Kamei Noriyasu, Tanaka Misa, Choi Hayoung, Okada Nobuyuki, Ikeda Takamasa, Itokazu Rei, Takeda-Morishita Mariko
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
Mol Pharm. 2017 Mar 6;14(3):916-927. doi: 10.1021/acs.molpharmaceut.6b01134. Epub 2017 Jan 27.
Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell-penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia. The pharmacological actions of insulin were investigated at different stages of memory impairment using a senescence-accelerated mouse-prone 8 (SAMP8) model. The results of spatial learning tests suggested that chronic intranasal administration of insulin with l-penetratin to SAMP8 slowed the progression of memory loss in the early stage of memory impairment. However, contrary to expectations, this strategy using penetratin was ineffective in recovering the severe cognitive dysfunction in the progressive stage, which involves brain accumulation of amyloid β (Aβ). Immunohistological examination of hippocampal regions of samples from SAMP8 in the progressive stage suggested that accelerated nose-to-brain insulin delivery had a partial neuroprotective function but unexpectedly increased Aβ plaque deposition in the hippocampus. These findings suggest that the efficient nose-to-brain delivery of insulin combined with noncovalent CPP strategy has different effects on dementia during the mild and progressive stages of cognitive dysfunction.
胰岛素现在被认为是一种治疗痴呆症（如阿尔茨海默病）的新药候选物，其病理与大脑中的胰岛素抵抗有关。我们最近的研究表明，一种涉及细胞穿透肽（CPPs）的非共价策略可以增加胰岛素从鼻腔直接转运到脑实质。本研究旨在确定通过将胰岛素与CPP穿膜肽鼻内联合给药提高脑胰岛素水平是否具有治疗痴呆症的潜力。使用衰老加速易患8型小鼠（SAMP8）模型，在记忆障碍的不同阶段研究了胰岛素的药理作用。空间学习测试结果表明，对SAMP8小鼠长期鼻内给予胰岛素和l-穿膜肽可减缓记忆障碍早期记忆丧失的进展。然而，与预期相反，这种使用穿膜肽的策略在恢复进展期严重认知功能障碍方面无效，该阶段涉及淀粉样β蛋白（Aβ）在大脑中的积累。对进展期SAMP8小鼠样本海马区的免疫组织学检查表明，加速胰岛素从鼻腔到大脑的递送具有部分神经保护作用，但意外地增加了海马体中Aβ斑块的沉积。这些发现表明，胰岛素与非共价CPP策略相结合的高效鼻腔到大脑递送在认知功能障碍的轻度和进展期对痴呆症有不同影响。
