Cell-type specific modulation of NMDA receptors triggers antidepressant actions.

Both the NMDA receptor (NMDAR) positive allosteric modulator (PAM), and antagonist, can exert rapid antidepressant effects as shown in several animal and human studies. However, how this bidirectional modulation of NMDARs causes similar antidepressant effects remains unknown. Notably, the initial cellular trigger, specific cell-type(s), and subunit(s) of NMDARs mediating the antidepressant-like effects of a PAM or an antagonist have not been identified. Here, we used electrophysiology, microdialysis, and NMR spectroscopy to evaluate the effect of a NMDAR PAM (rapastinel) or NMDAR antagonist, ketamine on NMDAR function and disinhibition-mediated glutamate release. Further, we used cell-type specific knockdown (KD), pharmacological, and behavioral approaches to dissect the cell-type specific role of GluN2B, GluN2A, and dopamine receptor subunits in the actions of NMDAR PAM vs. antagonists. We demonstrate that rapastinel directly enhances NMDAR activity on principal glutamatergic neurons in medial prefrontal cortex (mPFC) without any effect on glutamate efflux, while ketamine blocks NMDAR on GABA interneurons to cause glutamate efflux and indirect activation of excitatory synapses. Behavioral studies using cell-type-specific KD in mPFC demonstrate that NMDAR-GluN2B KD on Camk2a- but not Gad1-expressing neurons blocks the antidepressant effects of rapastinel. In contrast, GluN2B KD on Gad1- but not Camk2a-expressing neurons blocks the actions of ketamine. The results also demonstrate that Drd1-expressing pyramidal neurons in mPFC mediate the rapid antidepressant actions of ketamine and rapastinel. Together, these results demonstrate unique initial cellular triggers as well as converging effects on Drd1-pyramidal cell signaling that underlie the antidepressant actions of NMDAR-positive modulation vs. NMDAR blockade.

Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.

Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2R,6R)-HNK does not block NMDA receptors like ketamine, and the molecular signaling mechanisms for (2R,6R)-HNK remain unknown. Here, we examined the involvement of BDNF/TrkB/mechanistic target of rapamycin complex 1 (mTORC1) signaling in the antidepressant actions of (2R,6R)-HNK. Intramedial prefrontal cortex (intra-mPFC) infusion or systemic (2R,6R)-HNK administration induces rapid and long-lasting antidepressant effects in behavioral tests, identifying the mPFC as a key region for the actions of (2R,6R)-HNK. The antidepressant actions of (2R,6R)-HNK are blocked in mice with a knockin of the BDNF Val66Met allele (which blocks the processing and activity-dependent release of BDNF) or by intra-mPFC microinjection of an anti-BDNF neutralizing antibody. Blockade of L-type voltage-dependent Ca2+ channels (VDCCs), required for activity-dependent BDNF release, also blocks the actions of (2R,6R)-HNK. Intra-mPFC infusion of pharmacological inhibitors of TrkB or mTORC1 signaling, which are downstream of BDNF, also block the actions of (2R,6R)-HNK. Moreover, (2R,6R)-HNK increases synaptic function in the mPFC. These findings indicate that activity-dependent BDNF release and downstream TrkB and mTORC1 signaling, which increase synaptic function in the mPFC, are required for the rapid and long-lasting antidepressant effects of (2R,6R)-HNK, supporting the potential use of this metabolite for the treatment of MDD.

Evaluation of a chest rehabilitation project in Nepal using the St. George's Respiratory Questionnaire and Chronic Obstructive Pulmonary Disease Assessment Test.

[Purpose] The incidence of chronic obstructive pulmonary disease is rapidly increasing worldwide. In Nepal, it has the highest mortality rate among all noninfectious diseases. Since 2015, we have been involved in a project that aims to facilitate chest rehabilitation for patients with chronic obstructive pulmonary disease in Nepal. We compared the Nepali version of the St. George's Respiratory Questionnaire with the Chronic Obstructive Pulmonary Disease Assessment Test, the latter of which was translated into Nepali for this project. We also evaluated the extent to which patient quality of life improved after the rehabilitation program. [Participants and Methods] The Nepali St. George's Respiratory Questionnaire and Chronic Obstructive Pulmonary Disease Assessment Test were used to assess the health status of patients both before the intervention's initiation and one year after it. Between May and September of 2016, 122 patients with chronic obstructive pulmonary disease participated in this program. [Results] We collected valid responses from 57 patients both before and after the intervention. The scores of both screening tools were significantly lower after the intervention than before and showed a significant correlation with one another. [Conclusion] These results suggest that the Nepali version of the Chronic Obstructive Pulmonary Disease Assessment Test is a reliable tool for the evaluation of chronic obstructive pulmonary disease and that the intervention used in the project might be effective for patients afflicted with the disease. However, there are limitations to the research design, such as the limited number of participants used in the study.

Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT1A receptor agonistic activity.

We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.

Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.

We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT1A weak partial agonistic activity, which could work as a 5-HT1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model.

The ppuI-rsaL-ppuR quorum-sensing system regulates cellular motility, pectate lyase activity, and virulence in potato opportunistic pathogen Pseudomonas sp. StFLB209.

Pseudomonas sp. StFLB209 was isolated from potato leaf as an N-acylhomoserine lactone (AHL)-producing bacterium and showed a close phylogenetic relationship with P. cichorii, a known plant pathogen. Although there are no reports of potato disease caused by pseudomonads in Japan, StFLB209 was pathogenic to potato leaf. In this study, we reveal the complete genome sequence of StFLB209, and show that the strain possesses a ppuI-rsaL-ppuR quorum-sensing system, the sequence of which shares a high similarity with that of Pseudomonas putida. Disruption of ppuI results in a loss of AHL production as well as remarkable reduction in motility. StFLB209 possesses strong pectate lyase activity and causes maceration on potato tuber and leaf, which was slightly reduced in the ppuI mutant. These results suggest that the quorum-sensing system is well conserved between StFLB209 and P. putida and that the system is essential for motility, full pectate lyase activity, and virulence in StFLB209.

Detection of PPB-Level H2S Concentrations in Exhaled Breath Using Au Nanosheet Sensors with Small Variability, High Selectivity, and Long-Term Stability.

The continuous monitoring of hydrogen sulfide (H2S) in exhaled breath enables the detection of health issues such as halitosis and gastrointestinal problems. However, H2S sensors with high selectivity and parts per billion-level detection capability, which are essential for breath analysis, and facile fabrication processes for their integration with other devices are lacking. In this study, we demonstrated Au nanosheet H2S sensors with high selectivity, ppb-level detection capability, and high uniformity by optimizing their fabrication processes: (1) insertion of titanium nitride (TiN) as an adhesion layer to prevent Au agglomeration on the oxide substrate and (2) N2 annealing to improve nanosheet crystallinity. The fabricated Au nanosheets successfully detected H2S at concentrations as low as 5.6 ppb, and the estimated limit of detection was 0.5 ppb, which is superior to that of the human nose (8-13 ppb). In addition, the sensors detected H2S in the exhaled breath of simulated patients at concentrations as low as 175 ppb while showing high selectivity against interfering molecules, such as H2, alcohols, and humidity. Since Au nanosheets with uniform sensor characteristics enable easy device integration, the proposed sensor will be useful for facile health checkups based on breath analysis upon its integration into mobile devices.

DSP-6745, a novel 5-hydroxytryptamine modulator with rapid antidepressant, anxiolytic, antipsychotic and procognitive effects.

BACKGROUND: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention. OBJECTIVES: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms. RESULTS: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT2A, 5-HT2C, and 5-HT7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition. CONCLUSIONS: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression.

Two-minute standing endurance test for axial postural abnormalities in patients with Parkinson's disease.

BACKGROUND: Photo-based measurement methods are used to assess axial postural abnormalities (PA) in Parkinson's disease (PD). However, they capture only moments in time. We developed the 2-minute standing endurance test (2 M-SET), which specifically captures temporal changes in posture, as a novel dynamic method for measuring axial PA in patients with PD. RESEARCH QUESTION: This study aimed to verify the effectiveness and validity of the 2 M-SET for capturing temporal changes in axial PA in patients with PD. METHODS: Twenty-eight patients with PD participated. The participants attempted to maintain an upright posture for 2 minutes during three tasks: standing, stepping in place, and walking. The rate of change in postural angle was recorded at 10-second intervals. Based on the results, the 2 M-SET was developed. Therapists evaluated the 2 M-SET using the NeuroPostureApp© to measure anterior trunk flexion (ATF) angles and lateral trunk flexion (LTF) angles at 0, 10, 30, 60, and 120 seconds. To assess reliability, the congruence between the measurements obtained by the therapists and those obtained using a three-dimensional motion-analysis system was examined. For validity, we assessed whether the ATF and LTF angles measured by the therapists could accurately capture postural changes at regular intervals over time. RESULTS: The average postural changes over 2 minutes for the standing, stepping in place, and gait tasks were 59.2±83.5%, 37.6±30.7%, and 45.4±50.6%, respectively. The intraclass correlation coefficients showed high reliability, with values of 0.985 and 0.970 for the ATF and LTF angles, respectively. SIGNIFICANCE: The results of our proposed 2 M-SET method, which uses temporal photo-based measurements to assess the patient's ability to maintain an upright standing position for 2 minutes, demonstrate the potential to capture temporal changes in axial PA. DATA AVAILABILITY STATEMENT: The data supporting the findings of this study are available upon reasonable request and approval from the local ethics committee.

Role of mTOR1 signaling in the antidepressant effects of ketamine and the potential of mTORC1 activators as novel antidepressants.

Conventional antidepressant medications act on monoaminergic systems and have important limitations, including a therapeutic delay of weeks to months and low rates of efficacy. Recently, clinical findings have indicated that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate receptor channel activity, causes rapid and long-lasting antidepressant effects. Although the exact mechanisms underlying the antidepressant effects of ketamine are not fully known, preclinical studies have demonstrated a key role for mechanistic target of rapamycin complex 1 (mTORC1) signaling and a subsequent increase in synapse formation in the medial prefrontal cortex. In this review, we discuss the role of mTORC1 and its subsequent signaling cascade in the antidepressant effects of ketamine and other compounds with glutamatergic mechanisms of action. We also present the possibility that mTORC1 signaling itself is a drug discovery target.

Simultaneous Detection of Mixed-Gas Components by Ionic-Gel Sensors with Multiple Electrodes.

The sensing of gas components in a mixed gas is required for breath-based health monitoring and diagnosis. In this work, we report the simultaneous detection of mixed-gas components using a sensor consisting of [EMIM][BF4]-based ionic gel with four electrodes made of Au, Pt, Rh, and Cr. The voltage between any given pair of electrodes depends on the gas molecules absorbed in the ionic gel and the elements the electrodes are made of. When the voltage signals between all pairs of electrodes were used, H2, NH3, and C2H5OH concentrations were simultaneously estimated by a neural-network-based inference. From molecular dynamics simulations, the origin of the voltage signal was attributed to the catalytically generated adsorbates on the electrodes.

Origin of the High Selectivity of the Pt-Rh Thin-Film H2 Gas Sensor Studied by Operando Ambient-Pressure X-ray Photoelectron Spectroscopy at Working Conditions.

The Pt-Rh thin-film sensors exhibit excellent sensitivity and selectivity for H2 gas detection. Here, we studied the mechanism of highly selective detection of H2 by the Pt-Rh thin-film sensors with ambient-pressure X-ray photoelectron spectroscopy (AP-XPS) measurements at working conditions, which were paralleled with electric resistivity measurements. The elemental composition and chemical state of surface Pt and Rh drastically change depending on the background gas environments, which directly link to the sensor response. It is revealed that surface segregated Pt atoms accelerate dissociative adsorption of H2, resulting in a reduction of the sensor surface and then a decrease of electric resistivity of the film, whereas a thin oxidized Rh layer blocks dissociation of the other reducing agent, that is, NH3. This is supported from the adsorption energetics obtained by the density functional theory (DFT) calculations.

Repeated social defeat stress induces neutrophil mobilization in mice: maintenance after cessation of stress and strain-dependent difference in response.

BACKGROUND AND PURPOSE: Inflammation has been associated with stress-related mental disturbances. Rodent studies have reported that blood-borne cytokines are crucial for stress-induced changes in emotional behaviours. However, the roles and regulation of leukocytes in chronic stress remain unclear. EXPERIMENTAL APPROACH: Adult male C57BL/6N mice were subjected to repeated social defeat stress (R-SDS) with two protocols which differed in stress durations, stress cycles, and housing conditions, followed by the social interaction test. The numbers of leukocyte subsets in the bone marrow, spleen, and blood were determined by flow cytometry shortly after or several days after R-SDS. These leukocyte changes were studied in two strains of mice with different stress susceptibility, C57BL/6N and BALB/c mice. KEY RESULTS: R-SDS with both protocols similarly induced social avoidance in C57BL/6N mice. In the bone marrow, neutrophils and monocytes were increased, and T cells, B cells, NK cells, and dendritic cells were decreased with both protocols. In the blood, neutrophils and monocytes were increased with both protocols, whereas T cells, B cells, NK cells, and dendritic cells were decreased with one of these. Neutrophils and monocytes were also increased in the spleen. Changes in the bone marrow and increased levels of circulating neutrophils were maintained for 6 days after R-SDS. BALB/c mice showed greater social avoidance and increase in circulating neutrophils than C57BL/6N mice. CONCLUSION AND IMPLICATIONS: In two strains of mice, chronic stress induced neutrophil mobilization and its maintenance. These effects were strain-related and may contribute to the pathology of mental illness. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.

Rapastinel, a novel glutamatergic agent with ketamine-like antidepressant actions: Convergent mechanisms.

Conventional antidepressant medications, which act on monoaminergic systems, have significant limitations, including a time lag of weeks to months and low rates of therapeutic efficacy. Recently, clinical findings demonstrate that ketamine, a dissociative anesthetic that blocks N-methyl-d-aspartate (NMDA) receptor channel activity, causes rapid (within hours) and long-lasting (7 to 10 days) antidepressant effects. Rapastinel is a novel glutamatergic compound that acts as an NMDAR postive allosteric modulator and produces rapid antidepressant actions in depressed patients and in preclinical rodent models. In addition, rapastinel has no ketamine-like side effect such as cognitive impairment and psychotomimetic symptoms. Despite recent negative clinical trials, it remains possible that rapastinel could prove effective as an alternative rapid agent with reduced side effects. In this review, we discuss the pharmacological profile of rapastinel and the molecular and cellular mechanisms underlying the rapid and sustained antidepressant actions of this novel agent.

In situ AP-XPS analysis of a Pt thin-film sensor for highly sensitive H2 detection.

In situ ambient-pressure X-ray photoelectron spectroscopy (AP-XPS) combined with resistivity measurement was performed for a Pt thin-film H2 gas sensor. We experimentally demonstrate that the chemical state of the Pt surface changes under working conditions, and it directly links to the sensing performance. Moreover, the operating principle is discussed at the atomic scale.

Neurotrophic and Antidepressant Actions of Brain-Derived Neurotrophic Factor Require Vascular Endothelial Growth Factor.

BACKGROUND: Activity-dependent release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) is essential for the rapid and sustained antidepressant actions of ketamine, and a recent study shows a similar requirement for vascular endothelial growth factor (VEGF). Since BDNF is reported to stimulate VEGF expression and/or release in neuroblastoma cells, the present study tested the hypothesis that the actions of BDNF are mediated by VEGF. METHODS: The role of VEGF in the antidepressant behavioral actions of BDNF was tested by intra-mPFC coinfusion of a VEGF neutralizing antibody and by neuron-specific deletion of VEGF. The influence of BDNF on the release of VEGF and the role of VEGF in the neurotrophic actions of BDNF were determined in rat primary cortical neurons. The role of BDNF in the behavioral and neurotrophic actions of VEGF was also determined. RESULTS: The results show that the rapid and sustained antidepressant-like actions of intra-mPFC BDNF are blocked by coinfusion of a VEGF neutralizing antibody, and that neuron-specific mPFC deletion of VEGF blocks the antidepressant-like actions of BDNF. Studies in primary cortical neurons demonstrate that BDNF stimulates the release of VEGF and that BDNF induction of dendrite complexity is blocked by a selective VEGF-fetal liver kinase 1 receptor antagonist. Surprisingly, the results also show reciprocal interactions, indicating that the behavioral and neurotrophic actions of VEGF are dependent on BDNF. CONCLUSIONS: These findings indicate that the antidepressant-like and neurotrophic actions of BDNF require VEGF signaling, but they also demonstrate reciprocal interdependence for BDNF in the actions of VEGF.

Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation.

Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.

Role of Neuronal VEGF Signaling in the Prefrontal Cortex in the Rapid Antidepressant Effects of Ketamine.

OBJECTIVE: The N-methyl-d-aspartate receptor antagonist ketamine produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. Vascular endothelial growth factor (VEGF) has been implicated in the effects of conventional monoamine-based antidepressants, but the role of VEGF in the rapid antidepressant actions of ketamine remains unclear. The authors examined whether neuronal VEGF signaling in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant actions of ketamine. METHODS: The authors used a combination of approaches, including conditional, neuron-specific knockout of VEGF or its receptor, Flk-1; antibody neutralization; viral-mediated knockdown of Flk-1; and pharmacological inhibitors. Further in vitro and in vivo experiments were performed to examine whether neuronal VEGF signaling was required for the neurotrophic and synaptogenic actions of ketamine that underlie its behavioral actions. RESULTS: The behavioral actions of systemic ketamine are blocked by forebrain excitatory neuron-specific deletion of either VEGF or Flk-1 or by intra-mPFC infusion of a VEGF neutralizing antibody. Moreover, intra-mPFC infusions of VEGF are sufficient to produce rapid ketamine-like behavioral actions, and these effects are blocked by neuron-specific Flk-1 deletion. The results also show that local knockdown of Flk-1 in mPFC excitatory neurons in adulthood blocks the behavioral effects of systemic ketamine. Moreover, inhibition of neuronal VEGF signaling blocks the neurotrophic and synaptogenic effects of ketamine. CONCLUSIONS: Together, these findings indicate that neuronal VEGF-Flk-1 signaling in the mPFC plays an essential role in the antidepressant actions of ketamine.

A case of primary aldosteronism associated with renal artery stenosis and preclinical Cushing's syndrome.

We identified a left adrenal tumor, left renal atrophy, and left renal artery stenosis (RAS) in a 52-year-old man by MRI/magnetic resonance angiography (MRA) during evaluation of hypertension. Laboratory tests revealed hypokalemia, a high plasma aldosterone concentration (PAC), low plasma renin activity (PRA), and normal plasma cortisol. An excessive response of aldosterone and cortisol to adorenocorticotrophic hormone (ACTH) was found upon selective sampling of the left adrenal vein. Selective renal venous sampling showed a left/right renal venous PRA ratio of 1.7. A dexamethasone (8 mg) suppression test showed insufficient suppression of cortisol. We diagnosed this patient as having aldosterone-producing adrenal adenoma (APA) associated with renovascular hypertension (RVH) and preclinical Cushing's syndrome. As an initial treatment, percutaneous transluminal renal angioplasty was performed. Postoperatively, the patient's blood pressure decreased. One month later, the tumor was removed by complete laparoscopic left adrenalectomy. Postoperatively, blood pressure decreased further and both PAC and PRA were normalized. However, antihypertensive therapy could not be completely stopped. The renal dysfuntion that occurred prior to treatment seemed to prevent complete normalization of blood pressure.

Dorsal root ganglion regulates the transient ERK activation in the dorsal horn of the spinal cord during development.

In the dorsal horn of the chick embryo spinal cord, extracellular signal-regulated kinase (ERK) was phosphorylated transiently during embryonic days 6 and 9. Co-culture studies suggested that dorsal root ganglion (DRG) activated ERK in the dorsal horn. Brain-derived neurotrophic factor (BDNF) activated ERK in the dorsal horn, and anti-BDNF blocked the DRG-induced ERK activation. These results suggest roles of BDNF in the DRG-induced ERK activation in the embryonic dorsal horn.