Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Conventional MR and DW imaging findings of cerebellar primary CNS lymphoma: comparison with high-grade glioma.

Primary central nervous system lymphomas (PCNSLs) and high-grade gliomas (HGGs) arising in the cerebellum is extremely low, making the differential diagnosis difficult or even impossible. The purpose of this study was to define the MR features of cerebellar PCNSL in immunocompetent patients, and to determine whether a combination of conventional MR and DW imaging can assist in the differentiation of PCNSLs and HGGs. Twelve PCNSLs and 15 HGGs confirmed by pathological analysis were retrospectively identified. The apparent diffusion coefficient (ADC) and conventional MRI parameters were compared for differences between PCNSL and HGG groups using the independent sample t test or chi-square test. Both ADCmin and ADCtotal values were lower in the PCNSL group than those in the HGG group (ADCmin: 0.53 × 10-3 vs. 0.83 × 10-3 mm2/sec, P < 0.001; ADCtotal: 0.66 × 10-3 vs. 0.98 × 10-3 mm2/sec, P = 0.001). As for conventional MR features, there were significant difference in the tumor size, enhancement patterns, the presence of cystic changes, edema degree and streak-like edema (all P < 0.01); but there were no significant difference in lesion type, the presence of bleeding, and involvement of brain surface between two groups (P = 0.554, 0.657 and 0.157, respectively). The results revealed that several conventional MR features, including enhancement patterns, branch-like enhancement and streak-like edema may be useful for the differentiation of PCNSL and HGG in cerebellum and, when combined with ADC values, further improve the discriminating ability.

Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice.

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.

Amyloid ß-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons.

Amyloid ß protein (Aß) is responsible for the deficits of learning and memory in Alzheimer's disease (AD). The high affinity between Aß and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aß-induced damage of nAChRs. This study investigated the effects of Aß fragments on nAChR-mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole-cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4ß2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM-µM) of Aß25-35, Aß31-35, or Aß35-31 alone did not trigger any membrane current, but pretreatment with 1 µM Aß25-35 and Aß31-35 similarly and reversibly suppressed the nicotine-induced currents; (3) further, choline- and epibatidine-induced currents were also reversibly suppressed by the Aß pretreatment, but more prominent for the choline-induced response. These results demonstrate that the functional activity of both α7 and α4ß2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aß treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aß in AD. In addition, the similar suppression of nAChR currents by Aß25-35 and Aß31-35 suggests that the sequence 31-35 in Aß molecule may be a shorter active center responsible for the neurotoxicity of Aß in AD.

[Influences of percutaneous coronary intervention on myocardial activity in myocardial infarction patients with different viable myocardium].

OBJECTIVE: To evaluate the effect of percutaneous coronary intervention (PCI) on left ventricular function in patients with different types of myocardial infarction and to explore the correlation factors for the left ventricular function. METHODS: A total of 43 patients diagnosed as acute myocardial infarction were enrolled in this study. The perfusion and delayed enhancement magnetic resonance imaging (DE-MRI) was applied to observe the following parameters before the PCI and at month 6 after the procedure: infarct mass, left ventricular ejection fraction (LVEF) and abnormal wall motion score. The subjects were divided into the following three groups by the transmural extent of myocardial infarction manifested in the DE-MRI: the transmural enhancement group, the nontransmural group and the mixed group. Laboratory test was done to detect the level of endothelin (ET), matrix metal enzyme 9 (MMP-9) and high sensitive C reactive protein (hsCRP) before PCI and at month 6 after the procedure. The t test was used to compare the differences among the groups and the multiple regression analysis was taken to explore the correlation factors for the left ventricular function. RESULTS: Compared with the parameters before PCI, the infarct mass after PCI significantly decreased in the nontransmural group and the mixed group [(4.0 ± 2.9) g/cm(3) vs (9.8 ± 5.6) g/cm(3) and (6.0 ± 3.5) g/cm(3) vs (11.8 ± 6.2)g/cm(3), all P < 0.05], while LVEF was significantly improved after PCI in both groups [(52.6 ± 15.4)% vs (41.9 ± 16.3)%,(45.6 ± 15.4)% vs (38.9 ± 16.3)%, all P < 0.05]. The infarct mass was an independent correlation factor for LVEF before PCI (RR = 0.318, P < 0.05) and LVEF after PCI (RR = 0.293, P < 0.05) . LVEF before PCI was independently correlated with the level of hsCRP (RR = 0.318, P < 0.05). CONCLUSION: The effect of PCI on the improvement of left ventricular function differs in patients with different extent of myocardial infarction, which is correlated with the amount of survival myocardium and the inflammatory factors.