Intranasal administration of Exendin-4 antagonizes Aβ31-35-induced disruption of circadian rhythm and impairment of learning and memory.

Abstract

The deposition of β-amyloid protein (Aβ) is one of the pathological characteristics of Alzheimer's disease (AD) and can disrupt circadian rhythm and impair learning and memory. Exendin-4, a therapeutic drug for type II diabetes mellitus (T2DM), exerts neuroprotective effects from the toxicity of Aβ. However, it is not clear whether Exendin-4 protects against Aβ-induced disruption of circadian rhythm. The neuroprotective effects of Exendin-4 have been studied using injection of Exendin-4 into the lateral ventricle and abdomen. However, these procedures are not suitable for clinical application. First, male C57BL/6 mice received triple distilled water or Exendin-4 (0.1nmol, 0.5nmol) by intranasal administration. Exendin-4 levels were measured in the hippocampal samples using an ELISA Kit. Then, the study examined whether intranasal or hippocampal administration of Exendin-4 antagonized Aβ-induced disruption of circadian rhythm as well as impairment of learning and memory using the wheel-running activity assay and the Morris water maze test. The study showed that intranasally administered Exendin-4 passed through the blood-brain barrier. Aβ31-35 given by intrahippocampal injection disrupted circadian rhythm and impaired learning and memory in C57BL/6 mice, and Exendin-4 given by nasal cavity or hippocampal administration ameliorated Aβ31-35-induced circadian rhythm disturbance of locomotor activity and impairment of learning and memory. These findings provide pivotal experimental support for further study of the neuroprotective effects and clinical application of Exendin-4.