Effects of Melatonin on Diabetic Neuropathy and Retinopathy: Comparison
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Diabetes mellitus (DM) leads to complications, including neuropathy. Redox imbalance and inflammation are important components of the pathophysiology of these complications. Many studies have investigated the therapeutic potential of melatonin (MEL), an anti-inflammatory and antioxidant agent, for the specific treatment of the neural complications. In the present entry, we review studies published over the past 21 years on the therapeutic efficacy of MEL in the treatment of DM-induced neural complications. Reports suggest that there is a real prospect of using MEL as an adjuvant treatment for hypoglycemic agents.

  • melatonin
  • diabetes mellitus
  • diabetic neuropathy
  • diabetic retinopathy

1. Introduction

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia due to chronic or relative insulin deficiency. The main complications of DM are nephropathy, retinopathy, and neuropathy [1][2].

Diabetic neuropathy (DN) affects more than 50% of patients with diabetes and is a diabetic complication that affect the nervous system [3] whilst diabetic retinopathy (DR) affects the retina [4]. The few treatments available for DN and DR, are ineffective and have serious side effects. The compound melatonin (MEL) has been studied for the treatment of DM and its complications, such as DN and DR [4].

MEL is a hormone produced by the pineal gland. It has several pharmacological effects, such as: neuroprotective, anti-inflammatory, and inhibitory actions on the excitability of neurons in the central nervous system (CNS) and peripheral nervous system (PNS) [5][6][7]. Additionally, MEL has some effects opposite to those caused by DM. For example, MEL caused resting membrane potential (RMP) hyperpolarization, increased input resistance (Rin­), and reduced excitability in dorsal root ganglia neurons [7][8]. DM, on the other hand, caused opposite effects [9].

2. Relationship of Melatonin with Diabetic Neuropathy and Retinopathy

2.1. Effect of Melatonin Treatment on Diabetic Neuropathy

DM causes an increase in oxidative stress, as informed by measurements of several markers, such as increased malondialdehyde (MDA), lipid peroxidation, and reduced levels of glutathione (GSH), superoxide dismutase (SOD), and catalase. MEL has been shown to reverse the change in the levels of all of these markers, in addition to increasing the total antioxidant capacity (TAC) [10][11][12][13][14].

DM has been shown to increase the levels of inflammatory markers: Tumor Necrosis Factor alpha (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), while treatment with MEL reverted these parameters to normal [13][15].

Baydas et al.[10] investigated the effect of MEL on glial reactivity. DM caused an increase in astrocyte function markers, observed in glial reactivity, while MEL reduced these levels.

Regarding clinical studies, Shokri et al. [16] investigated the efficacy of MEL as an adjuvant to pregabalin for pain relief in diabetic neuropathy. This study reported a considerable reduction in pain and pain-related sleep interference scores in MEL-treated patients. MEL acted through different mechanisms.

2.2. Effect of Melatonin Treatment on Diabetic Retinopathy

Regarding the effects of MEL on parameters related to oxidative stress (levels of nitrotyrosine, MDA, lipid peroxidation, and GSH) and inflammation (release of pro-inflammatory cytokines, such as TNF-α, IL-1β, iNOS, and IL-6) which were altered on animal models of DR, they were reversed by MEL [17][18][19][20][21]. Increase in the expression of MT1 and MT2 receptors in the retinas of diabetic rats was aldo documented [17].

A neuroprotective anti-apoptotic effect of MEL on the retinal neurons of diabetic rats was reported [22].

In experimental model of prediabetes, serum concentrations of MEL levels were found reduced and of pro-angiogenic molecules (vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9) and MMP9), increased. This was reversed with MEL supplementation [23] .

Thus, studies that evaluated the effect of MEL on experimental models of DR suggest that this hormone may exert a protective effect on the retina of diabetic animals through mechanisms similar to those reported in animals with DN, such as antioxidant and anti- inflammatory effects.

3. Conclusions

Based on the studies presented, there are clear indications that MEL has a beneficial effect on DN and DR and is therefore promising from a therapeutic point of view. However, there is a certain difficulty in developing a unified view, as the studies present different approaches of dosage, neural structure, and moment of DM time-course in a progressive degenerative disease.

Finally, according to the studies available MEL may be suggested as a promising molecule in the treatment of complications from diabetes mellitus, specifically, DN and DR.

References

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  3. Eva L. Feldman; Brian C. Callaghan; Rodica Pop-Busui; Douglas W. Zochodne; Douglas E. Wright; David L. Bennett; Vera Bril; James W. Russell; Vijay Viswanathan; Diabetic neuropathy. Nature Reviews Disease Primers 2019, 5, 41, 10.1038/s41572-019-0092-1.
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  21. Yuanyuan Tu; Manhui Zhu; Zhenzhen Wang; Kun Wang; Lili Chen; Wangrui Liu; Qin Shi; Qingliang Zhao; Yake Sun; Xiaoyu Wang; et al.E. SongXiaojuan Liu Melatonin inhibits Müller cell activation and pro‐inflammatory cytokine production via upregulating the MEG3/miR‐204/Sirt1 axis in experimental diabetic retinopathy. Journal of Cellular Physiology 2020, 235, 8724-8735, 10.1002/jcp.29716.
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  23. Branka Djordjevic; Tatjana Cvetkovic; Tatjana Jevtovic Stoimenov; Milena Despotovic; Slavoljub Zivanovic; Jelena Basic; Andrej Veljkovic; Aleksandra Velickov; Gordana Kocic; Dusica Pavlovic; et al.Dusan Sokolovic Oral supplementation with melatonin reduces oxidative damage and concentrations of inducible nitric oxide synthase, VEGF and matrix metalloproteinase 9 in the retina of rats with streptozotocin/nicotinamide induced pre-diabetes. European Journal of Pharmacology 2018, 833, 290-297, 10.1016/j.ejphar.2018.06.011.
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  25. Branka Djordjevic; Tatjana Cvetkovic; Tatjana Jevtovic Stoimenov; Milena Despotovic; Slavoljub Zivanovic; Jelena Basic; Andrej Veljkovic; Aleksandra Velickov; Gordana Kocic; Dusica Pavlovic; et al.Dusan Sokolovic Oral supplementation with melatonin reduces oxidative damage and concentrations of inducible nitric oxide synthase, VEGF and matrix metalloproteinase 9 in the retina of rats with streptozotocin/nicotinamide induced pre-diabetes. European Journal of Pharmacology 2018, 833, 290-297, 10.1016/j.ejphar.2018.06.011.
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