Psychedelics Promote Structural and Functional Neural Plasticity

Cell Reports, Journal Year: 2018, Volume and Issue: 23(11), P. 3170 - 3182

Published: June 1, 2018

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role pathophysiology depression and related disorders. The ability to promote both structural functional plasticity PFC has been hypothesized underlie fast-acting antidepressant properties dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable robustly increasing neuritogenesis and/or spinogenesis vitro vivo. These changes neuronal structure accompanied by increased synapse number function, as measured fluorescence microscopy electrophysiology. induced appear result from stimulation TrkB, mTOR, 5-HT2A signaling pathways could possibly explain clinical effectiveness these compounds. Our results underscore therapeutic potential and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds safe, effective, treatments

Language: Английский

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CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature

Nature Neuroscience, Journal Year: 2018, Volume and Issue: 21(10), P. 1380 - 1391

Published: Sept. 17, 2018

Language: Английский

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Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(20), P. 7777 - 7777

Published: Oct. 21, 2020

Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in mammalian brain. BDNF signals through tropomycin receptor kinase B (TrkB) low affinity p75 neurotrophin (p75NTR). plays an important role proper growth, development, plasticity glutamatergic GABAergic synapses modulation neuronal differentiation, it influences serotonergic dopaminergic neurotransmission. acts as paracrine autocrine factor, on both pre-synaptic post-synaptic target sites. It crucial transformation synaptic activity into long-term memories. considered instructive mediator functional structural central nervous system (CNS), influencing dendritic spines and, at least hippocampus, adult neurogenesis. Changes rate neurogenesis spine density can influence several forms learning memory contribute to depression-like behaviors. The possible roles highlighted this review focus effect antidepressant therapies BDNF-mediated plasticity. Moreover, we will data that illustrate a potent protective able confer protection against neurodegeneration, particular Alzheimer’s disease. Finally, give evidence how involvement pathogenesis brain glioblastoma has emerged, thus opening new avenues for treatment deadly cancer.

Language: Английский

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Antidepressant drugs act by directly binding to TRKB neurotrophin receptors

Cell, Journal Year: 2021, Volume and Issue: 184(5), P. 1299 - 1313.e19

Published: Feb. 18, 2021

It is unclear how binding of antidepressant drugs to their targets gives rise the clinical effect. We discovered that transmembrane domain tyrosine kinase receptor 2 (TRKB), brain-derived neurotrophic factor (BDNF) promotes neuronal plasticity and responses, has a cholesterol-sensing function mediates synaptic effects cholesterol. then found both typical fast-acting antidepressants directly bind TRKB, thereby facilitating localization TRKB its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed site at region dimers. Mutation antidepressant-binding motif impaired cellular, behavioral, plasticity-promoting responses in vitro vivo. suggest allosteric facilitation BDNF signaling common mechanism for action, which may explain why act slowly are translated into mood recovery.

Language: Английский

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BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 1170 - 1170

Published: Feb. 10, 2020

Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson’s disease (PD), BDNF enhances the survival dopaminergic neurons, improves neurotransmission motor performance. Pharmacological therapies PD are symptom-targeting, their effectiveness decreases with progression disease; therefore, new therapeutical approaches needed. Since, in both patients models, decreased level was found nigrostriatal pathway, it has been hypothesized that may serve as a therapeutic agent. Direct delivery exogenous into patient’s brain did not relieve symptoms disease, nor attempts to enhance expression gene therapy. Physical training neuroprotective PD. This effect is mediated, at least partly, by BDNF. Animal studies revealed physical activity increases tropomyosin receptor kinase B (TrkB) expression, leading inhibition neurodegeneration through induction transcription factors genes related neuronal proliferation, survival, inflammatory response. review focuses on evidence increasing due modulation or exercise could be considered adjunctive therapy

Language: Английский

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Emerging connections between cerebellar development, behaviour and complex brain disorders

Nature reviews. Neuroscience, Journal Year: 2019, Volume and Issue: 20(5), P. 298 - 313

Published: March 28, 2019

Language: Английский

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Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

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

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Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

Journal of Experimental Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Jan. 1, 2018

Neural plasticity-the ability to change and adapt in response stimuli-is an essential aspect of healthy brain function and, principle, can be harnessed promote recovery from a wide variety disorders. Many neuropsychiatric diseases including mood, anxiety, substance use disorders arise inability weaken and/or strengthen pathologic beneficial circuits, respectively, ultimately leading maladaptive behavioral responses. Thus, compounds capable facilitating the structural functional reorganization neural circuits produce positive effects have broad therapeutic potential. Several known drugs experimental therapeutics been shown plasticity, but most rely on indirect mechanisms are slow-acting. Here, I describe psychoplastogens-a relatively new class fast-acting therapeutics, rapidly promoting plasticity. Psychoplastogenic include psychedelics, ketamine, several other recently discovered antidepressants. Their psychiatry represents paradigm shift our approach treating as we focus less rectifying "chemical imbalances" place more emphasis achieving selective modulation circuits.

Language: Английский

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Psychedelics and Other Psychoplastogens for Treating Mental Illness

Frontiers in Psychiatry, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 4, 2021

Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do produce sustained therapeutic effects following a single administration, also appear broad potential, demonstrating efficacy depression, post-traumatic stress disorder (PTSD), anxiety substance abuse disorder, and alcohol use among others. belong more general class of compounds known psychoplastogens, which robustly promote structural functional neural plasticity in key circuits relevant health. Here we discuss the importance treatment neuropsychiatric diseases, well evidence that psychedelics are most effective chemical modulators studied date. Furthermore, provide theoretical framework with potential explain why psychedelic long-lasting across wide range disorders. Despite their promise broadly efficacious neurotherapeutics, there several issues associated psychedelic-based medicines drastically limit clinical scalability. We these challenges how might overcome through development non-hallucinogenic psychoplastogens. The other psychoplastogenic marks paradigm shift neuropsychiatry toward approaches relying on selective modulation small molecule drugs. Psychoplastogen research brings us one step closer actually curing mental illness by rectifying underlying pathophysiology disorders like moving beyond simply disease symptoms. However, determining effectively deploy at scale will an important consideration field moves forward.

Language: Английский

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Stress induced microglial activation contributes to depression

Pharmacological Research, Journal Year: 2022, Volume and Issue: 179, P. 106145 - 106145

Published: Feb. 24, 2022

Language: Английский

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