Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA
Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA
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DOI：
10.1523/jneurosci.1508-04.2004
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发表时间：
2004-09-15
影响因子：
5.3
通讯作者：
Saragovi, HU
中科院分区：
文献类型：
--
作者：
Bruno, MA;Clarke, PBS;Saragovi, HU
以前，我们开发了一种蛋白水解稳定的小分子肽模拟物，称为D3作为选择性配体的TrkA受体的细胞外结构域的神经生长因子。离体D3定义为选择性部分TrkA激动剂。在此，在认知受损的老年大鼠中测试了D3作为胆碱能神经元的潜在治疗剂的体内功效，并且我们比较了部分TrkA激活（D3）与完全TrkA/p75激活（NGF）的结果。我们表明，在体内D3结合TrkA受体，并提供了一个显着的和长期的表型救援的胆碱能表型在皮质和基底核。胆碱能救援是选择性的，并与认知受损的老年大鼠的记忆/学习的显着改善。合成配体D3和天然配体NGF的效果相当。对生长因子受体具有选择性激动活性的蛋白水解稳定的小配体可能对神经退行性疾病具有治疗潜力。
Previously, we developed a proteolytically stable small molecule peptidomimetic termed D3 as a selective ligand of the extracellular domain of the TrkA receptor for the NGF. Ex vivo D3 was defined as a selective, partial TrkA agonist. Here, the in vivo efficacy of D3 as a potential therapeutic for cholinergic neurons was tested in cognitively impaired aged rats, and we compared the consequence of partial TrkA activation ( D3) versus full TrkA/p75 activation (NGF). We show that in vivo D3 binds to TrkA receptors and affords a significant and long-lived phenotypic rescue of the cholinergic phenotype both in the cortex and in the nucleus basalis. The cholinergic rescue was selective and correlates with a significant improvement of memory/learning in cognitively impaired aged rats. The effects of the synthetic ligand D3 and the natural ligand NGF were comparable. Small, proteolytically stable ligands with selective agonistic activity at a growth factor receptor may have therapeutic potential for neurodegenerative disorders.