Development of compounds to stimulate peripheral nerve regeneration viainduction of nerve growth factor synthesis.

神经生长因子（Nerve growth factor，NGF）是一种促进周围神经系统交感神经元和某些感觉神经元分化并维持其存活的蛋白质。最近的工作表明，在周围神经再生的神经生长因子的重要作用。这提出了NGF可用于神经损伤的治疗剂或促进剂的可能性。我们已经发现一些儿茶酚类化合物在体外能够刺激神经生长因子的合成。本研究旨在评价具有神经生长因子合成刺激活性的化合物作为神经生长因子合成刺激剂的体内活性。为此目的，我们筛选了各种化合物，并获得了一系列化合物，烷基儿茶酚，具有较强的刺激活性的神经生长因子的合成在体外。腹腔注射一种烷基儿茶酚可诱导成年大鼠心脏和颌下腺中NGF蛋白和NGF mRNA的增加。神经生长因子蛋白的增加是连续易位从坐骨神经感觉或交感神经节。重复给药的烷基儿茶酚的类似物引起的感觉神经节中的P物质水平和酪氨酸羟化酶活性在上级颈神经节的幼鼠显着升高。这些观察结果表明，烷基儿茶酚可以刺激神经生长因子的合成在体内，诱导的神经生长因子对周围神经元的生理作用。因此，我们测试了其中一种烷基儿茶酚是否可以刺激周围神经再生。每天注射甲基儿茶酚2周，增加了有髓和无髓轴突的数量，这些轴突在切断的大鼠坐骨神经的插管修复后穿过8mm的间隙生长。

Nerve growth factor (NGF) is a protein that stimulates differentiation and maintains survival of sympathetic nerirons and some sensory neurons in peripheral nervous system. Recent works suggest important roles of NGF during peripheral nerve regeneration. This presents a possibility that NGF may be useful for a therapeutic or a promoting agent for nerve injury. We have already found that some kinds of catechol compounds can stimulate NGF synthesis in vitro. In this research, we aimed to evaluate the compounds with NGF synthesis stimulatory activity as stimulators of NGF synthesis in vivo. For this purpose, we screened various compounds and obtain a series of compounds, alkylcatechols, with potent stimulatory activity of NGF synthesis in vitro. Intraperitoneal administration of one of the alkylcatechols induced an increase in NGF protein and NGF mRNA in the adult rat heart and submaxillary gland. The increase in NGF protein was successively translocated from the sciatic nerve to sensory or sympathetic ganglia. Repetitive administration of an analogue of alkylcatechol caused significant elevations of substance P level in sensory ganglia and tyrosine hydroxylase activity in superior cervical ganglia of infant rats. These observations indicate that alkylcatechols can stimulate NGF synthesis in vivo and that the induced NGF has physiological effects on peripheral neurons. Therefore, we tested one of the alkylcatechols whether it can stimulate peripheral nerve regeneration. Daily injection of methylcatechol for 2 weeks increased the numbers of both myelinated and unmyelinated axons that grew across an 8mm gap after entubational repair of sectioned rat sciatic nerve.