the treatment of AD. It has a neuroprotective effect by suppressing microglial activation, antioxidant, or anti-inflammatory potentials.
In the present work, we aimed to investigate the possible protective effects of LOS and DPZ, with their anti-inflammatory effects, to prevent OXL-induced PN on a rat model, using several behavioral, biochemical, and histopathological assessment methods.
Forty-eight adult male albino rats, weighing 190-250 g, were divided randomly into four groups, and each group consisted of twelve rats.
• Control group: Rats were administered distilled water (1 ml) daily by oral gavage through an oro-gastric tube for two weeks. In addition, they received glucose 5% i.p. for 5 consecutive days every week for two weeks.
• OXL group: Rats were administered OXL with a dose of 2.4 mg/kg/day i.p. for 5 consecutive days every week for two weeks.
• OXL + LOS group: Rats were administered OXL with a dose of 2.4 mg/kg/day i.p. for 5 consecutive days every week for two weeks and LOS (100 mg/kg daily) by oral gavage for 2 weeks.
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SUMMARY AND CONCLUSION
• OXL + DPZ group: Rats were administered OXL with a dose of 2.4 mg/kg/day i.p. for 5 consecutive days every week for two weeks and DPZ (1 mg/kg daily) by oral gavage for 2 weeks.
The study assessment included three major parameters: behavioral, biochemical, and histopathological. After 24 hours of the experiment, rats were sacrificed by cervical dislocation, and a biochemical assessment of spinal TNF-α and IL-β using the ELISA technique was performed by collecting L4-L6 spinal cord samples from the rats. sciatic nerve specimens were then collected in 10% formalin for a histopathological assessment by H&E stain. In addition, Sciatic nerve tissues were examined to determine the expression of MBP by immunohistochemistry.
Behaviorally, administration of OXL significantly induced mechanical dynamic allodynia, cold allodynia, and thermal hyperalgesia compared to the control group. Treatment with LOS was able to reverse mechanical allodynia and cold allodynia. Treatment with DPZ was able to significantly reverse mechanical allodynia and thermal hyperalgesia.
Histologically, OXL induced swelling and vacuolization of the axons, degeneration of nerve fibers, and demyelination. treatment with LOS and DPZ was able to reduce these changes.
Biochemically, OXL significantly increased the spinal level of pro-inflammatory cytokines TNF-α and IL-1β. Only treatment with LOS was significantly able to reduce the expression of proinflammatory cytokines induced by OXL.
Based on the results of the present study, it can be concluded that:
1. OXL induces behavioral, histopathological, and biochemical alterations in spinal cords which may lead to serious adverse effects.
2. Treatment with LOS and DPZ could be promising options for the prevention of OXL-induced PN which is very common in patients receiving OXL.