Remote Ischemic Postconditioning: Harnessing Endogenous Protection in a Murine Model of Vascular Cognitive Impairment

Abstract

We previously reported that remote limb ischemic conditioning (RLIC; PERconditioning) during acute stroke confers neuroprotection, possibly due to increased cerebral blood flow (CBF). Vascular cognitive impairment (VCI) is a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is regarded as the most valid model for VCI. We hypothesized that RLIC (postconditioning; RIPostC) will augment CBF during chronic cerebral hypoperfusion (CCH) and prevent cognitive impairment in the BCAS model. BCAS using customized microcoil was performed in C57/B6 male mice to establish CCH. A week after the BCAS surgery, mice were treated with RIPostC-therapy once daily for 2 weeks. CBF was measured with laser speckle contrast imager at different time points. Cognitive testing was performed at 4-week post-BCAS, and brain tissue was harvested for biochemistry. BCAS led to chronic hypoperfusion resulting into impaired cognitive function as tested by novel object recognition (NOR). Histological examinations revealed that BCAS triggered inflammatory responses and caused frequent vacuolization and cell death. BCAS also increased the generation and accumulation of amyloid beta protein (Aβ), resulting into the loss of white matter (WM) and myelin basic protein (MBP). RIPostC-therapy showed both acute increase as well as sustained improvement in CBF even after the cessation of therapy for a week. RIPostC improved cognitive function, inhibited inflammatory responses, prevented the cell death, reduced the generation and accumulation of Aβ, and protected WM integrity. RIPostC is effective in the BCAS model and could be an attractive low-cost conventional therapy for aged individuals with VCI. The mechanisms by which RIPostC improves CBF and attenuates tissue damage need to be investigated in the future.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-014-0374-6) contains supplementary material, which is available to authorized users.

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

“…Khan et al found that sham-operated animals have significantly greater novel object exploration time and increased discrimination index when compared to BCAS mice. They attribute this difference to subcortical frontal white matter injury in the BCAS cohort [34]. By contrast, Toyama et al found no significant difference in exploratory preferences between BCAS and sham-operated animals.…”

Models and mechanisms of vascular dementia

“…Lastly, the coils have to be procured from a company (like Sawane Spring Co., Ltd., Hamamatsu, Japan) and are typically not reusable which could compound costs when using large animal numbers. Additionally, accumulation of amyloid beta which is typical in AD had been reported after BCAS in mice [77]. The BCAS model does not reflect SVD pathology, instead the occlusion of both CCA’s induces chronic hypoperfusion and affects micro vascular flow to induce VaD [77].…”

“…Additionally, accumulation of amyloid beta which is typical in AD had been reported after BCAS in mice [77]. The BCAS model does not reflect SVD pathology, instead the occlusion of both CCA’s induces chronic hypoperfusion and affects micro vascular flow to induce VaD [77]. …”

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

“…In human stroke, white matter occupies about half of the lesion volume and is an important cause of long-term sensorimotor deficits and cognitive decline [3–5]. Many neuroprotective drugs that showed promise in preclinical testing failed in clinical stroke trials [6].…”