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.