Division of Neuroscience, Department of Psychology, Università La Sapienza di Roma, Rome, Italy.
Department of Pediatrics, University of Arizona School of Medicine, Tucson, AZ, 85724-5073, USA.
J Appl Genet. 2019 Nov;60(3-4):357-365. doi: 10.1007/s13353-019-00517-8. Epub 2019 Sep 4.
The Npc1-null model and the Npc1 hypomorph models of Niemann-Pick C1 (NPC1) disease show defects in olfaction. We have tested the effects of the life-prolonging treatment hydroxypropyl-beta-cyclodextrin (HPBCD) on olfaction and neural stem cell numbers when delivered either systemically or by nasal inhalation. Using the paradigm of finding a hidden cube of food after overnight food deprivation, Npc1 homozygous mice showed a highly significant delay in finding the food compared with wild-type mice. Npc1 homozygous mice showed an early loss of olfaction which was mildly corrected by somatic delivery of HPBCD which also increased the number of neural stem cells in the mutant but did not change the number in wild-type mice. In contrast, nasal delivery of this drug, at 1/5 the dosage used for somatic delivery, to Npc1 mutant mice delayed loss of olfaction but the control of nasal delivered saline did so as well. The nasal delivery of HPBCD to wild-type mice caused loss of olfaction but nasal delivery of saline did not. Neural stem cell counts were not improved by nasal therapy with HPBCD. We credit the delay in olfaction found with the treatment, a delay which was also found for time of death, to a large amount of stimulation the mice received with handling during the nasal delivery.
NPC1 疾病的 NPC1-缺陷模型和 NPC1 低功能模型显示嗅觉缺陷。我们已经测试了延长寿命的治疗羟丙基-β-环糊精（HPBCD）对嗅觉和神经干细胞数量的影响，当通过全身或鼻内吸入给药时。使用在一夜禁食后寻找隐藏的食物方块的范例，与野生型小鼠相比，Npc1 纯合子小鼠在寻找食物方面表现出显著的延迟。Npc1 纯合子小鼠表现出嗅觉的早期丧失，这被体细胞给予 HPBCD 轻度纠正，这也增加了突变体中的神经干细胞数量，但没有改变野生型小鼠中的数量。相比之下，将这种药物以体细胞给药剂量的 1/5 通过鼻内给予 NPC1 突变小鼠，可延迟嗅觉丧失，但给予生理盐水的对照也可延迟嗅觉丧失。HPBCD 经鼻内给予野生型小鼠会导致嗅觉丧失，但生理盐水经鼻内给予不会。经鼻内给予 HPBCD 对神经干细胞计数没有改善。我们将嗅觉的延迟归因于治疗，这种延迟也与死亡时间的延迟有关，这是由于在鼻内给药期间老鼠受到了大量的刺激。
