THE ROLE OF NEUROTROPHINS IN GLAUCOMA (BDNF)

 

• The neurons of the central nervous system, and by extension, the fibers of the retinal ganglion cells/optic nerve, are incapable of regeneration. In this regard, glaucoma can be regarded as a neurodegenerative disorder, much like Alzheimer’s or Parkinson’s diseases.

 

• There are a number of concepts which have been propounded for the development of glaucoma. These range from the mechanical to the vascular, biochemical and intraluminal pressure theories among others. Certain risk factors have also been enumerated regarding causation of glaucoma. Among them intra-ocular pressure, increasing age, genetic background, thinner central corneal thickness, vascular dysregulation, such as Flammer’s syndrome, certain systemic diseases such as diabetes and hypertension and also ocular diseases such as myopia and iridocorneal disorders are prominent.

• It is likely that in an individual, several molecular pathways converge and induce retinal ganglion cell (RGC) loss. The cellular, molecular, hormonal signals that promote RGC death in glaucoma are probably accentuated by risk factors, tilting the neuron’s fate towards dysfunction and demise.

• In this post, we take a look at NEUROTROPHINS, and their role in glaucoma.

• Neurotrophins are diffusible trophic molecules that exert a potent survival effect on adult CNS neurons undergoing degeneration. They are a family of small, secreted peptides that include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) in mammals.

• Apart from cell survival, Neurotrophins mediate several key cellular responses in the developing and mature CNS including proliferation, differentiation, axon growth, as well as dendrite and synapse formation.

• Among the Neurotrophins BDNF is an important factor, because of its role in cell survival. BDNF is strongly expressed in the superior colliculus, and it is retrogradely transported by RGC axons to the retina. Within the retina, BDNF is produced by cells in the ganglion cell layer and inner nuclear layer. Upregulation of BDNF is an early response to axonal injury.

• The biological effects of neurotrophins are mediated by two classes of cell surface receptors:

• i) the tropomyosin related kinase (Trk) family of receptor tyrosine kinases comprising TrkA, the receptor for NGF; TrkB, the receptor for BDNF and NT-4/5; and TrkC, the receptor for NT-3.

• ii) the p75 receptor (p75NTR) which binds all Neurotrophins.

• Activation of Trk receptors is typically associated with cell survival, while p75NTR can stimulate both survival and apoptotic pathways.

• It is now widely accepted that neurotrophic factors promote neuronal survival by inhibiting default apoptotic pathways.

• One way of looking at glaucoma is the slowing down of axonal transport in this disease. As a result, pro-cell survival neurotrophic factor levels and availability is reduced, leading to progressive RGC loss. Supplementation of neurotrophic factors could be a potential strategy to prevent the death of injured RGCs.

• Intraocular injection of exogenous BDNF protein or viral-mediated BDNF gene transfer using adenovirus or adeno-associated virus (AAV) promote robust RGC survival after optic nerve transection or crush.

• The combination of BDNF gene transfer with additional therapies including free radical scavengers and cell-permeable cAMP further increase RGC neuroprotection.

• Paradoxically, in spite of its robust survival effect, BDNF does not stimulate regrowth of injured RGC axons. Studies have reported no significant RGC axon regeneration beyond the lesion site following exogenous BDNF administration. The effect of exogenous BDNF is also temporary. It delays but does not prevent cell death. This short-term activity of BDNF is attributed to the variable level of BDNF receptor TrkB expression in RGCs following injury. This limits the intrinsic capacity of these neurons to respond to neurotrophin stimulation. Unsurprisingly, TrkB gene transfer combined with exogenous BDNF administration markedly increased RGC survival. 76% of RGCs were alive at two weeks after axotomy compared to 10% of neurons that remained in control eyes (66% protection).