Chronic psychosocial stress is a major precipitant of Major Depressive Disorder (MDD), yet the glial mechanisms that translate sustained stress into maladaptive myelin and immune changes remain unclear. Using chronic social defeat stress and single-nucleus RNA sequencing of anterior medial PFC (mPFC) oligodendroglia, we identified a mature-oligodendrocyte cluster almost exclusively from stress-susceptible animals, marked by immune genes (MHCII) and upregulated Pde4b. Integration with a human MDD single-nucleus RNA sequencing dataset confirmed a conserved immune-like oligodendrocyte (ImOL) subset coexpressing Plp1 and Cd74 and enriched for Pde4b. Mechanistically, PDE4 inhibition with crisaborole elevated cAMP-PKA-CREB signaling, blocked IFNγ-induced MHCII expression, and engaged the eIF2α-ATF4/CHOP arm of the integrated stress response (ISR). In vivo modulation of the ISR with ISRIB or guanabenz bidirectionally controlled ImOL prevalence and stress-related behaviors. These findings position Pde4b-cAMP-ISR signaling as a regulator of oligodendroglial immune phenotypes and a promising target to modulate myelination and neuroinflammation in stress-related disorders.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and although its pathogenesis is not yet clear, the multifactorial mechanisms that affect motor neuron death are intertwined, exacerbating the disease. Here, we explore the effectiveness and mechanism of a combination medication that combines guanabenz with α-lipoic acid in an in vitro as well as in vivo model of ALS. In this research, we initially determined the independent action targets and synergistic action targets of the two drugs through network pharmacology and molecular docking. Subsequently, we further investigated their specific action mechanisms in both in vivo and in vitro studies. In NSC34 cells transfected with hSOD1-G93A, we observed that the combined drugs could more effectively safeguard against cell damage and the production of reactive oxygen species (ROS) generated by mutant hSOD1, superior to monotherapy. This was achieved by upregulating the p-AKT/HO-1 pathway and synergistically suppressing the GRP78/CHOP pathway. Moreover, we found that combination drugs can effectively delay the decline in motor function of hSOD1-G93A transgenic mice by synergistically inhibiting GRP78/CHOP pathway. They can protect the motor neurons in the anterior horn of the spinal cord and suppress gliosis in hSOD1-G93A transgenic mice. In summary, our research indicates that the combination therapy of guanabenz and α-lipoic acid can serve as a viable treatment option for ALS.

The monoamine oxidase (MAO) enzymes are mitochondrial flavoenzymes that catalyse the oxidative deamination of neurotransmitter amines such as serotonin, norepinephrine and dopamine. Inhibitors of the MAOs are well-known antidepressant and antiparkinsonian agents, and act by reducing MAO-mediated metabolism of neurotransmitters in the brain. The present study attempted to identify compounds that inhibit the MAOs by virtual screening of existing drugs listed in the DrugBank using the Discovery Studio life science software. To identify the combinations of docking and scoring functions that most accurately identify known MAO inhibitors, the enrichment factor (EF[10%]) and area under the receiver operating characteristic curve (ROC-AUC) were evaluated. As a third validation metric, ligands that have been complexed with the MAOs were redocked and the root mean square deviation (RMSD) from the co-crystallized orientation was measured. The LibDock/LigScore 2 combination yielded the best results for both MAO-A (EF[10%]: 5.20, ROC-AUC: 0.82) and MAO-B (EF[10%]: 7.47, ROC-AUC: 0.89). Among the top 100 hits, ten compounds were selected and evaluated as in vitro inhibitors of human MAO. Guanabenz (IC50 = 3.46 µM) and proflavine (IC50 = 0.223 µM) were found to be the most potent MAO-A inhibitors. These compounds also inhibited MAO-B with IC50 values of 8.49 and 34.3 µM, respectively. Kinetic analysis showed a competitive mode of MAO-A inhibition for guanabenz (Ki = 0.16 µM) and proflavine (Ki = 0.066 µM). These results show that the validated virtual screening protocol is a useful tool to aid in the discovery of MAO inhibitors.

Previous studies have shown that Nox4 activates eIF2α/ATF4 signaling during the integrated stress response (ISR) and protects heart injury. However, their roles in calcific aortic valve disease (CAVD) remain unclear. Here, we show that both ATF4 and Nox4 are up-regulated in porcine aortic valve interstitial cells (AVIC) and in human aortic valves with CAVD. Nox4 knockdown promotes while Nox4 overexpression suppresses CAVD by modulating ISR. Importantly, ISR activators Guanabenz and Sephin1 effectively attenuate AVIC osteoblastic-like differentiation and mitigate CAVD in rabbits and mice, respectively. These findings highlight that pharmacological enhancement of the ISR is a promising therapeutic strategy for CAVD.

Vanishing white matter (VWM) is a rare disorder, characterized by degeneration of CNS white matter, clinically often exacerbated by stressors such as fever and minor head trauma. VWM is caused by biallelic pathogenic variants in the EIF2B1-5 genes, causing reduced activity of eukaryotic initiation of translation factor 2B, resulting in dysregulation of the integrated stress response (ISR). New scientific insights and increased clinical trials in experimental therapies highlight the need for clinical guidelines to improve and standardize care for patients with VWM worldwide. Standardized care is important for therapy development, as it lessens clinical variability of trial participants at study entry, enabling more sensitive evaluation of treatment outcomes. The aim of this study was to develop expert consensus-based recommendations for diagnosis and management of VWM. A real-time Delphi process with a multidisciplinary expert panel was conducted to formulate consensus-based recommendations. A literature review was performed to determine the strength of available evidence supporting each recommendation. The consensus yielded 43 recommendations on diagnosis, including genetic and MRI criteria, and on clinical management concerning disease progression, acute and long-term care, and preventive strategies. All known pathogenic and likely pathogenic EIF2B1-5 variants were identified from the literature and Amsterdam Leukodystrophy Center laboratory. An overview of these EIF2B1-5 variants was composed to facilitate diagnosis. Clinically used drugs may activate the ISR, posing a risk in VWM, or have no effect on or suppress the ISR, being probably safe in VWM. A second literature search explored the effects of clinically frequently used drugs on the ISR. Drugs were categorized into those likely to activate the ISR, suppress it, and have no likely effects on the ISR. Final judgment was achieved in a consensus meeting of experts. A patient management card was developed with input from clinical experts and patient advocates to provide information on these consensus-based recommendations in lay language and bridge the gap between scientific evidence and expert opinion on one side and the practical needs of clinicians and families on the other side. This study contributes to improving and standardizing VWM care based on scientific and expert insights, while highlighting key areas for future research.

Vanishing white matter is a leukodystrophy with remarkable regional variation in disease severity. The cerebral and cerebellar white matter chronically degenerates, while stress-induced episodes of rapid neurological deterioration coincide with the appearance of acute focal lesions in the deep gray structures and brainstem. With clinical recovery, these acute lesions spontaneously improve or completely resolve on magnetic resonance imaging, suggesting endogenous repair. Repair is not observed in cerebral and cerebellar white matter. Here, we investigated whether differences in cellular pathology might explain the regional variation in repair potential.

The pathophysiology of X-linked adrenoleukodystrophy (ALD) is not well-understood. New quantitative MRI (qMRI) sequences, such as myelin-water imaging (MWI) and multi-shell diffusion-weighted imaging (DWI), are non-invasive techniques that can investigate microstructural abnormalities in the brain. Using these techniques, this study investigated abnormal white matter of cerebral ALD (cALD) lesions and normal-appearing white matter (NAWM) in ALD and in controls. Adult participants were scanned on 3T MRI scanners. Fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were measured with diffusion tensor imaging (DTI). The neurite density index (NDI) was established using neurite orientation dispersion and density imaging (NODDI). Myelin water fractions (MWF) were evaluated with multi-compartment relaxometry diffusion-informed MWI (MCR-DIMWI) and multi-echo T2-relaxation imaging with compressed sensing (METRICS). Measures were evaluated in 10 regions of interest (ROIs) in participants with and without cALD, and in controls. A total of 81 ALD participants (69% males, of whom 17 had cALD), and 21 controls were included. FA, NDI, MWFMETRICS and MWFMCR-DIMWI were significantly lower in lesions in the corpus callosum of cALD participants than in controls. FA, NDI and MWFMETRICS also significantly differentiated the NAWM of male, but not female, ALD participants from controls. FA and NDI had the largest effect sizes for males. In the NAWM, RD was increased, whereas AD was mostly unaffected. In a few NAWM regions, qMRI measures also differed between males with and without cALD. The NAWM of males with ALD contains microstructural abnormalities. Myelin and myelinated axons are impacted by ALD pathophysiology. These techniques have potential for clinical applications.

BACKGROUND: Drug repurposing offers a promising strategy for drug discovery. Drug repurposing involves identifying new therapeutic indications for existing, marketed drugs, thereby reducing the risks, costs, and time typically required for drug development. Various methods exist for drug repurposing, including high-throughput screening of drug compound libraries, computation in silico approaches, literature-based methods, etc. Currently, numerous methods utilize literature for data mining in drug repositioning; however, relatively few approaches leverage literature citation networks for this purpose. RESULTS: We identified 19,553 potential drug pairs for repurposing by analyzing biomedical literature data through the Jaccard coefficient. Our results demonstrated that the literature-based Jaccard coefficient was the most effective similarity metric for identifying drug repurposing opportunities. To refine our selection process, we applied a threshold defined by the upper γth quantile value of the Jaccard coefficient, enabling us to prioritize promising de novo drug repurposing candidates. Among the identified drug pairs, we found several with strong potential for repurposing, including combinations such as adapalene and bexarotene, guanabenz and tizanidine, alvimopan and methylnaltrexone, etc. CONCLUSION: We created a validation set consisting of both true positives and true negatives for drug pairs using the repoDB dataset, a widely recognized resource for drug repurposing. To evaluate the performance of various similarity metrics for drug pairs, we compared their effectiveness based on AUC, F1 score, and AUCPR using the validation set.