Hippocampal damage and white matter lesions contribute to cognitive impairment in MPTP-lesioned mice with chronic cerebral hypoperfusion

Abstract

ObjectivesStrong evidence has proven that cerebral hypoperfusion is closely related to Parkinson's disease (PD) with cognitive impairment. The aim of this study was to investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive dysfunction, structural abnormalities of the hippocampus and white matter (WM), and levels of inflammatory cytokines in control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse models. MethodsIn the present study, bilateral common carotid artery stenosis (BCCAS) was performed using microcoils, and the cognitive function and WM lesions (WMLs) after BCCAS were compared between microcoil with 0.18 mm and 0.20 mm diameters. CCH and MPTP-lesioned mice were induced by intraperitoneal injection of MPTP and BCCAS. These mice were further divided into seven groups: a control group, sham-operated group, BCCAS group, PD with normal cognition (PDCN) group, PD with mild cognitive impairment (PDMCI) group, PDCN + BCCAS group, and PDMCI + BCCAS group. After 28 days of BCCAS, the mice were tested through pole-climbing experiments and by TUNEL, Nissl, and Bielschowsky silver staining. Immunohistochemistry was used to evaluate lesions in the dopaminergic (DAergic) nigrostriatal system and the number of activated microglia. Chip-based liquid chromatography was employed to measure the levels of inflammatory cytokines in the plasma. ResultsThe results indicated that the histological results of the 0.18 mm microcoil were superior to that of the 0.20 mm microcoil. Based on these finding, BCCAS impaired the climbing ability of MPTP-lesioned PD mice. Moreover, immunohistochemistry for tyrosine hydroxylase (TH) revealed a significant reduction in the number of DAergic neurons in the substantia nigra of PD mice following BCCAS, particularly in the PDMCI + BCCAS group. In addition, Nissl, TUNEL and Bielschowsky silver staining confirmed decreased hippocampal neuron numbers, increased neuronal apoptosis and more significant WM fiber damage in the corpus callosum of the PDMCI + BCCAS group. Finally,immunohistochemistry for ionized calcium binding adaptor molecule-1 (Iba-1) and chip-based liquid chromatography revealed significantly increased microglial activation (P < 0.01) and significantly increased levels of interleukin-1β (IL-1β) and interferon-γ (IFN-γ) (P < 0.05) in the PDMCI + BCCAS group compared with the corresponding levels in the PDCN + BCCAS group. ConclusionsCerebral hypoperfusion can aggravate the cognitive impairment in MPTP-lesioned PD mice. This finding may be related to the hypoperfusion-mediated deterioration of neuroinflammation, aggravation of WM damage, and induction of hippocampal neuron apoptosis in PD mice.