Changes in retinal expression of neurotrophins and neurotrophin receptors induced by ocular hypertension

Abstract

Open angle glaucoma is defined as a progressive and time-dependent death of retinal ganglion cells concomitant with high intraocular pressure, leading to loss of visual field. Because neurotrophins are a family of growth factors that support neuronal survival, we hypothesized that quantitative and qualitative changes in neurotrophins or their receptors may take place early in ocular hypertension, preceding extensive cell death and clinical features of glaucoma. We present molecular, biochemical, and phenotypic evidence that significant neurotrophic changes occur in retina, which correlate temporally with retinal ganglion cell death. After 7 days of ocular hypertension there is a transient up-regulation of retinal NGF, while its receptor TrkA is up-regulated in a sustained fashion in retinal neurons. After 28 days of ocular hypertension there is sustained up-regulation of retinal BDNF, but its receptor TrkB remains unchanged. Throughout, NT-3 levels remain unchanged but there is an early and sustained increase of its receptor TrkC in Müller cells but not in retinal ganglion cells. These newly synthesized glial TrkC receptors are truncated, kinase-dead isoforms. Expression of retinal p75 also increases late at day 28. Asymmetric up-regulation of neurotrophins and neurotrophin receptors may preclude efficient neurotrophic rescue of RGCs from apoptosis. A possible rationale for therapeutic intervention with Trk receptor agonists and p75 receptor antagonists is proposed.

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…96 NT-4 normally activates tyrosine kinase-B receptor (TrkB) present in the RGCs and therefore is considered to play a protective role against high IOP, ischemia and release of cytotoxins. [97][98][99][100][101] According to Pasutto et al 47 , mutations in the NTF4 gene resulted in the impairment of TrkB signaling, as well as neuronal growth, and therefore, the NTF4 variants may have a significant effect on neuronal survival. They postulated that agents activating TrkB could therefore be a novel glaucoma treatment.…”

Glaucoma: Current and Developing Concepts for Inflammation, Pathogenesis and Treatment

“…Furthermore, since p75 receptors are partially controlled by Trk receptors, truncated TrkC receptors may contribute to p75 activation. Under increased lOP, p75 was upregulated (14).…”

“…These factors bind and phosphorylate Trk receptors, resulting in an anti-apoptotic effect. The expression of Trk receptor families (TrkA, Band C) also partially regulates p75 receptors, which induce apoptosis when activated (14).…”

Neuroprotection in Glaucoma

“…Coassin et al (2008) demonstrated that during elevated IOP retinal NGF expression was upregulated and it correlated with RGC death, mainly as the ratio of TrkA to p75 was shifted toward pro-apoptotic p75. Rudzinski et al (2004) suggested that RGC apoptosis during elevated IOP was not only due to neurotrophic factor deprivation, but also dysfunction of NT receptors and their signaling pathways. It is clear that mere administration of NTs would not be efficacious as a neuroprotective strategy, suggesting that a concurrent regulation of receptor expression would be necessary for optimal neuroprotection.…”