Department of Ophthalmology, Emory University School of Medicine, 30322, Atlanta, GA, USA,
Adv Exp Med Biol. 2014;801:765-71. doi: 10.1007/978-1-4614-3209-8_96.
TrkB is the cognate receptor for brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family involved in neuronal survival, neurogenesis and synaptic plasticity. BDNF has been shown to protect photoreceptors from light-induced retinal degeneration (LIRD) and to improve ganglion cell survival following optic nerve damage. However, the utility of BDNF as a retinal neuroprotectant is limited by its short half-life, inability to cross the blood-brain and blood-retinal barriers, and activation of the proapoptotic p75 neurotrophin receptor. N-Acetylserotonin (NAS) is a naturally occurring chemical intermediate in the melatonin biosynthetic pathway in the pineal gland and retina. Its synthesis occurs in a circadian fashion with high levels at night and is suppressed by light exposure. Until recently, NAS was thought to function primarily as a melatonin precursor with little or no biological function of its own. We have now shown that TrkB activation in the retina and hippocampus is circadian in C3H/f(+/+) mice, which synthesize NAS, but not in C57BL/6 mice, which have a mutation in the gene encoding the enzyme that converts serotonin to NAS. In addition, treatment of mice exogenous NAS, but not with serotonin or melatonin, activates TrkB during the daytime in a BDNF-independent manner. NAS appears to have neuroprotective properties and its administration reduces caspase 3 activation in the brain in response to kainic acid, a neurotoxic glutamate analog. We have developed structural analogs of NAS that activate TrkB. One of these derivatives, N- [2-(-indol-3-yl)ethyl]-2-oxopiperideine-3-carboximide (HIOC), selectively activates TrkB with greater potency than NAS and has a significantly 5-hydroxy-1Hlonger biological half-life than NAS after systemic administration. HIOC administration results in long-lasting activation of TrkB and downstream signaling kinases. The compound can pass the blood-brain and blood-retinal barriers when administered systemically and reduces kainic acid-induced neuronal cell death in a TrkB-dependent manner. Systemic administration of HIOC mitigates LIRD, assessed electrophysiologically and morphometrically. Hence, NAS may function as an endogenous circadian neurotrophin-like compound and HIOC is a good lead compound for further drug development for treatment of retinal degenerative diseases.
TrkB 是脑源性神经营养因子 (BDNF) 的同源受体，BDNF 是神经营养因子家族的成员，参与神经元存活、神经发生和突触可塑性。BDNF 已被证明可保护光感受器免受光诱导的视网膜变性 (LIRD)，并改善视神经损伤后的节细胞存活。然而，BDNF 作为视网膜神经营养剂的效用受到其半衰期短、不能穿过血脑和血视网膜屏障以及激活促凋亡 p75 神经营养素受体的限制。N-乙酰血清素 (NAS) 是松果体和视网膜中褪黑素生物合成途径中的天然化学中间产物。其合成呈昼夜节律性，夜间水平较高，暴露于光线下会受到抑制。直到最近，NAS 被认为主要作为褪黑素前体发挥作用，自身几乎没有生物学功能。我们现在已经表明，在合成 NAS 的 C3H/f(+/+) 小鼠的视网膜和海马体中，TrkB 的激活呈昼夜节律性，而在 C57BL/6 小鼠中则没有，因为 C57BL/6 小鼠的基因编码将血清素转化为 NAS 的酶发生了突变。此外，在外源性给予 NAS 而不是给予血清素或褪黑素的情况下，在白天以 BDNF 独立的方式激活 TrkB。NAS 似乎具有神经保护特性，其给药可减少脑内对神经毒性谷氨酸类似物 kainic 酸的 caspase 3 激活。我们已经开发了 NAS 的结构类似物，它们可以激活 TrkB。其中一种衍生物，N-[2-(-吲哚-3-基)乙基]-2-氧代哌啶-3-羧酸酰胺 (HIOC)，比 NAS 更有效地选择性激活 TrkB，并且在系统给药后具有比 NAS 长的生物半衰期 5-hydroxy-1H。HIOC 给药导致 TrkB 和下游信号转导激酶的长期激活。该化合物在系统给药时可以穿过血脑和血视网膜屏障，并以 TrkB 依赖性方式减少 kainic 酸诱导的神经元细胞死亡。HIOC 的全身给药减轻了电生理学和形态计量学评估的 LIRD。因此，NAS 可能作为内源性昼夜节律神经营养素样化合物发挥作用，HIOC 是治疗视网膜退行性疾病的进一步药物开发的良好先导化合物。
