features (1) decreased NF synthesis, (2) disrupted transport of the NF in the neuronal cell, (3) modifications in the NF-associated signal transduction pathways, or (4) the ability of the cells that produce the NF is affected, including those cells that produce NF responsible for neuron survival [23].

Although the list of NFs associated with neural diseases is extensive, the roles that they play in DR have not been exhaustively studied. Several NFs are expressed in the retina, but some have not been confirmed to be expressed in retinal diseases including DR. Currently, there are several potential therapies employing the use of neurotrophic factors in neurological diseases in diseases such as DR. In fact, there are several ongoing studies that endeavor to develop practical therapies for DR using neurotrophic factors. The following sections provide a brief description of what is known about DR-associated neurotrophic factors.

NEUROTROPHINS AND OTHERS

Nerve Growth Factor

Nerve growth factor (NGF), a member of the neurotrophin gene family, has been widely studied in diabetic neuropathy [24]. However, a definitive characterization of this factor has not been examined in DR. The low-affinity NGF receptor, p75NGR, is expressed in both the Müller and retinal ganglion cells (RGCs) [12, 25]. Streptozotocin (STZ) injected rat retinas showed increased immunoreactivity of the receptor in the retina, including throughout the RGC and the outer nuclear layer [12]. Further examination revealed that upon the induction of diabetes, the Müller cells are the major source of the receptor upregulation [12].

Therapeutic intervention using NGF found that NGF prevented programmed cell death in both RGC and Müller cells in the diabetes-induced rat retina [12]. NGF’s therapeutic potential will need to be examined further to determine its efficacy in treating patients with DR.

Glial-Cell-Derived Neurotrophic Factor

Glial-cell-derived neurotrophic factor (GDNF) was originally characterized as a neurotrophic differentiation factor in the central nervous system and retina [26]. GDNF and its receptor have been well documented in DR and have been shown to be secreted by the glial cells of the retina [27]. GDNF’s role in maintaining neural cell survival is known, but GDNF has also been linked to proper glial cell development [28, 29]. Along with its roles in development and cell survival, GDNF may also modulate vascular permeability in the BRB via modulating the function of tight junctions [30].

The therapeutic potential of GDNF in the treatment of DR has not been studied.

Ciliary Neurotrophic Factor

Ciliary neurotrophic factor (CNTF) was first identified as a factor that supported the survival of ciliary neurons in the chick embryo [31]. It is a member of the interleukin-6 (IL-6) family of cytokines and binds to two common IL-6 family receptor components, gp130 and LIFRb [32, 33]. In order to facilitate proper function, CNTF also