Lycium barbarum polysaccharide protects diabetic peripheral neuropathy by enhancing autophagy via mTOR/p70S6K inhibition in Streptozotocin-induced diabetic rats

https://doi.org/10.1016/j.jchemneu.2017.12.011Get rights and content

Highlights

Abstract

Lycium barbarum polysaccharide (LBP), the major active component of Lycium barbarum, has been found to be effective in the management of some diabetic complications. We evaluated the protective effect of LBP in diabetic peripheral neuropathy (DPN) and explored the possible mechanisms. We found that LBP mildly decreased blood glucose levels and partially rescued allodynia and hyperalgesia in the diabetes mellitus (DM) rats. For the electrophysiological function of the sciatic nerve, the decrease in sensory nerve conduction velocity (SNCV) and sensory nerve action potential (SNAP) amplitudes in DM rats were partially rescued. Moreover, DM-induced structural damage to the nerve fiber myelination showed great improvement by 12 weeks of LBP treatment. The decreased expression of the myelin-related proteins, myelin protein zero (P0) and myelin basic protein (MBP), in the DM sciatic nerve was also markedly rescued after 12 weeks of LBP treatment. Furthermore, the possible role of mammalian target of rapamycin (mTOR)-mediated autophagy during these protective processes was examined. The expression of microtubule-associated protein light chain 3-II(LC3-II) and Beclin1 in the sciatic nerve was significantly decreased while the expression of P62 increased in DM rats, demonstrating an decreased activation of autophagy. As expected, the LC3-II and Beclin1 protein levels were markedly increased, and P62 was markedly decreased after LBP treatment. The expression of mTOR, p-mTOR, p70 ribosomal protein S6 kinase (p70S6K) and p-p70S6K in the DM group were markedly increased, while all of these proteins decreased in LBP group. These results demonstrate that LBP exerts protective effects on DPN, which is likely to be mediated through the induction of autophagy by inhibiting the activation of the mTOR/p70S6K pathways.

Introduction

Diabetic peripheral neuropathy (DPN) is one of the major chronic complications of diabetes (Tsapas et al., 2014), diminishing the quality of life for up to 50% of people with diabetes (Tesfaye et al., 2010). The pathogenesis of DPN has not been elucidated, and effective therapies for the condition are still lacking (Zychowska et al., 2013).

Lycium barbarum polysaccharide (LBP) is extracted from the fruit of the goji berry (solanaceae) and is a traditional medicine in China, which has reported health benefits. Interestingly, a recent clinical study of 67 type 2 diabetic patients found that 3 months of LBP administration significantly decreased their serum glucose levels and improved their insulinogenic index during oral metabolic tolerance test (OMTT) (Cai et al., 2015). Many other reports have demonstrated that LBP protects against neuronal loss induced by β-amyloid peptide (Ho et al., 2007, Yu et al., 2005), glutamate excitotoxicity (Ho et al., 2009), and other neurotoxic insults (Ho et al., 2010). LBP has also been reported to protect retinal ganglion cells in an experimental model of acute ocular hypertension (Mi et al., 2012). However, few studies have focused on the mechanisms of LBP action in DPN.

Although oxidative stress and mitochondrial dysfunction are major factors in DPN, recent evidence supports an emerging role for autophagy. Autophagy may play a protective role in diabetic neuropathy (Towns et al., 2005), functioning primarily as a cytoprotective mechanism, and is essential for the survival of neural cells. Microtubule-associated protein light chain 3 (LC3) to form LC3-II is generally considered to be a good indicator of autophagy (Nishida et al., 2009, Kabeya et al., 2000). Beclin1, a mammalian autophagy-related genes (Atg), is an essential autophagy inducer (Liang et al., 1999). Another study with STZ rats and Schwan cells (SCs) reported that diabetic peripheral nerve tissues demonstrated pathological morphology and reduced autophagic structure, accompanied by a down-regulation of Beclin1. Down-regulation of autophagy in SCs might contribute to the pathogenesis of DPN (Qu et al., 2016). A recent study with 44 male streptozotocin (STZ)-induced diabetic rats demonstrated that up-regulated autophagy in the spinal cord partially contributes to the maintenance of diabetic neuropathic pain, while rapamycin injection decreased the mechanical pain threshold. In the spinal cords of rapamycin-treated rats, the expression of LC3-II and Beclin1 protein was significantly higher than in those of non-supplemented diabetic rats. These reports suggest that mammalian target of rapamycin (mTOR)-mediated autophagy may play an important role in DPN.

In the present study, we investigated the protective effects of LBP in diabetic peripheral neuropathy. Moreover, we demonstrated that LBP alleviated the symptoms of DPN related to the induction of autophagy by inhibiting the activation of the mammalian target of rapamycin/p70 ribosomal protein S6 kinase (mTOR/p70S6K) pathways.

Section snippets

Animals

Sixty-five (65) male SD rats (8 weeks, body weight 220 ± 20 g) were used in this study (from the Experimental Animal Center of Ningxia Medical University, Yinchuan, China, with certificate no. SCXK Ningxia 20150001). The rats were housed in a temperature- and humidity-controlled environment with a 12 h light/12 h dark cycle and fed with normal food and water adlibitum. The animal research study protocol was in compliance with the National Institutes of Health guide for the care and use of

LBP decreases blood glucose levels mildly and partially rescues allodynia and hyperalgesia in the DM rats

The effects of LBP on the blood glucose levels of the DM rats are summarized in Fig. 1B. The blood glucose of DM rats remained at high levels during the experiments. LA, a drug for the treatment of diabetic neuropathy, did not affect the blood glucose, as shown in Fig. 1B and was used here as a positive control. A clear separation of the blood glucose level curves of the LBP and DM groups appeared after 4 weeks, illustrating a decrease in the treated groups. The LBP group exhibited

Discussion

Lycium barbarum has been used as a traditional herbal medicine for thousands of years in China. LBP has been reported to prevent or delay the onset of diabetic complications. A previous clinical study indicated that LBP exerts a remarkable protective effect in patients with type 2 diabetes, significantly decreasing serum glucose, increasing the insulinogenic index, and increasing high density lipoprotein (HDL) levels (Cai et al., 2015). In our study, we report that LBP treatment partially

Conclusion

In summary, our data indicate that LBP protects diabetic peripheral neuropathy by promoting autophagy through the inhibition of the activation of mTOR/p70S6K pathways in STZ-induced diabetic rats.

Ethical statement

The animal research study protocol was in compliance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978) and approved by the Institutional Animal Ethics Committee of Ningxia Medical University (Ethical number: 2016-036).

Author contributions

Si-Yang Liu, Qi-Kuan Hu and Lan-Jie He designed research; Si-Yang Liu, Ling Chen and Xiao-Cheng Li performed research and analyzed the data; Si-Yang Liu wrote the paper. All authors read and approved the final manuscript.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgment

This study was supported by grants of the National Natural Science Foundation of China (81360130, 31460300, 31260246).

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