Functions and dysfunctions of nitric oxide in brain

Nitric oxide (NO) works as a retrograde neurotransmitter in synapses, allows the brain blood flow and also has important roles in intracellular signaling in neurons from the regulation of the neuronal metabolic status to the dendritic spine growth. Moreover NO is able to perform post-translational modifications in proteins by the S-nitrosylation of the thiol amino acids, which is a physiological mechanism to regulate protein function. On the other hand, during aging and pathological processes the behavior of NO can turn harmful when reacts with superoxide anion to form peroxynitrite. This gaseous compound can diffuse easily throughout the neuronal membranes damaging lipid, proteins and nucleic acids. In the case of proteins, peroxynitrite reacts mostly with the phenolic ring of the tyrosines forming nitro-tyrosines that affects dramatically to the physiological functions of the proteins. Protein nitrotyrosination is an irreversible process that also yields to the accumulation of the modified proteins contributing to the onset and progression of neurodegenerative processes such as Alzheimer's disease or Parkinson's disease.     

Network-Specific Synchronization of Electrical Slow-Wave Oscillations Regulates Sleep Drive in Drosophila

1. Download : Download high-res image (224KB)
2. Download : Download full-size image

     

天香胶囊对晕动病模型大鼠前庭核NMDAR1信号通路的影响*

目的:观察天香胶囊对晕动病模型大鼠前庭核NMDAR1(N-甲基-D-天冬氨酸受体1,N-methyl-D-aspartate acid receptor 1)、P-CaMKⅡ (磷酸化钙调蛋白激酶Ⅱ-亚基,the phosphorylation of calmodulin protein kinase Ⅱ alpha subunit)、P-CREB(磷酸化cAMP反应元件结合蛋白,the phosphorylation of cAMP response element binding protein)表达的影响,探讨天香胶囊调节晕动病模型大鼠前庭核兴奋性的内在分子机制。方法:将36只雄性SD大鼠随机分为正常对照组、模型组、阳性药对照组(东莨菪碱)、天香胶囊低、中、高剂量组。灌胃预给药3天后,采用双轴旋转刺激法复制大鼠晕动病模型,通过Western blotting法检测各组大鼠前庭核NMDAR1、P-CaMKⅡ/CaMKⅡ、P-CREB/CREB的表达情况。结果:与正常组大鼠相比,模型组大鼠前庭核NMDAR1、P-CaMKⅡ、P-CREB蛋白表达水平显著增加;与模型组相比,中、高剂量天香胶囊可显著下调晕动病模型大鼠前庭核组织NMDAR1、P-CaMKⅡ、P-CREB蛋白表达。结论:天香胶囊可抑制晕动病模型大鼠前庭核NMDAR1信号通路的活化,这可能是其在治疗晕动病中降低前庭核兴奋性的内在分子机制之一。     

NMDAR 在瑞芬太尼引起痛觉过敏机制和防治的研究进展

阿片类药物引起痛觉过敏(opioid-induced hyperalgesia,OIH)是指暴露于阿片类药物的患者出现一种痛阈降低和对正常疼痛刺激的超敏反应为特点的感觉异常现象。瑞芬太尼是一种μ受体激动剂,且由于起效迅速,时量半衰期短而恒定,重复用药亦无蓄积,这些良好的药代动力学特点导致它发生的痛觉过敏现象也明显频于、强于其他阿片类药物。N-甲基-D-天冬氨酸受体(N-methyl-D-aspartate receptor,NMDAR)激活在产生超敏现象中是非常重要的。但是关于NMDAR在瑞芬太尼诱发痛觉过敏的机制尚未完全清楚,仍然缺乏系统的预防和治疗方案。本文简要介绍了NMDAR,总结了NMDAR在瑞芬太尼引起痛觉过敏的机制中的作用,归纳了临床上一些NMDAR拮抗药物来预防瑞芬太尼引起的痛觉过敏现象,以期对后续的围术期的疼痛管理提供理论依据。     

慢性低O2高CO2对大鼠空间学习记忆及脑内NMDA R1亚基表达的影响

目的探讨慢性低O2高CO2诱导大鼠空间学习记忆改变及其可能机制.方法将清洁级雄性SD大鼠58只,随机分为三组正常对照组(NC组,n=18),低O2高CO2 2周组(2HH组,n=20),低O2高CO2 4周组(4HH组,n=20).Morris水迷宫观察动物空间学习记忆的变化,采用原位杂交法观察大鼠海马及皮层区N-甲基-D-门冬氨酸受体R1亚单位(NMDAR1 mRNA)的表达情况.结果与NC组比较,模型组大鼠寻找障台的平均逃避潜伏期延长2HH组(38.59±8.35)s,4HH组(60.59±17.28)s;游泳总距离增加2HH组(9893.45±1958.16)mm,4HH组(18077.57±6878.85)mm.模型组大鼠海马皮层区NMDAR1mRNA表达的平均光密度较NC组相比均有减少,其中4HH组海马CA1区减少了21.4%(P＜0.01).结论慢性低O2高CO2可导致大鼠空间学习记忆能力下降,可能与海马CA1区的NMDAR1mRNA表达下调有关.     

NMDA receptors‐dependent plasticity in the phototaxis preference behavior induced by visual deprivation in young and adult flies

Adult mammals have experience‐dependent plasticity in visual system, but it is unclear whether adult insects also have this plasticity after the critical period of visual development. Here, we have established a modified Y‐maze apparatus for investigating experience‐dependent plasticity in Drosophila. Using this setup we demonstrate that flies after the critical period have bidirectional modifications of the phototaxis preference behavior (PPB) induced by visual deprivation and experience: Visual deprivation decreases the preference of flies for visible light, while visual experience exerts the opposite effect. We also found an age‐dependent PPB plasticity induced by visual deprivation. Molecular and cellular studies suggest that the N‐methyl‐ d ‐aspartate receptors (NMDARs) mediate ocular dominance plasticity in visual cortex in mammals, but direct behavioral evidence is lacking. Here, we used the genetic approaches to demonstrate that NMDAR1, which is NMDARs subunit in Drosophila, can mediate PPB plasticity in young and adult flies. These findings provide direct behavioral evidence that NMDAR1 mediates PPB plasticity in Drosophila. Our results suggest that mammals and insects have analogous mechanisms for experience‐dependent plasticity and its regulation by NMDAR signaling.     

Tyrosine phosphorylation of HPK1 by activated Src promotes ischemic brain injury in rat hippocampal CA1 region

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. We recently reported that HPK1 is involved in c-Jun NH2-terminal kinase (JNK) signaling pathway by sequential activation of MLK3-MKK7-JNK3 after cerebral ischemia. Here, we used 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2) and MK801 to investigate the events upstream of HPK1 in ischemic brain injury. Immunoprecipitation and immunoblot results showed that PP2 and MK801 significantly decreased the activation of Src, HPK1, MLK3, JNK3 and c-Jun, respectively, during ischemia/reperfusion. Histology and TUNEL staining showed PP2 or MK801 protects against neuron death after brain ischemia. We speculate that this unique signaling pathway through the tyrosine phosphorylation of HPK1 promotes ischemic brain injury by activated Src via N-methyl-d-aspartate receptor and, ultimately, the activation of the MLK3-MKK7-JNK3 pathway after cerebral ischemia.     

Brain energy metabolism in glutamate-receptor activation and excitotoxicity: Role for APC/C-Cdh1 in the balance glycolysis/pentose phosphate pathway

Recent advances in the field of brain energy metabolism strongly suggest that glutamate receptor-mediated neurotransmission is coupled with molecular signals that switch-on glucose utilization pathways to meet the high energetic requirements of neurons. Failure to adequately coordinate energy supply for neurotransmission ultimately results in a positive amplifying loop of receptor over-activation leading to neuronal death, a process known as excitotoxicity. In this review, we revisited current concepts in excitotoxic mechanisms, their involvement in energy substrate utilization, and the signaling pathways that coordinate both processes. In particular, we have focused on the novel role played by the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1, in cell metabolism. Our laboratory identified 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) –a key glycolytic-promoting enzyme– as an APC/C-Cdh1 substrate. Interestingly, APC/C-Cdh1 activity is inhibited by over-activation of glutamate receptors through a Ca²⁺-mediated mechanism. Furthermore, by inhibiting APC/C-Cdh1 activity, glutamate-receptors activation promotes PFKFB3 stabilization, leading to increased glycolysis and decreased pentose-phosphate pathway activity. This causes a loss in neuronal ability to regenerate glutathione, triggering oxidative stress and delayed excitotoxicity. Further investigation is critical to identify novel molecules responsible for the coupling of energy metabolism with glutamatergic neurotransmission and excitotoxicity, as well as to help developing new therapeutic strategies against neurodegeneration.     

Calorie restriction modulates hippocampal NMDA receptors in diet-induced obese rats

Calorie restriction (CR) has attracted increased interest since CR enhances lifespan and alters age-related decline in hippocampal-dependent cognitive functions. Obesity is associated with poor neurocognitive outcome including impaired hippocampal synaptic plasticity and cognitive abilities such as learning and memory. N-Methyl-d-aspartate receptors (NMDARs) are linked to hippocampal-dependent learning and memory, which may be stabilized by CR. In the present study, we aimed to establish the effects of CR on NMDARs in CA1 region of hippocampus in obese and non-obese rats. In addition, malondialdehyde (MDA) levels were determined as a marker for lipid peroxidation (LPO) in hippocampus. Four groups were constituted as control group (C, n?=?9), obese group (OB, n?=?10), obese calorie-restricted group (OCR, n?=?9), and non-obese calorie-restricted group (NCR, n?=?10). OCR and NCR were fed with a 60% CR diet for 10 weeks. After 10 weeks of CR, the MDA levels significantly decreased in the calorie-restricted groups. Obesity caused significant decreases in NR2A and NR2B subunit expressions in the hippocampus. The hippocampal NR2A and NR2B levels significantly increased in the OCR group compared with the OB group (P?<?0.05). In contrast, the hippocampal NR2A and NR2B levels significantly decreased in the NCR group compared with the C group (P?<?0.05). Oxidative stress can be prevented by CR, and these data may provide a molecular and cellular mechanism by which CR may regulate NMDAR-mediated response against obesity-induced changes in the hippocampus.     

Effects of lisinopril on NMDA receptor subunits 2A and 2B levels in the hippocampus of rats with l-NAME-induced hypertension

Hypertension is major risk factor leading to cerebrovascular pathologies. N-methyl d-aspartate receptors (NMDARs) and renin-angiotensin system are involved in neuronal plasticity, as well as cognitive functions in the hippocampus. In this study, we examined the effects of lisinopril, an ACE inhibitor, on the levels of hippocampal NMDAR subunits; NR2A and NR2B in l-NAME (N^?-nitro-l-arginine Methyl Ester)-induced hypertensive rats. In addition, malondialdehyde (MDA) levels were measured as a marker for lipid peroxidation. Compared with the control group, the MDA level was significantly increased after 8 weeks in the l-NAME-treated group. Rats treated with lisinopril and l-NAME plus lisinopril were found to have significantly decreased hippocampal MDA levels. Regarding the hippocampal concentrations of NR2A and NR2B, there were no statistically significant differences between groups. We demonstrated that lisinopril treatment has no direct regulatory effect on the levels of NR2A and NR2B in the rat hippocampus. Our results showed that Lisinopril could act as an antioxidant agent against hypertension-induced oxidative stress in rat hippocampus. The findings support that the use of lisinopril may offer a good alternative in the treatment of hypertension by reducing not only blood pressure but also prevent hypertensive complications in the brain.