Golexanolone reduces glial activation in the striatum and improves non-motor and some motor alterations in a rat model of Parkinson's disease.

Background: Parkinson's disease (PD) affects more than 6 million people worldwide. Along with motor impairments, patients and animal models exhibiting PD symptoms also experience cognitive impairment, fatigue, anxiety, and depression. Currently, there are no drugs available for PD that alter the progression of the disease. A body of evidence suggests that increased GABA levels contribute to the reduced expression of tyrosine hydroxylase (TH) and accompanying behavioral deficits. TH expression may be restored by blocking GABAA receptors. We hypothesized that golexanolone (GR3027), a well-tolerated GABAA receptor-modulating steroid antagonist (GAMSA), may improve Parkinson's symptoms in a rat model of PD. Objectives: The aims of this study were to assess whether golexanolone can ameliorate motor and non-motor symptoms in a rat model of PD and to identify some underlying mechanisms. Methods: We used the unilateral 6-OHDA rat model of PD. The golexanolone treatment started 4 weeks after surgery. Motor symptoms were assessed using Motorater and CatWalk tests. We also analyzed fatigue (using a treadmill test), anhedonia (via the sucrose preference test), anxiety (with an open field test), and short-term memory (using a Y maze). Glial activation and key proteins involved in PD pathogenesis were analyzed using immunohistochemistry and Western blot. Results: Rats with PD showed motor incoordination and impaired locomotor gait, increased fatigue, anxiety, depression, and impaired short-term memory. Golexanolone treatment led to improvements in motor incoordination, certain aspects of locomotor gait, fatigue, anxiety, depression, and short-term memory. Notably, golexanolone reduced the activation of microglia and astrocytes, mitigated TH loss at 5 weeks after surgery, and prevented the increase of α-synuclein levels at 10 weeks. Conclusions: Golexanolone may be useful in improving both motor and non-motor symptoms that adversely affect the quality of life in PD patients, such as anxiety, depression, fatigue, motor coordination, locomotor gait, and certain cognitive alterations.

Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment.

Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.

The GABA system, a new target for medications against cognitive impairment-Associated with neuroactive steroids.

The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.

Accurate identification and measurement of the precipitate area by two-stage deep neural networks in novel chromium-based alloys.

The performance of advanced materials for extreme environments is underpinned by their microstructure, such as the size and distribution of nano- to micro-sized reinforcing phase(s). Chromium-based superalloys are a recently proposed alternative to conventional face-centred-cubic superalloys for high-temperature applications, e.g., Concentrated Solar Power. Their development requires the determination of precipitate volume fraction and size distribution using Electron Microscopy (EM), as these properties are crucial for the thermal stability and mechanical properties of chromium superalloys. Traditional approaches to EM image processing utilise filtering with a fixed contrast threshold, leads to weak robustness to background noise and poor generalisability to different materials. It also requires an enormous amount of time for manual object measurements on large datasets. Efficient and accurate object detection and segmentation are therefore highly desired to accelerate the development of novel materials like chromium-based superalloys. To address these bottlenecks, based on YOLOv5 and SegFormer structures, this study proposes an end-to-end, two-stage deep learning scheme, DT-SegNet, to perform object detection and segmentation for EM images. The proposed approach can thus benefit from the training efficiency of CNNs at the detection stage (i.e., a small number of training images required) and the accuracy of the ViT at the segmentation stage. Extensive numerical experiments demonstrate that the proposed DT-SegNet significantly outperforms the state-of-the-art segmentation tools offered by Weka and ilastik regarding a large number of metrics, including accuracy, precision, recall and F1-score. This model forms a useful tool to aid alloy development microstructure examinations, and offers significant advantages to address the large datasets associated with high-throughput alloy development approaches.

Golexanolone, a GABAA receptor modulating steroid antagonist, restores motor coordination and cognitive function in hyperammonemic rats by dual effects on peripheral inflammation and neuroinflammation.

AIMS: Hyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. Golexanolone reduces GABAA receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms. METHODS: Rats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways, and cognitive and motor function were analyzed. RESULTS: Hyperammonemic rats show increased TNFα and reduced IL-10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short-term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short-term memory. This was associated with reversal of the hyperammonemia-enhanced activation in cerebellum of the TNFR1-glutaminase-GAT3 and TNFR1-CCL2-TrkB-KCC2 pathways. CONCLUSION: Reducing GABAA receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation.

Towards ML-Based Diagnostics of Laser-Plasma Interactions.

The power of machine learning (ML) in feature identification can be harnessed for determining quantities in experiments that are difficult to measure directly. However, if an ML model is trained on simulated data, rather than experimental results, the differences between the two can pose an obstacle to reliable data extraction. Here we report on the development of ML-based diagnostics for experiments on high-intensity laser-matter interactions. With the intention to accentuate robust, physics-governed features, the presence of which is tolerant to such differences, we test the application of principal component analysis, data augmentation and training with data that has superimposed noise of gradually increasing amplitude. Using synthetic data of simulated experiments, we identify that the approach based on the noise of increasing amplitude yields the most accurate ML models and thus is likely to be useful in similar projects on ML-based diagnostics.

Tetraethylphosphorodiamidate-Directed Metalation Group: Directed Ortho and Remote Metalation, Cross Coupling, and Remote Phospha Anionic Fries Rearrangement Reactions.

The linked directed ortho and remote metalation (DoM and DreM) and cross-coupling reactions of aryl phosphorodiamidates (Ar-OP(O)(NEt2)2) is reported. The o-iodo and o-boronato aryl tetraethylphosphorodiamidates 3, prepared by DoM, undergo orthogonal Ni- and Pd-catalyzed Suzuki-Miyaura cross coupling to furnish biaryls 4 and 5 in good to excellent yields. Silicon group protection of biaryl 4 via DoM followed by previously unobserved DreM phospha anionic Fries rearrangement affords biaryls 11 which, under acidic conditions, furnish oxaphosphorine oxides 12.

Depressive disorders: Treatment failures and poor prognosis over the last 50 years.

Depression like many diseases is pleiotropic but unlike cancer and Alzheimer's disease for example, is still largely stigmatized and falls into the dark shadows of human illness. The failure of depression to be in the spotlight for successful treatment options is inherent in the complexity of the disease(s), flawed clinical diagnosis, overgeneralization of the illness, inadequate and biased clinical trial design, restrictive and biased inclusion/exclusion criteria, lack of approved/robust biomarkers, expensive imaging technology along with few advances in neurobiological hypotheses in decades. Clinical trial studies summitted to the regulatory agencies (FDA/EMA) for approval, have continually failed to show significant differences between active and placebo. For decades, we have acknowledged this failure, despite vigorous debated by all stakeholders to provide adequate answers to this escalating problem, with only a few new antidepressants approved in the last 20 years with equivocal efficacy, little improvement in side effects or onset of efficacy. It is also clear that funding and initiatives for mental illness lags far behind other life-treating diseases. Thus, it is no surprise we have not achieved much success in the last 50 years in treating depression, but we are accountable for the many failures and suboptimal treatment. This review will therefore critically address where we have failed and how future advances in medical science offers a glimmer of light for the patient and aid our future understanding of the neurobiology and pathophysiology of the disease, enabling transformative therapies for the treatment of depressive disorders.

In memory of Norman Bowery (1944-2016).

This article is in memory of Professor Norman Bowery (1944-2016). Norman was a pharmacologist who spent most of his career researching the pharmacology of γ-aminobutyric acid (GABA). He discovered a novel metabotropic receptor subtype, GABAB, that is pharmacologically, and structurally different from the original ionotropic receptor now designated as GABAA. In his research he also studied the neurotransmitters glutamate and substance P, two molecules whose release in parts of the spinal cord is inhibited by baclofen a GABAB receptor agonist. Norman was interested in the therapeutic potential of interacting with the GABAB receptor, in particular spasticity, pain and absence epilepsy.

The synthesis of chiral periodic organosilica materials with ultrasmall mesopores.

Helical organosilica materials were synthesized for the first time using a novel binaphthyl-based chiral co-monomer in less than 1 hour. The incorporation of a chiral co-monomer in the wall was shown to influence the curvature of the helical materials. As the amount of the chiral co-monomer was increased, the degree of curvature increased, illustrating the importance of this monomer to the overall morphology.

Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study.

We examined the effect of the administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and paroxetine on the activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized adult male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular recording. A single injection of 2.5 mg/kg (i.p.) of fluoxetine significantly increased the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of either 1 mg/kg (i.p.) of paroxetine or 5 mg/kg of fluoxetine significantly increased the number of spontaneously active VTA DA neurons. The repeated administration (one injection per day for 21 days) of all of the SSRIs produced a significant increase in the number of spontaneously active VTA DA neurons. Overall, our results indicate that the systemic administration of SSRI alters the activity of midbrain DA neurons with differential effects on VTA compared with SNC DA neurons.

3-arylimino-2-indolones are potent and selective galanin GAL3 receptor antagonists.

A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).

The acute and chronic administration of the 5-HT(2B/2C) receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study.

This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.

Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299.

The neuropeptide galanin mediates its effects through the receptor subtypes Gal(1), Gal(2), and Gal(3) and has been implicated in anxiety- and depression-related behaviors. Nevertheless, the receptor subtypes relevant to these behaviors are not known because of the lack of available galanin-selective ligands. In this article, we use behavioral, neurochemical, and electrophysiological approaches to investigate the anxiolytic- and antidepressant-like effects of two potent small-molecule, Gal(3)-selective antagonists, SNAP 37889 and the more soluble analog SNAP 398299. Acute administration of SNAP 37889 or SNAP 398299 enhanced rat social interaction. Furthermore, acute SNAP 37889 was also shown to reduce guinea pig vocalizations after maternal separation, to attenuate stress-induced hyperthermia in mice, to increase punished drinking in rats, and to decrease immobility and increase swimming time during forced swim tests with rats. Moreover, SNAP 37889 increased the social interaction time after 14 days of treatment and maintained its antidepressant effects during forced swim tests with rats after 21 days of treatment. In microdialysis studies, SNAP 37889 partially antagonized the galanin-evoked reduction in hippocampal serotonin (5-hydroxytryptamine, 5-HT), as did the 5-HT(1A) receptor antagonist WAY100635. Their combination produced a complete reversal of the effect of galanin. SNAP 398299 partially reversed the galanin-evoked inhibition of dorsal raphe cell firing and galanin-evoked hyperpolarizing currents. These results indicate that Gal(3)-selective antagonists produce anxiolytic- and antidepressant-like effects, possibly by attenuating the inhibitory influence of galanin on 5-HT transmission at the level of the dorsal raphe nucleus.

Trace amine receptors as targets for novel therapeutics: legend, myth and fact.

Trace amines are attracting attention as neurotransmitters because they are believed to play a role in human disorders such as schizophrenia, depression, attention deficit disorder and Parkinson's disease. Research to date is promising and confirms the need for continuing work to forge the way for new drug discovery.