Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity

Neuropsychopharmacology, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Язык: Английский

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Beyond PDE4 inhibition: A comprehensive review on downstream cAMP signaling in the central nervous system

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 177, С. 117009 - 117009

Опубликована: Июнь 21, 2024

Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates signal transduction pathways pivotal for numerous biological functions. Intracellular cAMP levels are spatiotemporally regulated by their hydrolyzing enzymes called phosphodiesterases (PDEs). It has been shown increased in the central nervous system (CNS) promote neuroplasticity, neurotransmission, neuronal survival, and myelination while suppressing neuroinflammation. Thus, elevating through PDE inhibition provides therapeutic approach multiple CNS disorders, including sclerosis, stroke, spinal cord injury, amyotrophic lateral traumatic brain Alzheimer's disease. In particular, of cAMP-specific PDE4 subfamily widely studied because its high expression CNS. So far, clinical translation full inhibitors hampered dose-limiting side effects. Hence, focusing on signaling cascades downstream activated upon presents promising strategy, offering novel pharmacologically safe targets treating disorders. Yet, underlying PDE(4) remain partially elusive. This review comprehensive overview existing knowledge regarding mediators induced or stimulators. Furthermore, we highlight gaps future perspectives may incentivize additional research concerning inhibition, thereby providing approaches

Язык: Английский

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Alleviation of migraine related pain and anxiety by inhibiting calcium-stimulating AC1-dependent CGRP in the insula of adult rats

The Journal of Headache and Pain, Год журнала: 2024, Номер 25(1)

Опубликована: Май 17, 2024

Abstract Background Recent animal and clinical findings consistently highlight the critical role of calcitonin gene-related peptide (CGRP) in chronic migraine (CM) related emotional responses. CGRP antibodies receptor antagonists have been approved for CM treatment. However, underlying CGRP-related signaling pathways pain-related cortex remain poorly understood. Methods The SD rats were used to establish model by dural infusions inflammatory soup. Periorbital mechanical thresholds assessed using von-Frey filaments, anxiety-like behaviors observed via open field elevated plus maze tests. Expression c-Fos, NMDA GluN2B receptors was detected immunofluorescence western blotting analyses. excitatory synaptic transmission whole-cell patch-clamp recording. A human-used adenylate cyclase 1 (AC1) inhibitor, hNB001, applied insula stereotaxic intraperitoneal injections rats. Results insular (IC) activated Glutamate-mediated IC potentiated. levels significantly increased during nociceptive activities. Locally hNB001 or intraperitoneally alleviated periorbital anxiety Furthermore, expression decreased after application. Conclusions Our study indicated that AC1-dependent plasticity contributes AC1 may be a promising target treating future.

Язык: Английский

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Unleashing Spinal Cord Repair: The Role of cAMP-Specific PDE Inhibition in Attenuating Neuroinflammation and Boosting Regeneration after Traumatic Spinal Cord Injury

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(9), С. 8135 - 8135

Опубликована: Май 2, 2023

Traumatic spinal cord injury (SCI) is characterized by severe neuroinflammation and hampered neuroregeneration, which often leads to permanent neurological deficits. Current therapies include decompression surgery, rehabilitation, in some instances, the use of corticosteroids. However, golden standard corticosteroids still achieves minimal improvements functional outcomes. Therefore, new strategies tackling initial inflammatory reactions stimulating endogenous repair later stages are crucial achieving SCI patients. Cyclic adenosine monophosphate (cAMP) an important second messenger central nervous system (CNS) that modulates these processes. A sustained drop cAMP levels observed during SCI, elevating associated with improved outcomes experimental models. regulated a spatiotemporal manner its hydrolyzing enzyme phosphodiesterase (PDE). Growing evidence suggests inhibition cAMP-specific PDEs (PDE4, PDE7, PDE8) strategy orchestrate regeneration CNS. this review focuses on current related immunomodulatory neuroregenerative role PDE pathophysiology.

Язык: Английский

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Altered DNA methylation and gene expression predict disease severity in patients with Aicardi-Goutières syndrome

Clinical Immunology, Год журнала: 2023, Номер 249, С. 109299 - 109299

Опубликована: Март 22, 2023

Aicardi-Goutières Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in associated with innate antiviral responses. Disease presentation and severity vary, even between patients identical from the same family. This study investigated DNA methylation signatures PBMCs to understand phenotypic heterogeneity AGS RNASEH2B. presented hypomethylation ISGs differential patterns (DMPs) involved "neutrophil platelet activation". Patients "mild" phenotypes exhibited DMPs "DNA damage repair", whereas "severe" had "cell fate commitment" "organ development" genes. two (IFI44L, RSAD2) gene when compared phenotypes. In conclusion, altered ISG as biomarkers potential future treatment targets AGS.

Язык: Английский

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Multiple Roles of cAMP in Vertebrate Retina

Cells, Год журнала: 2023, Номер 12(8), С. 1157 - 1157

Опубликована: Апрель 14, 2023

cAMP is a key regulatory molecule that controls many important processes in the retina, including phototransduction, cell development and death, growth of neural processes, intercellular contacts, retinomotor effects, so forth. The total content changes retina circadian manner following natural light cycle, but it also shows local even divergent faster time scales response to transient environment. Changes might manifest or cause various pathological virtually all cellular components retina. Here we review current state knowledge understanding mechanisms by which influences physiological occur retinal cells.

Язык: Английский

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Significant miRNAs as Potential Biomarkers to Differentiate Moyamoya Disease From Intracranial Atherosclerotic Disease

Journal of Clinical Neurology, Год журнала: 2025, Номер 21

Опубликована: Янв. 1, 2025

Язык: Английский

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Genomics of Bipolar Disorder

Psychiatric Clinics of North America, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Social hierarchy modulates drug reinforcement and protein phosphorylation in the nucleus accumbens

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 11, 2025

Introduction Drug reinforcement, a form of behavioral plasticity in which changes happen response to reinforcing drug, would finally lead drug addiction after chronical exposure. reinforcement is affected by genetic and environmental factors. Social hierarchy has been reported regulate drug-seeking behaviors, but the underlying molecular mechanism almost unknown. Methods We take advantage tube test assess social between two co-housed rats. And then, we investigated dominant subordinate rats via conditioned place preference (CPP). Then adopted 4-D label-free mass spectrometry explore complex phosphoproteome nucleus accumbens (NAc) Functional enrichment, protein-protein, motif analysis kinase prediction interaction were used investigate substance use disorder hierarchy. Specifically, identified histone deacetylase 4 (HDAC4) previously shown play critical roles as key node protein phosbind-SDS. Finally, forcibly altered through training, follow accessed HDAC4 phosphorylation levels reinforcement. Results In this study, found that methamphetamine exhibited stronger 660 sites differing spectrometry. enrichment protein-protein revealed synaptic remodeling related pathways pathway are significantly characterized Motif showed CaMKIIδ its downstream proteins maybe central hub. Phosbind-SDS higher dominants. After differences induced eliminated, correspondingly also reversed group Discussion conclusion, our research proves NAc may be vital link

Язык: Английский

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The Vodka Trial: Clinical and Genetic Characteristics of Alcohol Responsiveness in Laryngeal Dystonia

Movement Disorders Clinical Practice, Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

Abstract Background Laryngeal dystonia (LD) is isolated task‐specific focal dystonia, predominantly impairing speech production. Clinical observations and population survey studies have reported that up to 58% of patients with LD may symptom improvement following alcohol intake. Objectives To determine the objective characteristics responsiveness in using a standardized challenge test genetic testing. Methods A total 109 participated study. Patients were administered two non‐diluted drinks 40‐proof vodka 30 min apart, followed by assessments voice symptoms, breath content, side effects. considered alcohol‐responsive (EtOH+) if their symptoms changed ≥10% from baseline. Whole‐exome sequencing was performed identify variants associated LD. Results All tolerated without major adverse events. Fifty‐two (47.7%) had an average 44.4 ± 25.0% about 45 after Five GABAergic pathway‐related genes enriched EtOH+ patients, these, rs11644926 ( ADCY7 ) rs2230741 ADCY9 ), dystonic symptoms. Conclusions Alcohol robust feature related regulating synapses. This finding provides support for evaluation novel oral medications mechanisms action similar treatment dystonia.

Язык: Английский

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