Polysaccharide from Ganoderma lucidum Alleviates Congnitive Impairment in a Mice Model of Chronic Cerebral Hypoperfusion by Regulating CD4+CD25+Foxp3+ regulatory T cells

Ganoderma lucidum (G. lucidum) is a kind of edible and medicinal mushroom. G. lucidum polysaccharide-1 (GLP-1) is one of the polysaccharide purificated from crude GLP. Chronic cerebral hypoperfusion (CCH) as...

Preischemic Treadmill Exercise Ameliorates Memory Impairment and Microvasculature Damage in Rat Model of Chronic Cerebral Hypoperfusion

Purpose: Silent information regulator 1 (SIRT1) in the brain is essential for maintaining cellular homeostasis and plays a neuroprotective role in cerebral ischemia and neurodegenerative disorders. The effect of preischemic treadmill exercise on chronic cerebral hypoperfusion (CCH)-induced spatial learning memory impairment, microvascular injury, and blood-brain barrier (BBB) disruption in relation with SIRT1 expression was evaluated.Methods: Prior to bilateral common carotid artery occlusion (BCCAO) surgery, the rats in the exercise groups performed low-intensity treadmill running for 30 minutes once daily during 8 weeks. BCCAO surgery was performed on male Wistar rats at 12 weeks of age. Spatial learning memory was measured using the Morris water maze test. Neuronal nuclear antigen, SIRT1, and rat endothelial cells antigen 1 were determined by immunohistochemistry and platelet-derived growth factor receptor beta was determined by immunofluorescence.Results: Preischemic treadmill exercise ameliorated spatial learning memory impairment and enhanced SIRT1 expression in the BCCAO rats. Preischemic treadmill exercise ameliorated BCCAO-induced damage to microvasculature and pericytes that make up the BBB. The effect of preischemic treadmill exercise was lost with sirtinol treatment.Conclusions: These results can apply treadmill exercise prior to cerebral ischemia as a rational preventive and therapeutic intervention strategy to improve cognitive dysfunction in CCH patients.

Chronic cerebral hypoperfusion in male rats results in sustained HPA activation, and hyperinsulinemia

Vascular contributions to cognitive impairment and dementia (VCID) is a spectrum of cognitive deficits caused by cerebrovascular disease, for which insulin resistance is a major risk factor. A major cause of VCID is chronic cerebral hypoperfusion (CCH). Under stress, sustained hypothalamic-pituitary-adrenal axis (HPA) activation can result in insulin resistance. Little is known about the effects of CCH on the HPA axis. We hypothesized that CCH causes sustained HPA activation and insulin resistance. Male rats were subjected to bilateral carotid artery stenosis (BCAS) for 12 weeks to induce CCH and VCID. BCAS reduced cerebral blood flow and caused memory impairment. Plasma adrenocorticotropic hormone was increased in the BCAS rats (117.2 ± 9.6 vs. 88.29 ± 9.1 pg/mL, BCAS vs. sham, p = 0.0236), as was corticosterone (220 ± 21 vs. 146 ± 18 ng/g feces, BCAS vs. sham, p = 0.0083). BCAS rats were hypoglycemic (68.1 ± 6.1 vs. 76.5± 5.9 mg/dL, BCAS vs. sham, p = 0.0072), with increased fasting insulin (481.6 ± 242.6 vs. 97.94± 40.02 pmol/L, BCAS vs. sham, p = 0.0003) indicating BCAS rats were insulin resistant (HOMA-IR:11.71 ± 6.47 vs. 2.62 ± 0.93; BCAS vs. control, p = 0.0008). Glucose tolerance tests revealed that BCAS rats had lower blood glucose AUCs than controls (250 ± 12 vs. 326 ± 20 mg/dL/h, BCAS vs. sham, p = 0.0075). These studies indicate that CCH causes sustained activation of the HPA and results in insulin resistance, a condition that is expected to worsen VCID.

Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

Objectives. Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Methods. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. Results. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. Conclusions. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway

Background Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. Methods The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation. Results NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia. Conclusions NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.