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ACS Medicinal Chemistry Letters Sep 2023Neurological diseases often involve changes in synaptic connectivity and plasticity. Psychoplastogens, substances that stimulate neuronal growth and enhance neural...
Neurological diseases often involve changes in synaptic connectivity and plasticity. Psychoplastogens, substances that stimulate neuronal growth and enhance neural structures, show promise in mitigating these changes. They activate key biological targets, including AMPA receptors, TrkB, and mTOR. Substances like ketamine, scopolamine, ,-dimethyltryptamine, and rapastinel have psychoplastogenic properties. In clinical trials, psychedelic psychoplastogens have demonstrated antidepressant, anxiolytic, and anti-addictive effects. The research described in this Patent Highlight suggests the potential for novel therapies in neurological disorders that leverage psychoplastogens, which modulate synaptic connections and plasticity.
PubMed: 37736170
DOI: 10.1021/acsmedchemlett.3c00309 -
European Journal of Pharmacology Oct 2023Depression is a profound mental disorder that dampens the mood and undermines volition, which exhibited an increased incidence over the years. Although drug-based... (Review)
Review
Depression is a profound mental disorder that dampens the mood and undermines volition, which exhibited an increased incidence over the years. Although drug-based interventions remain the primary approach for depression treatment, the available medications still can't satisfy the patients. In recent years, the newly discovered therapeutic targets such as N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, and tyrosine kinase B (TrkB) have brought new breakthroughs in the development of antidepressant drugs. Moreover, it has come to light that certain anesthetics possess pharmacological mechanisms intricately linked to the aforementioned therapeutic targets for depression. At present, numerous preclinical and clinical studies have explored the therapeutic effects of anesthetic drugs such as ketamine, isoflurane, NO, and propofol, on depression. These investigations suggested that these drugs can swiftly ameliorate patients' depression symptoms and engender long-term effects. In this paper, we provide a comprehensive review of the research progress and potential molecular mechanisms of various anesthetic drugs for depression treatment. By shedding light on this subject, we aim to facilitate the development and clinical implementation of new antidepressant drugs based on anesthetic medications.
Topics: Humans; Depression; Anesthetics; Isoflurane; Ketamine; Propofol; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 37660970
DOI: 10.1016/j.ejphar.2023.176032 -
Molecular Psychiatry Apr 2024The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions... (Review)
Review
The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.
Topics: Humans; Antidepressive Agents; Neuronal Plasticity; Ketamine; Animals; Depression; Long-Term Potentiation; Receptors, N-Methyl-D-Aspartate; Synapses
PubMed: 38177353
DOI: 10.1038/s41380-023-02397-1 -
Molecular Metabolism Oct 2023The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following...
OBJECTIVE
The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior.
METHODS
C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP).
RESULTS
1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gα) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gα-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior.
CONCLUSIONS
We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction.
Topics: Mice; Animals; Orexins; Hypothalamic Area, Lateral; Neuropeptides; Caloric Restriction; Glucose; Mice, Inbred C57BL; Dopaminergic Neurons; Glutamates
PubMed: 37536499
DOI: 10.1016/j.molmet.2023.101788 -
ENeuro Aug 2023AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic...
AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic targeting, pharmacology, and function of AMPARs are influenced by auxiliary subunits including the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is unclear which TARP subunits are present at retinal synapses and how they influence receptor localization and function. Here, we show that TARPɣ2 (stargazin) is associated with AMPARs in the synaptic layers of the mouse, rabbit, macaque, and human retina. In most species, TARPɣ2 expression was high where starburst amacrine cells (SACs) ramify and transcriptomic analyses suggest correspondingly high gene expression in mouse and human SACs. Synaptic expression of GluA2, GluA3, and GluA4 was significantly reduced in a mouse mutant lacking TARPɣ2 expression (stargazer mouse; ), whereas GluA1 levels were unaffected. AMPAR-mediated light-evoked EPSCs in ON-SACs from mice were ∼30% smaller compared with heterozygous littermates. There was also loss of a transient ON pathway-driven GABAergic input to ON-SACs in mutants. Direction-selective ganglion cells in the mouse showed normal directional tuning, but their surround inhibition and thus spatial tuning was reduced. Our results indicate that TARPɣ2 is required for normal synaptic expression of GluA2, GluA3, and GluA4 in the inner retina. The presence of residual AMPAR expression in the stargazer mutant suggests that other TARP subunits may compensate in the absence of TARPɣ2.
Topics: Animals; Humans; Mice; Rabbits; Mammals; Neurons; Receptors, AMPA; Retina; Synapses; Synaptic Transmission
PubMed: 37491367
DOI: 10.1523/ENEURO.0158-23.2023 -
Chemico-biological Interactions Oct 2023Cervical cancer is one of the most leading causes of cancer death worldwide, and ferroptosis is implicated in the progression of cervical cancer. Cornichon family AMPA...
Cervical cancer is one of the most leading causes of cancer death worldwide, and ferroptosis is implicated in the progression of cervical cancer. Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) is involved in the progression of various human cancers; however, its function in cervical cancer remains unclear. The present study aims to investigate the role and mechanism of CNIH4 in cervical cancer using gain- and loss-of-function studies in vitro. SiHa and CaSki cells were infected with lentiviral vectors to manipulate the expression of CNIH4 in vitro, and cell viability, migration, invasion as well as ferroptosis were evaluated. Transcriptome sequencing analysis was performed to further validate the mechanism through which CNIH4 regulated the progression of cervical cancer. The expression of CNIH4 was upregulated in human cervical cancer tissues and cells, and strongly correlated with the decreases in overall survival and disease free survival rates of cervical cancer patients. CNIH4 silence inhibited, while CNIH4 overexpression facilitated the survival of human cervical cancer cells. Mechanistically, CNIH4 elevated solute carrier family 7 member 11 (SLC7A11)-mediated cystine import, and subsequently increased intracellular glutathione synthesis and glutathione peroxidase 4 activity, thereby inhibiting ferroptosis of human cervical cancer cells. SLC7A11 silence significantly abolished CNIH4-mediated inhibition of ferroptosis in cervical cancer cells in vitro. Our study for the first time reveals that CNIH4 inhibits ferroptosis of human cervical cancer cells through upregulating SLC7A11, defining CNIH4 as an attractive therapeutic and prognostic target for cervical cancer.
PubMed: 37716418
DOI: 10.1016/j.cbi.2023.110712 -
BMC Cancer Jan 2024Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glioblastoma is the most frequent and a particularly malignant primary brain tumor with no efficacy-proven standard therapy for recurrence. It has recently been discovered that excitatory synapses of the AMPA-receptor subtype form between non-malignant brain neurons and tumor cells. This neuron-tumor network connectivity contributed to glioma progression and could be efficiently targeted with the EMA/FDA approved antiepileptic AMPA receptor inhibitor perampanel in preclinical studies. The PerSurge trial was designed to test the clinical potential of perampanel to reduce tumor cell network connectivity and tumor growth with an extended window-of-opportunity concept.
METHODS
PerSurge is a phase IIa clinical and translational treatment study around surgical resection of progressive or recurrent glioblastoma. In this multicenter, 2-arm parallel-group, double-blind superiority trial, patients are 1:1 randomized to either receive placebo or perampanel (n = 66 in total). It consists of a treatment and observation period of 60 days per patient, starting 30 days before a planned surgical resection, which itself is not part of the study interventions. Only patients with an expected safe waiting interval are included, and a safety MRI is performed. Tumor cell network connectivity from resected tumor tissue on single cell transcriptome level as well as AI-based assessment of tumor growth dynamics in T2/FLAIR MRI scans before resection will be analyzed as the co-primary endpoints. Secondary endpoints will include further imaging parameters such as pre- and postsurgical contrast enhanced MRI scans, postsurgical T2/FLAIR MRI scans, quality of life, cognitive testing, overall and progression-free survival as well as frequency of epileptic seizures. Further translational research will focus on additional biological aspects of neuron-tumor connectivity.
DISCUSSION
This trial is set up to assess first indications of clinical efficacy and tolerability of perampanel in recurrent glioblastoma, a repurposed drug which inhibits neuron-glioma synapses and thereby glioblastoma growth in preclinical models. If perampanel proved to be successful in the clinical setting, it would provide the first evidence that interference with neuron-cancer interactions may indeed lead to a benefit for patients, which would lay the foundation for a larger confirmatory trial in the future.
TRIAL REGISTRATION
EU-CT number: 2023-503938-52-00 30.11.2023.
Topics: Humans; Glioblastoma; Quality of Life; Neoplasm Recurrence, Local; Seizures; Nitriles; Pyridones; Treatment Outcome; Double-Blind Method
PubMed: 38279087
DOI: 10.1186/s12885-024-11846-1 -
Brain, Behavior, and Immunity Oct 2023Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is...
Joint pain is one of the most debilitating symptoms of rheumatoid arthritis (RA) and patients frequently rate improvements in pain management as their priority. RA is hallmarked by the presence of anti-modified protein autoantibodies (AMPA) against post-translationally modified citrullinated, carbamylated and acetylated proteins. It has been suggested that autoantibody-mediated processes represent distinct mechanisms contributing to pain in RA. In this study, we investigated the pronociceptive properties of monoclonal AMPA 1325:01B09 (B09 mAb) derived from the plasma cell of an RA patient. We found that B09 mAb induces pain-like behavior in mice that is not associated with any visual, histological or transcriptional signs of inflammation in the joints, and not alleviated by non-steroidal anti-inflammatory drugs (NSAIDs). Instead, we found that B09 mAb is retained in dorsal root ganglia (DRG) and alters the expression of several satellite glia cell (SGC), neuron and macrophage-related factors in DRGs. Using mice that lack activating FcγRs, we uncovered that FcγRs are critical for the development of B09-induced pain-like behavior, and partially drive the transcriptional changes in the DRGs. Finally, we observed that B09 mAb binds SGC in vitro and in combination with external stimuli like ATP enhances transcriptional changes and protein release of pronociceptive factors from SGCs. We propose that certain RA antibodies bind epitopes in the DRG, here on SGCs, form immune complexes and activate resident macrophages via FcγR cross-linking. Our work supports the growing notion that autoantibodies can alter nociceptor signaling via mechanisms that are at large independent of local inflammatory processes in the joint.
Topics: Animals; Mice; Autoantibodies; Receptors, IgG; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Arthritis, Rheumatoid; Pain
PubMed: 37437817
DOI: 10.1016/j.bbi.2023.07.001 -
Frontiers in Behavioral Neuroscience 2023Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which...
Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which is then converted to a more stable long-term memory through a process called memory consolidation. At the neuronal level, synaptic plasticity is crucial for memory storage. It includes the formation of new spines, as well as the modification of existing spines, thereby tuning and shaping synaptic efficacy. Cofilin critically contributes to memory processes as upon activation, it regulates the shape of dendritic spines by targeting actin filaments. We previously found that prolonged activation of cofilin in hippocampal neurons attenuated the formation of long-term object-location memories. Because the modification of spine shape and structure is also essential for short-term memory formation, we determined whether overactivation of hippocampal cofilin also influences the formation of short-term memories. To this end, mice were either injected with an adeno-associated virus expressing catalytically active cofilin, or an eGFP control, in the hippocampus. We show for the first time that cofilin overactivation improves short-term memory formation in the object-location memory task, without affecting anxiety-like behavior. Surprisingly, we found no effect of cofilin overactivation on AMPA receptor expression levels. Altogether, while cofilin overactivation might negatively impact the formation of long-lasting memories, it may benefit short-term plasticity.
PubMed: 37638111
DOI: 10.3389/fnbeh.2023.1243524 -
BioRxiv : the Preprint Server For... Sep 2023Neural circuits, which constitute the substrate for brain processing, can be traced in the retrograde direction, from postsynaptic to presynaptic cells, using methods...
Neural circuits, which constitute the substrate for brain processing, can be traced in the retrograde direction, from postsynaptic to presynaptic cells, using methods based on introducing modified rabies virus into genetically marked cell types. These methods have revolutionized the field of neuroscience. However, similarly reliable, transsynaptic, and non-toxic methods to trace circuits in the anterograde direction are not available. Here, we describe such a method based on an antibody-like protein selected against the extracellular N-terminus of the AMPA receptor subunit GluA1 (AMPA.FingR). ATLAS (Anterograde Transsynaptic Label based on Antibody-like Sensors) is engineered to release the AMPA.FingR and its payload, which can include Cre recombinase, from presynaptic sites into the synaptic cleft, after which it binds to GluA1, enters postsynaptic cells through endocytosis and subsequently carries its payload to the nucleus. Testing in vivo and in dissociated cultures shows that ATLAS mediates monosynaptic tracing from genetically determined cells that is strictly anterograde, synaptic, and non-toxic. Moreover, ATLAS shows activity dependence, which may make tracing active circuits that underlie specific behaviors possible.
PubMed: 37745471
DOI: 10.1101/2023.09.12.557425