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Neurotrophic Factors in Diabetic Retinopathy

Anne R. Murray and Jian-xing Ma

CONTENTS

DIABETIC RETINOPATHY

NEUROTROPHIC FACTORS

NEUROTROPHINS AND OTHERS

ANTI-ANGIOGENIC NEUROTROPHIC FACTORS

THE DOUBLE-EDGED SWORDS: PRO-ANGIOGENIC NEUROTROPHIC FACTORS

NEUROTROPHIC FACTORS AND THE FUTURE OF DR RESEARCH

REFERENCES

Keywords Angiogenesis • Diabetic retinopathy • Neurotrophic factors • PEDF • VEGF

DIABETIC RETINOPATHY

The incidence of diabetes worldwide is staggering. Millions of people have been diagnosed with either Type 1 or Type 2 diabetes, and it is estimated that approximately 10% of diabetes cases are Type 1 [1], while approximately 90% of patients diagnosed with diabetes are Type 2. Type 2 diabetes currently affects more than 150 million people worldwide [1, 2], and it has been estimated that with an increasingly sedentary lifestyle and prevalence of obesity, the incidence of diabetes worldwide is expected to reach 366 million by the year 2020 [2, 3].

The maintenance of normal glucose levels is essential for the health of most organs. In fact, it has been shown that the incidence of issues such as peripheral neuropathy [4], oxidative stress [5], and vascular complications [4, 6, 7] increases greatly upon chronic exposure of elevated glucose levels. One severe diabetic complication involves the eye. Chronic exposure of the retina to elevated glucose levels leads to proliferative diabetic retinopathy (DR), a condition that is characterized by retinal inflammation, vascular leakage, abnormal blood vessel formation (neovascularization), and intraretinal hemorrhages [8]. Upon the progression of DR, the microvascular circulation in the retina fails, leading to ischemia (Fig. 1) [8]. If not properly monitored and regulated, the newly

From: Ophthalmology Research: Visual Dysfunction in Diabetes

Edited by: J. Tombran-Tink et al. (eds.), DOI 10.1007/978-1-60761-150-9_15 © Springer Science+Business Media, LLC 2012

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glial cell activation [14] have been observed. The changes in these cells lead to retinal hypoxia, a damaging precursor to the angiogenesis, and further DR pathologies.

NEUROTROPHIC FACTORS

The retina is comprised of several cell types that each play a specific role in maintaining normal visual function. In order to ensure neuronal cell survival, several of these cells produce neurotrophic factors (NF). NFs have several functions in the neuron including neuronal cell development, synapse formation, synaptic plasticity, proper neuronal cell function, and the promotion of neuronal cell survival [15]. Several NFs promote these cellular functions via two classes of transmembrane receptor proteins, the tropomyosin receptor kinase (Trk) and neurotrophin receptor p75 (Fig. 2 and Table 1) [16]. Binding of the NF to the p75 receptor acts to signal cell death, while binding of a NF to the Trk family promotes signaling for cell survival and differentiation [16].

Several studies have shown that in the diabetic retina, even before the onset of DR and DR-associated retinal neovascularization, there is an increase in neuronal cell death along with glial changes and a reduction in the levels of several NFs [11, 17–19]. A caveat to this phenomenon is that although a decrease is observed in many of the retinal NFs, there is an increase in the pro-angiogenic NF VEGF [20–22]. The disruption in NF function observed in the pre-DR retina can be caused by several potential

Fig. 2. Neurotrophic factors in the retina are responsible for several functions via two receptor families. Some neurotrophic factors, such as BDNF, can interact with two cell-surface receptors, the Trk and/or the p75 family. Upon binding to the Trk family of receptors, neurotrophic factor-associated intracellular signaling can occur through three major pathways, the Ras/ Raf/MEK/MAPK, PKB/Akt, or PLCg/PKC, to induce neuronal cell differentiation, cell survival, or neurotrophin-mediated neurotrophin release. Binding of a neurotrophic factor to the p75 receptor results in activation of the JNK signaling pathway and leads to the promotion of cell death.