Abstract
Neuropathy is a complication that affects more than 50% of long-standing diabetic patients. One of the causes of diabetes neuropathy (DN) is the apoptosis of Schwann cells due to prolonged exposure to high glucose and build-up of oxidative stress. Melatonin is a hormone that has a known antioxidant property. In this study, we investigated the protective effect of melatonin on high glucose-induced Schwann cells’ apoptosis. Our results revealed that high glucose promoted apoptosis via mitochondrial-related oxidative stress and downregulated Bcl-2 family proteins in Schwann cells. In this signalling pathway, Bcl-2, Bcl-XL and Mcl-1 proteins were down-regulated while p-BAD and Puma proteins were up-regulated by high glucose treatment. Besides, we also proved that high glucose promoted apoptosis in Schwann cells through decreasing the p-NF-κB in the NF-κB signalling pathway. Key regulators of mTOR signalling pathway such as p-mTOR, Rictor and Raptor were also down-regulated after high glucose treatment. Additionally, high glucose treatment also decreased the Wnt signalling pathway downstream proteins (Wnt 5a/b, p-Lrp6 and Axin). Our results showed that melatonin treatment significantly inhibited high glucose-induced ROS generation, restored mitochondrial membrane potential and inhibited high glucose-induced apoptosis in Schwann cells. Furthermore, melatonin reversed the alterations of protein expression caused by high glucose treatment. Our results concluded that melatonin alleviates high glucose-induced apoptosis in Schwann cells through mitigating mitochondrial-related oxidative stress and the alterations of Bcl-2, NF-κB, mTOR and Wnt signalling pathways.
Highlights
50% of patients with longstanding diabetes mellitus (DM) eventually developdiabetes neuropathy (DN) [1]
The effects of melatonin on cell viability of high glucose-treated Schwann cell was measured by MTT assay
Our results showed that Bcl-2, Bcl-xL and expression of pro-survival Bcl-2 family were downregulated after high glucose treatment
Summary
50% of patients with longstanding diabetes mellitus (DM) eventually developDN [1]. Growing evidence suggests that the pathophysiology of diabetes neuropathy (DN) is constituted by a number of interwoven pathways including increased flux of glucose to the polyol pathway, increased hexosamine shunt, aldose reductase activation, decrease in nerve myo-inositol content, formation of advanced glycation end product (AGE), impaired neurotrophic support and activation of protein kinase C (PKC). All these events result in the overproduction of reactive oxygen species (ROS). ROS has been reported to be associated with impaired mitochondrial function. The resulting depolarisation is followed by collapse of the mitochondrial membrane potential (MMP) leading to the release of pro-apoptotic factors such as cytochrome c, caspases, and subsequently promotes apoptosis [5,6,7,8,9]
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