Effective nose-to-brain delivery of exendin-4 via coadministration with cell-penetrating peptides for improving progressive cognitive dysfunction.

In a recent study, we demonstrated the potential of a cell-penetrating peptide (CPP) penetratin to deliver the peptide drug insulin to the brain via nasal administration, and its pharmacological effect on the mild cognitive dysfunction in senescence-accelerated mouse (SAMP8). However, the therapeutic potential of intranasal insulin administration was attenuated when applied to the aged SAMP8 with severe cognitive dysfunction. The present study, therefore, aimed to overcome the difficulty in treating severe cognitive dysfunction using insulin by investigating potential alternatives, glucagon-like peptide-1 (GLP-1) receptor agonists such as exendin-4. Examination using normal ddY mice demonstrated that the distribution of exendin-4 throughout the brain was dramatically increased by intranasal coadministration with the L-form of penetratin. The activation of hippocampal insulin signaling after the simultaneous nose-to-brain delivery of exendin-4 and an adequate level of insulin were confirmed by analyzing the phosphorylation of Akt. Furthermore, spatial learning ability, evaluated in the Morris water maze test after daily administration of exendin-4 with L-penetratin and supplemental insulin for 4 weeks, suggested therapeutic efficacy against severe cognitive dysfunction. The present study suggests that nose-to-brain delivery of exendin-4 with supplemental insulin, mediated by CPP coadministration, shows promise for the treatment of progressive cognitive dysfunction in SAMP8.

Effect of an Enhanced Nose-to-Brain Delivery of Insulin on Mild and Progressive Memory Loss in the Senescence-Accelerated Mouse.

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 ß (Aß). 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 Aß 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.