(AS1) Neuropeptide Cocktail Induced by Non-invasive Diving Reflex Improves Cognitive Function After Vascular Dementia

Introduction: Vascular dementia (VaD) is a common type of dementia caused by reduced cerebral blood flow (CBF). Neuropeptides play a critical role in the regulation of CBF and cognitive functions. Previous studies have shown that depletion of various neuropeptides strongly correlates with cognitive deterioration after VaD. However, it is challenging to administration of neuropeptides as therapeutics due to their short half-life, BBB permeability, and side effects. The trigeminal nerve forms extensive networking in cerebrovasculature and is the source/sink/signaling site of various neuropeptides. Non-invasive stimulation of the trigeminal nerve can induce diving reflex (DR), a powerful endogenous mechanism, to focally release neuropeptide cocktail in the brain. Therefore, we hypothesize that DR can improve cognitive function in VaD by restoring multiple neuropeptides.

Methods: The VaD model was established via permanent bilateral common carotid artery occlusion (2VO). Total 29 Male Sprague-Dawley rats were randomized to three groups: sham, 2VO control, and 2VO with DR treatment. The DR was delivered 3 days after 2VO for 6 weeks. At 6 weeks, we employed a behavioral battery and molecular and histopathological analysis.

Results: After 2VO, neuropeptide CGRP and PACAP were significantly decreased by 11% and 44%, respectively; and DR treatment upregulated by 1.6-fold and 3.3-fold, respectively. Compared to sham, 2VO significantly impaired working memory (42% decrease), reference memory (27% decrease), long-term memory (41% decrease), and anxiety (24% increase). Conversely, DR significantly improved working memory (9%), reference memory (31%), long-term memory (31%), and anxiety (60%). Furthermore, DR significantly reduced the hippocampal neuronal pyknosis (CA1: 57% reduction) and cytotoxic edema (CA1: 73% reduction) as well as amygdala neuronal apoptosis (36% reduction) and cytotoxic edema (49% reduction).

Conclusion : Our study is the first-ever treatment approach in which a non-invasive, non-pharmacological mechanism has been harnessed to ameliorate the adverse consequences of VaD by fast restoration of neuropeptides, including CGRP and PACAP.