不同波形低频率电刺激对小鼠海马电点燃癫痫的作用比较

目的观察比较不同脉冲波形的低频率电刺激对海马电点燃癫痫模型小鼠的作用差异。方法采用电点燃刺激法建立小鼠癫痫模型, 观察正弦波、单相方波、双相方波低频率电刺激对模型小鼠癫痫行为发作及后放电持续时间的影响, 并比较不同时间点给予正弦波低频率电刺激的抗癫痫作用。结果与对照组比较, 正弦波低频率电刺激30 s能降低小鼠海马电点燃癫痫发作等级(2.85 ± 0.27 vs 4.75 ±0.12, P < 0.05)、减少大发作概率(53.6% vs 96.5%, P < 0.01) 和缩短后放电持续时间[(16.22 ± 1.69) s vs (30.29 ± 1.12) s, P < 0.01], 而单相方波和双相方波低频率电刺激30 s没有明显的抗癫痫作用。常用的单相方波低频率电刺激15 min能降低小鼠海马电点燃发作等级(3.58 ± 0.16, P < 0.05)、减少大发作概率(66.7%, P < 0.01);但对海马后放电持续时间及大发作持续时间无影响(均 P>0.05)。此外, 电点燃刺激前预先给予或结束后3 s内给予正弦波低频率电刺激具有明显的抗癫痫作用( P < 0.05或 P < 0.01), 而电点燃刺激结束10 s给予正弦波低频率电刺激则无上述抗癫痫作用。 结论低频率电刺激抗癫痫作用受波形参数的影响, 其中正弦波低频率电刺激能有效抑制小鼠海马电点燃癫痫的发作。     

Comparison between a new platelet count drop method PL-11, light transmission aggregometry,VerifyNow aspirin system and thromboelastography for monitoring short-term aspirin effects in healthy individuals

Platelet function has been described by many laboratory assays, and PL-11 is a new point-of-care platelet function analyzer based on platelet count drop method, which counts platelet before and after the addition of agonists in the citrated whole blood samples. The present study sought to compare PL-11 with other three major more established assays, light transmission aggregometry (LTA), VerifyNow? aspirin system and thromboelastography (TEG), for monitoring the short-term aspirin responses in healthy individuals. Ten healthy young men took 100?mg/d aspirin for 3-day treatment. Platelet function was measured via PL-11, LTA, VerifyNow and TEG, respectively. The blood samples were collected at baseline, 2 hour, 1 day during the aspirin treatment and 1 day, 5?±?1 days, 8?±?1 days after the aspirin withdrawal. Moreover, 90 additional healthy subjects were recruited to establish a reference range for PL-11. Platelet function of healthy subjects decreased significantly 2 hours after 100?mg/d aspirin intake and began to recover during 4–6 days after the aspirin withdrawal. Correlations between methods were PL-11 vs. LTA (r?=?0.614, p?<?0.01); PL-11 vs. VerifyNow (r?=?0.829, p?<?0.01); PL-11 vs. TEG (r?=?0.697, p?<?0.001). There was no significant bias between PL-11 and LTA at baseline (bias?=?1.94%, p?=?0.804) using Bland-Altman analysis, while the data of PL-11 were significantly higher than LTA (bias?=?24.02%, p?<?0.001) during the aspirin therapy. The reference range for PL-11 in healthy young individuals was from 66.8 to 90.5% (95%CI). When aspirin low-responsiveness was defined as LTA?>?20%, the cut-off values for each method were, respectively: PL-11?>?50%, VerifyNow?>?533 ARU, TEG?>?60.2%. The results of different platelet function assays were uninterchangeable for monitoring aspirin response and correlations among them were also varied. Correlations among PL-11 and other three major assays suggested the ability of PL-11 to assess the treatment effects of aspirin. But a large cohort study is needed to confirm the cut-off value of aspirin response detected by PL-11.     

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.