Inflammation and Rho-Associated Protein Kinase-Induced Brain Changes in Vascular Dementia

Abstract

Patients with vascular dementia, caused by cerebral ischemia, experience long-term cognitive impairment due to the lack of effective treatment. The mechanisms of and treatments for vascular dementia have been investigated in various animal models; however, the insufficient information on gene expression changes that define pathological conditions hampers progress. To investigate the underlying mechanism of and facilitate treatment development for vascular dementia, we established a mouse model of chronic cerebral hypoperfusion, including bilateral carotid artery stenosis, by using microcoils, and elucidated the molecular pathway underlying vascular dementia development. Rho-associated protein kinase (ROCK) 1/2, which regulates cellular structure, and inflammatory cytokines (IL-1 and IL-6) were upregulated in the vascular dementia model. However, expression of claudin-5, which maintains the blood–brain barrier, and MAP2 as a nerve cell-specific factor, was decreased in the hippocampal region of the vascular dementia model. Thus, we revealed that ROCK pathway activation loosens the tight junction of the blood–brain barrier and increases the influx of inflammatory cytokines into the hippocampal region, leading to neuronal death and causing cognitive and emotional dysfunction. Our vascular dementia model allows effective study of the vascular dementia mechanism. Moreover, the ROCK pathway may be a target for vascular dementia treatment development in the future.

Integrating Armchair, Bench, and Bedside Research for Behavioral Neurology and Neuropsychiatry: Editorial

“…Surgical intervention can simulate vascular dementia, the second most common neurocognitive disorder. Employing bilateral carotid artery stenosis in mice, Lee and colleagues reported that pro-inflammatory cytokines, rho-associated protein kinase, and mRNA levels of blood–brain barrier-related tight junction proteins were decreased; smooth muscle alpha-actin positive vessels were increased, cortex cell rearrangement was decreased, and microtubule-associated protein-2-positive neural cells was decreased in the hippocampus, simulating the clinical pathology of vascular dementia [ 39 ]. Thus, this model ensures high face validity.…”

Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission

“…Preclinical translational animal studies play a major role in neuroscience research to understand the roles of neuropeptides, neurohormones, and endogenous biomolecules in the normal function of human life such as cognition, emotion, and social interaction, and in pathological alterations developing into neurological and psychiatric disorders [82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97]. Various bioactive molecules are synthesized in the Try-KYN metabolic system.…”

ROCK and PDE-5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis

“…NO production of eNOS inhibited by ROCK ultimately reduces the cGMP of VSMCs, thereby constricting blood vessels. In animal experiments of the VD model, an increase in ROCK expression was shown [ 60 ].…”