Intermittent Fasting Alleviates Cognitive Impairments and Hippocampal Neuronal Loss but Enhances Astrocytosis in Mice with Subcortical Vascular Dementia.

BACKGROUND

Intermittent fasting (IF) is found to exhibit neuroprotection against various insults, including ischemia; however, IF has been mainly applied before disease onset. It remains unknown whether IF implementation alleviates the long-term detrimental effects of a disease after its establishment.

OBJECTIVES

To investigate the IF effects on cognitive impairments and cerebrovascular pathologies in a subcortical vascular dementia (SVaD) mouse model.

METHODS

The SVaD model was developed by inducing hypoperfusion and hyperlipidemia in apoE-deficient (apoE-/-) mice. We subjected 10-week-old apoE-/- mice to bilateral common carotid artery stenosis using micro-coils after they were fed a high-fat diet (HFD; 45% energy) for 6 weeks to induce hyperlipidemia. Age-matched wild-type C57BL/6J mice received sham surgery after undergoing an identical HFD treatment. Both the SVaD model and wild-type mice either started a 1-month IF regimen (time-restricted feeding for 6 hours per day) or continued the standard diet ad libitum (6.2% fat energy) at 8 weeks post-surgery. We assessed mice weight, food intake, and outcomes in a behavioral test battery before, during, and after the IF regimen, prior to histopathological analyses (microvessel density, neuronal density, white matter damage, astrocytosis) of their brains.

RESULTS

SVaD model mice on the IF regimen (SVaD-IF) exhibited higher mean recognition and spatial working memory performance compared to SVaD mice fed ad libitum (SVaD-AL; P < 0.01). Additionally, SVaD-IF mice had ∼5% higher hippocampal neuronal density in the dentate gyrus (DG) and cornu ammonis 1 regions than SVaD-AL mice (P < 0.001), which paralleled their post-IF cognitive enhancements. However, SVaD-IF mice showed an ∼50% increase in hippocampal DG astrocytosis compared to SVaD-AL mice (P < 0.05), with no significant differences in microvessel densities among the 2 groups.

CONCLUSIONS

The improvements in SVaD-IF mice suggest that IF could be a potential nonpharmacological remedy for SVaD. This finding could stimulate future investigations on IF's neuroprotective potential across many neurovascular diseases.