Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder

Neuropharmacology, Journal Year: 2023, Volume and Issue: 226, P. 109418 - 109418

Published: Jan. 6, 2023

Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, effective in alleviating symptoms posttraumatic disorder (PTSD), at least some individuals, but have unwanted side-effects do not resolve underlying pathophysiology. After period stagnation, there is renewed enthusiasm from public, academic commercial parties designing developing drug treatments for these disorders. Here, we aim to provide snapshot the current state this field that written neuropharmacologists, also practicing clinicians interested lay-reader. introducing currently available treatments, summarize recent/ongoing clinical assessment novel medicines PTSD, grouped according primary neurochemical targets their potential produce acute and/or enduring effects. The evaluation putative targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic neuropeptide systems, amongst others, discussed. We emphasize importance clinically assessing new medications based on firm understanding neurobiology stemming rapid advances being made neuroscience. This includes harnessing neuroplasticity bring about lasting beneficial changes brain rather than – as many transient attenuation symptoms, exemplified by combining psychotropic/cognitive enhancing drugs psychotherapeutic approaches. conclude noting other emerging trends promising phase development.

Language: Английский

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Neurosteroids: mechanistic considerations and clinical prospects

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 49(1), P. 73 - 82

Published: June 27, 2023

Abstract Like other classes of treatments described in this issue’s section, neuroactive steroids have been studied for decades but risen as a new class rapid-acting, durable antidepressants with distinct mechanism action from previous antidepressant and compounds covered issue. Neuroactive are natural derivatives progesterone proving effective exogenous treatments. The best understood is that positive allosteric modulation GABA A receptors, where subunit selectivity may promote their profile action. Mechanistically, there some reason to think separate themselves liabilities modulators, although research ongoing. It also possible intracellular targets, including inflammatory pathways, be relevant beneficial actions. Strengths opportunities further development include exploiting non-GABAergic structural analogs, enzymatic production steroids, precursor loading, novel formulations. molecular mechanisms behavioral effects not fully understood, study brain network states involved emotional processing demonstrate robust influence on affective evident at least GABAergic drugs benzodiazepines. Ongoing studies will elucidate the these well likely underpinnings disease.

Language: Английский

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Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress

Biological Psychiatry, Journal Year: 2023, Volume and Issue: 94(3), P. 249 - 261

Published: Feb. 1, 2023

Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby leads to mood disorders remain unclear. Allopregnanolone acts as positive allosteric modulator preferentially on δ subunit-containing GABA

Language: Английский

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Multifaceted Actions of Neurosteroids

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Neurosteroids modulate neuronal function and are promising therapeutic agents for neuropsychiatric disorders. Neurosteroid analogues approved treating postpartum depression of interest in other GABA-A receptors well characterized targets natural neurosteroids, but biological pathways likely relevant to mechanisms and/or off-target effects. We performed hypothesis-generating silico analyses broad vitro screens assess the range actions neurosteroids varying structural attributes. employed molecular similarity analysis network pharmacology elucidate targets. This confirmed beyond receptors. then functionally screened 19 distinct neurosteroid structures across 78 representing interconnected signaling pathways, complemented with a limited screen kinase activation. Results revealed unanticipated modulation by some selectivity. Many compounds-initiated androgen receptor translocation little or no enantioselectivity. Modulation multiple G-protein was also unexpected. ascendant treatments neuropsychiatry, their full spectrum remains unclear. virtual screening discovery approach opens new vistas exploring mechanism analogues. The multifaceted provides an unbiased, holistic exploration potential effects various platform future validation studies aid drug discovery.

Language: Английский

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Cryo-EM: The Resolution Revolution and Drug Discovery

SLAS DISCOVERY, Journal Year: 2020, Volume and Issue: 26(1), P. 17 - 31

Published: Oct. 5, 2020

Single-particle cryogenic electron microscopy (cryo-EM) has been elevated to the mainstream of structural biology propelled by technological advancements in numerous fronts, including imaging analysis and development direct detectors. The drug discovery field watched with (initial) skepticism wonder at progression technique how it revolutionized molecular understanding previously intractable targets. This article critically assesses cryo-EM impacted diverse therapeutic areas. Targets that have brought into realm structure-based design are thus reviewed here include membrane proteins like GABAA receptor, several TRP channels, G protein-coupled receptors, multiprotein complexes ribosomes, proteasome, eIF2B. We will describe these studies highlighting achievements, challenges, caveats.

Language: Английский

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Androgen Therapy in Neurodegenerative Diseases

Journal of the Endocrine Society, Journal Year: 2020, Volume and Issue: 4(11)

Published: Aug. 21, 2020

Abstract Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson (PD), multiple sclerosis (MS), amyotrophic lateral (ALS), and Huntington disease, are characterized by the loss of neurons as well neuronal function in regions central peripheral nervous systems. Several studies animal models have shown that androgens neuroprotective effects brain stimulate axonal regeneration. The presence androgen receptors system suggests therapy might be useful treatment neurodegenerative diseases. To illustrate, reduced inflammation, amyloid-β deposition, cognitive impairment patients with AD. As well, improvements remyelination MS been reported; comparison, only variable results observed PD. In ALS, administration stimulated motoneuron recovery from progressive damage regenerated both axons dendrites. Only a few clinical available human individuals despite safety low cost therapy. Clinical evaluations on these devastating diseases using large populations strongly needed.

Language: Английский

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Site-specific effects of neurosteroids on GABAA receptor activation and desensitization

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Sept. 21, 2020

This study examines how site-specific binding to three identified neurosteroid-binding sites in the α 1 β 3 GABA A receptor (GABA R) contributes neurosteroid allosteric modulation. We found that potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds canonical (+)–α (-) intersubunit site mediates activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind intrasubunit subunit, promoting desensitization subunit effects vary between Two analogues with diazirine moieties replacing 3-hydroxyl (KK148 KK150) all sites, do potentiate R currents. KK148 is a desensitizing agent, whereas KK150 devoid of activity. These compounds provide potential chemical scaffolds for antagonists. Collectively, these data show differential occupancy efficacy at discrete determine whether has potentiating, inhibitory, or competitive antagonist activity on Rs.

Language: Английский

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Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 14

Published: Jan. 14, 2021

Diverse populations of GABA A receptors (GABA Rs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands therapeutic drugs. Deficits in R signaling underlie pathophysiology behind neurological neuropsychiatric disorders such as epilepsy, anxiety, depression. Pharmacological intervention for these relies on several drug classes that target Rs, benzodiazepines more recently neurosteroids. It has been widely demonstrated subunit composition receptor stoichiometry impact biophysical pharmacological properties Rs. However, current R-targeting drugs have limited selectivity produce their effects concomitantly with undesired side effects. Therefore, there is still a need to develop selective pharmaceuticals, well evaluate potential developing next-generation can accessory proteins associated native In this review, we briefly discuss neurosteroids use therapeutics, some pitfalls adverse We also recent advances toward understanding structure, function, pharmacology Rs focus neurosteroids, newly identified transmembrane modulate

Language: Английский

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Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 1758 - 1758

Published: Feb. 10, 2021

Even though major depressive disorder (MDD) and post-traumatic stress (PTSD) are among the most prevalent incapacitating mental illnesses in world, their diagnosis still relies solely on characterization of subjective symptoms (many which shared by multiple disorders) self-reported patients. Thus, need for objective measures that aid detection differentiation between psychiatric disorders becomes urgent. In this paper, we explore potential neurosteroids neurotrophic proteins as biomarkers MDD PTSD. Circulating levels GABAergic neuroactive steroid, allopregnanolone, diminished PTSD patients, corroborates finding depleted neurosteroid observed animal models these disorders. The protein, brain-derived neurotropic factor (BDNF), is also reduced periphery brain patients depressed-like animals express lower levels. Although role BDNF psychopathology seems less clear merits more research, propose a causal link allopregnanolone expression could function biomarker axis both

Language: Английский

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Premenstrual Syndrome and Premenstrual Dysphoric Disorder as Centrally Based Disorders

Endocrines, Journal Year: 2022, Volume and Issue: 3(1), P. 127 - 138

Published: March 16, 2022

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) encompass a variety of symptoms that occur during the luteal phase menstrual cycle impair daily life activities relationships. Depending on type severity physical, emotional or behavioral symptoms, women reproductive age followed for at least two prospective cycles may receive one diagnoses. PMDD is most severe form PMS, predominantly characterized by not due to another psychiatric disorder. PMS are common neuro-hormonal gynecological disorders with multifaceted etiology. Gonadal steroid hormones their metabolites influence plethora biological systems involved in occurrence specific but there no doubt PMS/PMDD centrally based disorders. A more sensitive neuroendocrine threshold cyclical variations estrogens progesterone under physiological hormonal therapies present. Moreover, altered brain sensitivity allopregnanolone, metabolite produced after ovulation potentiating GABA activity, along an impairment opioid serotoninergic systems, justify symptoms. Even neuro-inflammation expressed via GABAergic system investigation as etiological factor PMS/PMDD. Pharmacological management aims stabilize fluctuations restore balance. The rationale suppressing supports prescription combined contraception (CHC). Its effect mood highly variable depends biochemical characteristics exogenous steroids Hormonal regimens reducing estrogen-free interval menstruation seem better choices. Psychoactive agents, such serotonin reuptake inhibitors (SSRIs), effective be prescribed continuously only phase. Novel therapeutic approaches include inhibition receptors brain, i.e., ulipristal acetate, reduced conversion dutasteride, modulation action allopregnanolone sepranolone.

Language: Английский

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