Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB

Abstract

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future neuroprotective strategies.

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

“…Upon ONC, the number of brain-specific homeobox/POU domain protein 3A (Brn3a) + RGCs both in vehicle-and inhibitor-treated mice decreased progressively over time post-lesion, with a Brn3a + RGC survival rate in vehicle mice of approximately 62% at four days post injury (dpi), which is similar to previous reported studies [24,25,26]. However, MMP-12 inhibitor-treated mice showed a Brn3a + RGC survival of 74% at the same time post ONC (Figure 6A–C), clearly indicating that the number of Brn3a + RGCs was significantly higher in the MMP-12 inhibitor treated group compared to the vehicle control group, at 4 dpi (2.535 ± 35 vs. 2.149 ± 61; p < 0.001) (Figure 6C).…”

Physical exercise and glaucoma: a review on the roles of physical exercise on intraocular pressure control, ocular blood flow regulation, neuroprotection and glaucoma‐related mental health

“…Upregulation of BDNF expression preserved RGC loss and retina function from ischaemia/reperfusion injury caused by acute IOP elevation model (Igarashi et al 2016), and the effect could be sustained for up to 70 weeks (Ren et al 2012). Brainderived neurotrophic factor (BDNF) was also effective in transiently slowing down axotomy-induced RGC loss Zhi et al 2005;Parrilla-Reverter et al 2009;Nakatani et al 2011;Galindo-Romero et al 2013;Dekeyster et al 2015; Junyi et al (Blanco et al 2008).…”

Glaucoma: the retina and beyond

“…However, Dekeyster et al [37] found that viral-vector-mediated upregulation of BDNF in the superior colliculus alone was unable to elicit a significant neuroprotective activity in murine models of optic nerve crush or laser-induced ocular hypertension. The authors suggest their observations to be a result of viral-vector-induced neurotrophin desensitisation, resulting in a failure of BDNF expressed in the superior colliculus to reach the retina via retrograde transport in both healthy mice and injury models.…”