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

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.

根据神经营养因子剥夺假说（neurotrophin deprivation hypothesis），青光眼发病早期阶段神经营养支持的逆向转运减少，是诱导视网膜神经节细胞（retinal ganglion cell, RGC）变性的主要诱因之一。因此，干预神经营养信号通路似乎是实现神经保护的极具吸引力的策略。已有研究证实，向眼部外源性给予神经营养因子，可在青光眼动物模型中减少RGC丢失；然而其神经保护作用大多不足以维持RGC的长期存活。我们提出假说：针对神经营养因子释放的脑区进行干预可能具有获益，因为靶组织源性神经营养因子激活的信号通路，被认为与胞体膜起始的信号通路存在差异。本研究首先在视神经钳夹术（optic nerve crush, ONC）或激光诱导高眼压症（laser induced ocular hypertension, OHT）造模的小鼠中，对RGC变性的时空进程进行了表征。随后，选取经典神经营养因子脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）作为目标分子，检测了ONC和OHT造模后小鼠视网膜及上丘（superior colliculus, SC）中BDNF及其高亲和力受体原肌球蛋白受体激酶B（tropomyosin receptor kinase B, TrkB）的表达水平。两种造模方式对BDNF和TrkB的表达水平产生了不同的影响。接下来，我们尝试通过病毒载体介导的上丘BDNF过表达，以增强逆向神经营养转运，从而实现RGC保护。尽管本研究证实了此前报道的玻璃体内递送重组BDNF的短暂神经保护作用，但在本研究使用的青光眼模型中，病毒载体诱导的SC中BDNF过表达并未对RGC产生保护作用。该结果很可能与载体介导的BDNF过表达后神经营养因子应答性下降有关。本研究结果揭示了神经营养因子治疗的复杂性，这一点在未来的神经保护策略中理应得到充分重视。