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Inactivation Of Serine Racemase: A Possible Treatment Strategy For Diabetic Retinopathy

Diabetic retinopathy (DR) is a leading cause of adult blindness and a deleterious complication of diabetes mellitus. After a decade of diabetes, ~80-90% of patients develop DR, in which ~ 5-10% of them develop blindness due to macular edema, retinal neovascularization, and others.

At the early stage of DR called non-proliferative DR, patients have no clinical symptoms, but the typical pathologies such as retinal ganglion cell loss, degeneration of retinal nerve fiber, as well as pericyte loss, change the permeability of blood-retinal barrier, and microaneurysm, have already set in. At a later stage, patients develop proliferative DR, which is characterized by retinal neovascularization, vitreous hemorrhage, and secondary effects such as tractional retinal detachment and a fibrovascular membrane.

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The most effective treatments for DR include photocoagulation, vitrectomy, and intravitreal injection of anti-VEGF medicine and steroid hormones. However, the efficacy is limited and the interventions cause new problems. For example, photocoagulation may create new spots of hemorrhage and repeated intravitreal injection of anti-VEGF monoclonal antibodies or aptamer causes retinal detachment, retinal atrophy, and endophthalmitis. Obviously, the current treatments target the later stages of DR, i.e. retinal microvascular abnormalities.

Notably, diabetic retinal neuropathy (DRN) was described in the 1960s (Wolter 1961, Bloodworth 1962), although the relative research placed DRN in the spotlight only during the last decade.  After decades of discontinuation of DRN research in the scientific community, a study entitled Neural apoptosis in the retina during experimental and human diabetes: Early onset and effects of insulin documented DRN in experimental and human diabetes (Barber et al. 1998). A series of studies from a research group at Wenzhou Medical University connected DRN with an enzyme, serine racemase (Jiang et al. 2011, Jiang et al. 2014, Jiang et al. 2016, Jiang et al. 2018). Serine racemase is an enzyme that synthesizes L-serine to its enantiomers, D-serine and pyruvate, and is found in high amounts in the cerebral cortex and retinae. Deficiency of serine racemase has been connected with schizophrenia, cognitive decline, and memory deficiency, whereas ablation of serine racemase significantly reduces neuronal loss under the condition of ischemia or excitotoxicity (Mustafa et al. 2010, Inoue et al. 2008, Jiang et al. 2016).

A very recent publication, entitled Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice, indicates that loss-of-function mutation of serine racemase significantly mitigates retinal ganglion cell loss in Ins2Akita mice, a genetic model for type I diabetes (Jiang et al. 2018). Back in 2011, they documented an increased level of serine racemase in retinae and increased amount of D-serine in aqueous humor from diabetic rats in a paper entitled Overexpression of serine racemase in retina and overproduction of D-serine in eyes of streptozotocin-induced diabetic retinopathy (Jiang et al. 2011).

A recent study from the University of Toyama indicates that a knockout of serine racemase not only prevents retinal ganglion cell loss, but also significantly mitigates the number of acellular retinal capillaries in chemical-induced type I diabetic mice in a paper entitled Serine racemase deletion attenuates neurodegeneration and microvascular damage in diabetic retinopathy (Ozaki et al. 2018).  These studies suggest that intervention at the early stages of DR, particularly inactivation of serine racemase, benefits DR.

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These fidings are described in the article entitled Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice, recently published in the journal Experimental Eye ResearchThis work was conducted by Haiyan Jiang, Jinlin Du, Juan Song, Yanqi Li, Mengjuan Wu, Jing Zhou, and Shengzhou Wu from Wenzhou Medical University and the State Key Laboratory of Optometry, Ophthalmology, and Visual Science.

References:

  1. Barber, A. J., Lieth, E., Khin, S. A., Antonetti, D. A., Buchanan, A. G. and Gardner, T. W. (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest, 102, 783-791.
  2. Bloodworth, J. M., Jr. (1962) Diabetic retinopathy. Diabetes, 11, 1-22.
  3. Inoue, R., Hashimoto, K., Harai, T. and Mori, H. (2008) NMDA- and beta-amyloid1-42-induced neurotoxicity is attenuated in serine racemase knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28, 14486-14491.
  4. Jiang, H., Du, J., He, T., Qu, J., Song, Z. and Wu, S. (2014) Increased D-serine in the aqueous and vitreous humour in patients with proliferative diabetic retinopathy. Clinical & experimental ophthalmology, 42, 841-845.
  5. Jiang, H., Du, J., Song, J., Li, Y., Wu, M., Zhou, J. and Wu, S. (2018) Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice. Exp Eye Res, 175, 90-97.
  6. Jiang, H., Fang, J., Wu, B., Yin, G., Sun, L., Qu, J., Barger, S. W. and Wu, S. (2011) Overexpression of serine racemase in retina and overproduction of D-serine in eyes of streptozotocin-induced diabetic retinopathy. J Neuroinflammation, 8, 119.
  7. Jiang, H., Wang, X., Zhang, H., Chang, Y., Feng, M. and Wu, S. (2016) Loss-of-function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N-methyl-D-aspartate. J Neurochem, 136, 186-193.
  8. Mustafa, A. K., Ahmad, A. S., Zeynalov, E. et al. (2010) Serine racemase deletion protects against cerebral ischemia and excitotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30, 1413-1416.
  9. Ozaki, H., Inoue, R., Matsushima, T., Sasahara, M., Hayashi, A. and Mori, H. (2018) Serine racemase deletion attenuates neurodegeneration and microvascular damage in diabetic retinopathy. PLoS One, 13, e0190864.
  10. Wolter, J. R. (1961) Diabetic retinopathy. Am J Ophthalmol, 51, 1123-1141.

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