NMDA receptor blockade ameliorates abnormalities of spike firing of subthalamic nucleus neurons in a parkinsonian nonhuman primate.

N-methyl-D-aspartate receptors (NMDARs) are ion channels comprising tetrameric assemblies of GluN1 and GluN2 receptor subunits that mediate excitatory neurotransmission in the central nervous system. Of the four different GluN2 subunits, the GluN2D subunit-containing NMDARs have been suggested as a target for antiparkinsonian therapy because of their expression pattern in some of the basal ganglia nuclei that show abnormal firing patterns in the parkinsonian state, specifically the subthalamic nucleus (STN). In this study, we demonstrate that blockade of NMDARs altered spike firing in the STN in a male nonhuman primate that had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In accompanying experiments in male rodents, we found that GluN2D-NMDAR expression in the STN was reduced in acutely or chronically dopamine-depleted animals. Taken together, our data suggest that blockade of NMDARs in the STN may be a viable antiparkinsonian strategy, but that the ultimate success of this approach may be complicated by parkinsonism-associated changes in NMDAR expression in the STN.

Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys.

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 µl of a 2.5-mM solution, injected at 0.1-0.2 µl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.

Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

The striatum and the subthalamic nucleus are the main entry points for cortical information to the basal ganglia. Parkinson's disease affects not only the function, but also the morphological integrity of some of these inputs and their synaptic targets in the basal ganglia. Significant morphological changes in the cortico-striatal system have already been recognized in patients with Parkinson's disease and in animal models of the disease. To find out whether the primate cortico-subthalamic system is also subject to functionally relevant morphological alterations in parkinsonism, we used a combination of light and electron microscopy anatomical approaches and in vivo electrophysiological methods in monkeys rendered parkinsonian following chronic exposure to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the light microscopic level, the density of vesicular glutamate transporter 1-positive (i.e. cortico-subthalamic) profiles in the dorsolateral part of the subthalamic nucleus (i.e. its sensorimotor territory) was 26.1% lower in MPTP-treated parkinsonian monkeys than in controls. These results were confirmed by electron microscopy studies showing that the number of vesicular glutamate transporter 1-positive terminals and of axon terminals forming asymmetric synapses in the dorsolateral subthalamic nucleus was reduced by 55.1% and 27.9%, respectively, compared with controls. These anatomical findings were in line with in vivo electrophysiology data showing a 60% reduction in the proportion of pallidal neurons that responded to electrical stimulation of the cortico-subthalamic system in parkinsonian monkeys. These findings provide strong evidence for a partial loss of the hyperdirect cortico-subthalamic projection in MPTP-treated parkinsonian monkeys.

Preparation and Properties of Hydrophobic Polyurethane Based on Silane Modification.

Waterborne coatings have obtained more and more attention from researchers with increasing concerns in environmental protection, and have the advantages of being green, environmentally friendly and safe. However, the introduction of hydrophilic groups leads to lower hydrophobicity and it is difficult to meet the requirements of complex application environments. Herein, we proposed an optimization approach of waterborne polyurethane (WPU) with vinyl tris(ß-methoxyethoxy) silane (A172), and it was found that the surface roughness, mechanical properties, thermal stability and water resistance of WPU will be increased to a certain extent with the addition of A172. Moreover, the hydrophobicity of the coating film is best when the silicon content is 10% of the acrylic monomer mass and the water contact angle reaches 100°, which could exceed two-thirds of the research results in the last decade. Therefore, our study can provide some theoretical basis for the research of hydrophobic polyurethane coatings.

Evaluation system of coastal wetland ecological vulnerability under the synergetic influence of land and sea: A case study in the Yellow River Delta, China.

A comprehensive evaluation system and model of Coastal Wetland Ecological Vulnerability (CWEV) was constructed and applied to reveal spatial heterogeneity of the ecological vulnerability of the Yellow River Delta Wetland (YRDW). The results showed that the score of the ecological vulnerability (EVS) of the YRDW was 0.49, which was generally at a medium vulnerability level. The wetland area of high vulnerability was up to 943km2, accounting for 35.2% of the total area, followed by the medium vulnerable area with an area of 750km2, accounting for 28.1% of the total area. From the coastline perpendicularly to the land, the "seaward" gradient effect gradually decreased, the vulnerability-increasing "hydrologic connectivity" effect increased with the distance from the river channel, and the "land source influence" effect gradually decayed along with the vulnerability of population and economy gathering areas.

Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis.

Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91(phox) are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O2*- production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91(phox) antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91(phox) antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91(phox-/-) mice, suggesting that ROS derived from gp91(phox)-containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.

Clomipramine suppresses postnatal REM sleep without increasing wakefulness: implications for the production of depressive behaviors.

Clomipramine (CLI), a REM sleep suppressant, alleviates symptoms of depression in adults but produces depressive behaviors if applied neonatally. Both effects of CLI as applied to adults and to neonates have been interpreted as consequences of its involvement in REM sleep deprivation. However, the paradox of these conflicting effects remains to be understood. The current study attempts to find the possible answer by studying the effects of CLI on postnatal sleep. Eight postnatal rats were evaluated polysomnographically for nine days. Four rats were treated with CLI, 40 mg/kg/day for six days, and four rats were treated with equivolume saline during the same period. The results showed that 1) CLI treatment did not reduce the time of phasic muscle activity which appears during slow wave EEG as it did during REM sleep; 2) during treatment, rats treated with CLI had 44.66%-68.62% REM sleep reduction, varied according to age; 3) REM sleep reduction during treatment was generally compensated by non-REM sleep, so that total sleep (and wakefulness) was comparable to that experienced by rats treated with saline; 4) an obvious REM sleep rebound was observed after drug withdrawal at the age of P19. These results suggest that 1) the stage that shows phasic muscle activity simultaneously with a high amplitude EEG is not REM sleep and is likely to be independent from non-REM sleep in terms of the percentile change; 2) REM sleep reduction without a corresponding increase in wakefulness in postnatal rats is likely the mediator of postnatal RSD in the production of adult depression; and 3) the neuronal bases responsible for REM rebound function by the end of the postnatal third week.

Instrumental REM sleep deprivation in neonates leads to adult depression-like behaviors in rats.

STUDY OBJECTIVES: Previous studies have demonstrated that neonatal suppression of rapid eye movement (REM) sleep by pharmacologic agents, particularly clomipramine, produces adult depressive behavior. These findings suggest the hypothesis that REM sleep deprivation (RSD) mediates the depressogenic behaviors of neonatally administered antidepressant drugs. Drug suppression of RSD, however, was thought to be confounded by the other effects of the drugs. The current study was aimed to show the adult effect of neonatal RSD in rats by instrumental means, ie, a computer-controlled shaking method. DESIGN: Three treatment groups were studied: an instrumental RSD group, a yoked control group, and a nonshaken, maternally separated, control group. All treatments began at the age of 14 days and lasted for 7 days. Adult behavior measurements including tests of sexual activity, locomotor activity, shock-induced fighting, and sleep recording were subsequently performed. MEASUREMENTS AND RESULTS: The major findings of our investigation were that rats subjected to neonatal instrumental RSD demonstrated diminished sexual activity, decreased aggressive behavior, increased percentage of REM sleep, and decreased wake-REM sleep ratio compared with yoked control rats. These data are compatible with the findings from adult rats subjected to neonatal treatment with the REM-sleep suppressant, clomipramine, and supports the hypothesis that neonatal RSD results in adult depressive abnormalities. CONCLUSION: Neonatal RSD induced by a nondrug method results in adult depression-like changes similar to those induced by a REM-sleep suppressant drug, although the extent of these changes varies.