الفهرس 
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Abstract
The present study was designed to evaluate the effect of chemotherapy on the peripheral nerves functionally and structurally using electrophysiological studies and electron-microscopy. Also, to demonstrate the role of oxidant/antioxidant balance along with inflammatory markers in CIPN. Moreover, to investigate the role of NGF in the treatment of this type of neuropathy.
Furthermore, the present study investigated the preventive role of L carnitine in the management of CIPN. Moreover, the role of local insulin injection in the treatment of this type of neuropathy was investigated. Also, to evaluate the concomitant injection of L-carinitine in the enhancement of the response to local insulin injection in the treatment of CIPN.
The present study was carried out on 64 adult Wistar male rats allocated into 2 main sub studies, the 10 days study and the 4 weeks study.
I- 10 days study:
Rats in the 10 days study were subdivided into control group, vincristine induced neuropathy group and vincristine induced neuropathy concomitantly treated with L-carnitine group.
a- Control group (n=10): rats in this group received i.p. injection of saline in a volume equivalent to the volume in which the dose of vincristine sulfate was introduced into the test rats every other day for 10 days
b- Vincristine induced neuropathy group (n=10): Peripheral neuropathy was induced in this group by i.p injection of vincristine sulfate in a dose of 0.1 mg/kg every other day for 10 days
c- Vincristine induced neuropathy concomitantly treated with L-carnitine group (n=10): rats in this group received concomitantly with the vincristine sulfate i.p injection of L-carnitine in a dose of 100 mg/kg every day for 10 days.
Electrophysiological studies as well as collection of blood samples directly from the aorta via aortic cannulation and dissection of the sciatic nerve, were performed after 10 days from the start of injection.
A small tissue block was formed from the right sciatic nerve of a rat from each group of the studied groups at the end of the study for histopathological examination using electron microscope
II- 4 weeks study:
Rats in the 4 weeks study were subdivided into control group, vincristine induced neuropathy group, vincristine induced neuropathy treated with local insulin injection group and vincristine induced neuropathy treated with L-carnitine and with local insulin injection group.
a- Control group (n=9): rats in this group received i.p. injection of saline in a volume equivalent to the volume in which the dose of vincristine sulfate was introduced into the test rats every other day for 10 days.
b- Vincristine induced neuropathy group (n=10): Peripheral neuropathy was induced in this group by i.p injection of vincristine sulfate in a dose of 0.1 mg/kg every other day for 10 days.
c- Vincristine induced neuropathy treated with local insulin injection group (n=8): peripheral neuropathy was induced in this group as in the previous groups. At the end of the 10 days, vincristine injected rats were treated with near nerve local insulin injection of the right sciatic nerve in a dose of 0.1 unit of insulin thrice weekly for 4 weeks
d- Vincristine induced neuropathy treated with L-carnitine and with local insulin injection group (n=7): Peripheral neuropathy was induced in this group as in the previous groups. Rats were concomitantly treated by i.p injection of L-carnitine in a dose of 100 mg/kg every day for 10 days, Thereafter, these rats were treated with near nerve local insulin injection of the right sciatic nerve in a dose of 0.1 unit of insulin thrice weekly for 4 weeks.
Electrophysiological studies along with blood sample collection directly from the aorta and dissection of the sciatic nerve were done after 4 weeks from the last day of vincristine sulfate injection.
A small tissue block was formed from the right sciatic nerve of a rat from each group of the studied groups at the end of the study for histopathological examination using electron microscope.
Rats in all groups were subjected to determination of the next parameters in sciatic nerve tissue and serum:
1. Tumor necrosis factor alpha (TNF α)
2. oxidative stress markers malondialdehyde (MDA).
3. Antioxidant marker glutathione (GSH)
Also, rats in all studied groups were subjected to determination of Nerve growth factor (NGF) in the sciatic nerve tissue.
Regarding the vincristine induced neuropathy group (10 days and 4 weeks study), there was electrophysiological evidence of mixed axonal – demyelinating neuropathy (with predominance of the axonal element) with more affection of the motor function rather than sensory. The 4 weeks study show evidence of the time dependency of this type of neuropathy represented in the form of more affection of the myelin sheath as presence of vacuoles in the myelin along with decrease axon thickness that was also reflected electrophysiologically. Rats in these groups showed significant increases in serum and tissue levels of oxidative and inflammatory markers (MDA and TNF) with significant reduction in the level of antioxidant marker GSH and NGF.
The preventive role of L-carnitine in vincristine induced neuropathy concomitantly treated with L-carnitine group was evident. The myelin function of the motor nerves was preserved unlikely the axons which were more affected. Also, there was evidence of less affection of the sensory axons. Histopathologically there was evidence of improvement of the myelin function which was represented in the form of less lamellar separation of the myelin sheath yet the decrease in the thickness of the axons representing the decrease in the number of the axons supporting the axonal affection. Rats in this group showed improvement regarding the oxidant/ antioxidant disbalance in the form of the significant increase in the serum and tissue levels of GSH with significant reduction in MDA and TNF levels along with significant increase in the NGF tissue level.
Local insulin injection ameliorated the sensory and motor changes caused by vincristine sulfate in vincristine induced neuropathy treated with local insulin injection group. Moreover, the local insulin injection allowed new nerve fiber sprouting along with early signs of reinnervation that was mainly detected histologically. Electro-physiological there was evidence of improvement of the myelination of the motor fibers along with the axonal function of the sensory nerves. Also, there was a significant increase in the serum and tissue levels of GSH with significant reduction in the MDA and TNF with significant increase in the NGF.
The additive effect of L-carnitine to the local insulin injection studied in vincristine induced neuropathy treated with L-carnitine and with local insulin injection group was not obvious. Almost the same electro-physiological changes were seen compared to local insulin injection. This improvement could be related more to the effect of insulin than the L-carnitine as attributed by the possible effect of LC in reducing the level of insulin. The inability of LC to add to the protective effect of insulin in this group may be related to its inability to increase NGF or to decrease TNF.