الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 145 |  |  |
| | | from | 145 | | |
Abstract
Background: Diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus. It is a condition associated with progressive degeneration of nerve fibers. Long term exposure to ischemia, hypoxia, lack of neurotrophic factors and oxidative stress injury in the nerve tissues of patients with DPN causes abnormal autophagy. Autophagy is a vital in vivo process which is known to preserve the balance between the synthesis and the clearance of organelles and proteins that serves to maintain normal neurological function. Trimetazidine has demonstrated protective effects in various cardiovascular diseases and has potential applications in neurological diseases, including protecting against peripheral nerve damage, influencing glycemic levels and diabetic neurological complications, promoting nerve regeneration and remyelination, and stimulating nerve growth factors. Metformin has been proved to possess beneficial effects on nervous system in several studies. Metformin regulates cell survival and increases autophagy through AMPK pathway activation. Therefore, metformin is suggested to be a potential bioactive compound which takes part in nervous system regeneration. The aim of the work: The present study is a trial to clarify and evaluate the role of autophagy process changes in the development of diabetic peripheral neuropathy and to evaluate the protective effect of trimetazidine and metformin each of them alone or combined on autophagy in a rat model of diabetic peripheral neuropathy. Materials and Methods: Forty-six adult male Sprague-Dawley rats were used. Type 1 diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ. After confirming hyperglycemia, diabetic rats were divided into four subgroups: Untreated diabetic, trimetazidine treated diabetic, metformin treated diabetic, combined trimetazidine and metformin treated diabetic groups; in addition to a control normal group. At the end of study (8 weeks), rats were subjected to hot plate test for assessment of pain sensation. Then, all animals were sacrificed using an over-dose of thiopental sodium (120 mg/kg, i.p) for blood and tissue analyses. Measurement of serum glucose level, insulin concentration and serum nerve growth factor (NGF) were done. In addition, histopathological assessment {(H,E stain) and immunohistochemical assessment of LC3 and P62} of the right sciatic nerve were done. The ultrastructure of left sciatic nerve was examined by the electron microscope. Results: Treatment of diabetic rats with either trimetazidine or metformin showed significant reduction in the serum blood glucose levels and significant increase in the insulin level, attenuated thermal hyperalgesia and a significant improvement of serum level of NGF. In addition, improved histopathological and ultrastructural changes in sciatic nerve has been observed compared to the pathological group. A significant increase in LC3 expression, a significant decrease in P62 expression and decreased autophagosomes, indicating autophagy activation, were reported. Combination of metformin and trimetazidine produced more favorable effect. Conclusion: Either trimetazidine or metformin established a significant improvement of pathological finding in sciatic nerve in rat model of DPN. These findings may be a result of induction of the autophagy process or secondary to improved hyperglycemia. Therefore, Trimetazidine represents as potentially useful drug for DPN especially group of patients who have concomitant diabetic cardiomyopathy. Metformin also is suggested to be a potential neuroprotective drug against DPN especially for patients already use it for diabetic control. In addition, combination therapy of these drugs was more effective in improvement of DPN. Key words: Diabetic peripheral neuropathy – Trimetazidine – Metformin – Autophagy