Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications DOI Open Access
Jaclyn N. Highland, Panos Zanos, Lace M. Riggs

et al.

Pharmacological Reviews, Journal Year: 2021, Volume and Issue: 73(2), P. 763 - 791

Published: March 5, 2021

Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers distinguished by the position of cyclohexyl ring hydroxylation (at 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because lack anesthetic effects, more recent studies have begun to reveal biologic activities. In particular, (2R,6R)- (2S6)-HNK exert antidepressant-relevant behavioral physiologic effects preclinical models, which led a rapid increase seeking clarify mechanisms pharmacological effects. To date, majority research has focused on actions (2R,6R)-HNK its robust tests antidepressant effectiveness limited adverse This review describes pharmacokinetics pharmacodynamics, well putative cellular, molecular, synaptic thought underlie both following metabolism from ketamine direct administration studies. Converging evidence indicates that modulate glutamatergic neurotransmission downstream signaling pathways several brain regions, including hippocampus prefrontal cortex. Effects other neurotransmitter systems, possible neurotrophic inflammatory processes, energy metabolism, also discussed. Additionally, therapeutic applications described, treatment unipolar bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, anti-inflammatory analgesic uses. SIGNIFICANCE STATEMENT: Preclinical indicate hydroxynorketamines may analgesic, anti-inflammatory, physiological relevant for variety human diseases. details pharmacodynamics HNKs, actions, action, potential applications.

Language: Английский

BDNF signaling in context: From synaptic regulation to psychiatric disorders DOI Creative Commons
Camille S. Wang, Ege T. Kavalali, Lisa M. Monteggia

et al.

Cell, Journal Year: 2021, Volume and Issue: 185(1), P. 62 - 76

Published: Dec. 27, 2021

Language: Английский

Citations

361
Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action DOI Creative Commons
Eero Ċastrén, Lisa M. Monteggia

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 90(2), P. 128 - 136

Published: May 14, 2021

Neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), have been associated with depression and antidepressant drug action. A variety of preclinical clinical studies implicated impaired signaling through its receptor TrkB (neurotrophic tyrosine kinase 2) in the pathophysiology mood disorders, but many initial findings not fully supported by more recent meta-analyses, both basic research is needed. In contrast, increased expression has repeatedly mechanisms typical rapid-acting drugs, started to elucidate which antidepressants regulate signaling. a critical regulator various types neuronal plasticities brain, plasticity increasingly connected Although some equivocal data exist, hypothesis connection between factors disorders action recently further strengthened converging evidence from reviewed here.

Language: Английский

Citations

358
Major depressive disorder: hypothesis, mechanism, prevention and treatment DOI Creative Commons
Lulu Cui,

Shu Li,

Siman Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 9, 2024

Abstract Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, pathological mechanisms MDD underlying effects pharmacological treatments for are complex unclear, additional diagnostic therapeutic strategies still needed. The currently widely accepted theories pathogenesis include neurotransmitter receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis cytokine neuroplasticity hypothesis systemic influence but these cannot completely explain mechanism MDD. Even it hard to adopt only one reveal MDD, thus recent years, great progress has been made elucidating roles multiple organ interactions identifying novel approaches multitarget modulatory strategies, further revealing disease features Furthermore, some newly discovered potential targets studied antidepressants have attracted widespread attention, reagents even approved clinical treatment methods such as phototherapy acupuncture effective improvement symptoms. In this work, we comprehensively summarize latest research on diagnosis preventive medicines, well related trials.

Language: Английский

Citations

266
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors DOI
Maxemiliano V. Vargas, Lee E. Dunlap, Chunyang Dong

et al.

Science, Journal Year: 2023, Volume and Issue: 379(6633), P. 700 - 706

Published: Feb. 16, 2023

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and ability to promote cortical neuron growth has been hypothesized underlie rapid sustained therapeutic effects psychedelics. Activation 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) essential for psychedelic-induced plasticity, but it currently unclear why some 5-HT2AR agonists neuroplasticity, whereas others do not. We used molecular genetic tools demonstrate that intracellular 5-HT2ARs mediate plasticity-promoting properties psychedelics; these results explain serotonin does not engage similar plasticity mechanisms. This work emphasizes role location bias signaling, identifies as target, raises intriguing possibility might be endogenous ligand cortex.

Language: Английский

Citations

257
Brain–gut–microbiota axis in depression: A historical overview and future directions DOI Creative Commons
Lijia Chang, Wei Yan, Kenji Hashimoto

et al.

Brain Research Bulletin, Journal Year: 2022, Volume and Issue: 182, P. 44 - 56

Published: Feb. 11, 2022

Depression is the most common mental disorder and a leading cause of disability worldwide. Despite abundant research, precise mechanisms underlying pathophysiology depression remain elusive. Accumulating evidence from preclinical clinical studies suggests that alterations in gut microbiota, microbe-derived short-chain fatty acids, D-amino acids metabolites play key role via brain–gut–microbiota axis, including neural immune systems. Notably, axis might crucial susceptibility versus resilience rodents exposed to stress. Vagotomy reported block depression-like phenotypes after fecal microbiota transplantation "depression-related" microbiome, suggesting vagus nerve influences through axis. In this article, we review recent findings regarding discuss its potential as therapeutic target for depression.

Language: Английский

Citations

249
Molecular pathways of major depressive disorder converge on the synapse DOI Creative Commons
Gabriel R. Fries, Valeria Saldana, Johannes Finnstein

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(1), P. 284 - 297

Published: Oct. 6, 2022

Abstract Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different levels point to high complexity numerous interrelated pathways as the underpinnings depression. systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, opioid system, myelination, gut-brain axis, among others. This review aims illustrating how these multiple signaling may interact provide more comprehensive view MDD’s neurobiology. In particular, considering pattern synaptic activity closest physical representation mood, emotion, conscience we can conceptualize, each pathway or system will be scrutinized for links neurotransmission. Models neurobiology MDD discussed well future actions improve understanding treatment options.

Language: Английский

Citations

245
Psychedelics promote plasticity by directly binding to BDNF receptor TrkB DOI Creative Commons
Rafael Moliner, Mykhailo Girych, Cecilia A. Brunello

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(6), P. 1032 - 1041

Published: June 1, 2023

Abstract Psychedelics produce fast and persistent antidepressant effects induce neuroplasticity resembling the of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine ketamine, act by binding to TrkB, receptor for BDNF. Here we show lysergic acid diethylamide (LSD) psilocin directly bind TrkB with affinities 1,000-fold higher than those other psychedelics antidepressants distinct but partially overlapping sites within transmembrane domain dimers. The on neurotrophic signaling, plasticity antidepressant-like behavior in mice depend promotion endogenous BDNF signaling are independent serotonin 2A (5-HT ) activation, whereas LSD-induced head twitching is dependent 5-HT binding. Our data confirm as a common primary target suggest high-affinity positive allosteric modulators lacking activity may retain potential without hallucinogenic effects.

Language: Английский

Citations

234
Phenotypic drug discovery: recent successes, lessons learned and new directions DOI
Fabien Vincent, Arsenio Nueda, Jonathan Lee

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(12), P. 899 - 914

Published: May 30, 2022

Language: Английский

Citations

201
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor DOI Creative Commons
Wei Yan, Lijia Chang, Kenji Hashimoto

et al.

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(1), P. 559 - 573

Published: May 7, 2021

The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. is racemic mixture equal amounts (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & was approved United States America Europe for treatment-resistant depression. However, increasing number preclinical studies show that arketamine greater potency longer-lasting antidepressant-like effects than rodents, despite lower binding affinity NMDAR. clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like patients with depression, these showing rodents. Thus, rodent data do necessarily translate to humans due complexity human psychiatric disorders. Collectively, available indicate it unlikely NMDAR plays major role action its enantiomers, although precise molecular mechanisms underlying enantiomers remain unclear. this paper, we review recent findings on potent enantiomer arketamine. Furthermore, discuss possible brain-gut-microbiota axis brain-spleen stress-related disorders Finally, potential as treatment cognitive impairment disorders, Parkinson's disease, osteoporosis, inflammatory bowel diseases, stroke.

Language: Английский

Citations

180
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders DOI
Gerard Sanacora, Zhen Yan, Maurizio Popoli

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 23(2), P. 86 - 103

Published: Dec. 10, 2021

Language: Английский

Citations

127