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International Immunopharmacology Sep 2023Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these...
Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these effects are still unclear. This study aimed to investigate the antidepressant mechanisms of levomilnacipran to discover new perspectives on the treatment of depression in male rats. Intraperitoneal injection of lipopolysaccharide (LPS) was used to induce depressive behaviors in rats. Activation of microglia and apoptosis of neurons verified by immunofluorescence. Inflammatory related proteins and neurotrophic related proteins were verified by immunoblotting. The mRNA expression of apoptosis markers was verified by real-time quantitative PCR. Finally, electron microscopy analysis was used to observe the ultrastructural pathology of neuron. Here, we found that the anti-depression and anti-anxiety effects of levomilnacipran in the LPS-induced rat model of depression was resulted from the suppression of neuroinflammation and neuronal apoptosis within prefrontal cortex of rats. Furthermore, we found that levomilnacipran could decrease the number of microglia and suppress its activation in prefrontal cortex of rats. This effect may be mediated by suppressing the TLR4/NF-κB and Ras/p38 signaling pathways. In addition, levomilnacipran plays a neuroprotective role by increasing the expression of neurotrophic factors. Taken together, these results suggest that levomilnacipran exerts antidepressant effects by attenuating neuroinflammation to inhibit the damage in central nervous system and plays a neuroprotective role to improve depressive behaviors. These findings suggest that suppression of neuroinflammation in prefrontal cortex could ameliorate depressive behavioral disorder of rats induced by LPS, which provided a new perspective for the treatment of depression.
Topics: Rats; Male; Animals; Lipopolysaccharides; Levomilnacipran; Toll-Like Receptor 4; Neuroinflammatory Diseases; Signal Transduction; NF-kappa B; Antidepressive Agents; Microglia
PubMed: 37413934
DOI: 10.1016/j.intimp.2023.110595 -
Critical Reviews in Food Science and... Jan 2024In this manuscript, we conducted a comprehensive review of the diverse effects of peppermint on human health and explored the potential underlying mechanisms. Peppermint... (Review)
Review
In this manuscript, we conducted a comprehensive review of the diverse effects of peppermint on human health and explored the potential underlying mechanisms. Peppermint contains three main groups of phytochemical constituents, including essential oils (mainly menthol), flavonoids (such as hesperidin, eriodictyol, naringenin, quercetin, myricetin, and kaempferol), and nonflavonoid phenolcarboxylic acids. Peppermint exhibits antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, anti-cancer, anti-aging, and analgesic properties and may be effective in treating various disorders, including gastrointestinal disorders (e.g., irritable bowel syndrome, dyspepsia, constipation, functional gastrointestinal disorders, nausea/vomiting, and gallbladder stones). In addition, peppermint has therapeutic benefits for psychological and cognitive health, dental health, urinary retention, skin and wound healing, as well as anti-depressant and anti-anxiety effects, and it may improve memory. However, peppermint has paradoxical effects on sleep quality and alertness, as it has been shown to improve sleep quality in patients with fatigue and anxiety, while also increasing alertness under conditions of monotonous work and relaxation. We also discuss its protective effects against toxic agents at recommended doses, as well as its safety and potential toxicity. Overall, this review provides the latest findings and insights into the properties and clinical effects of peppermint/menthol and highlights its potential as a natural therapeutic agent for various health conditions.
PubMed: 38168664
DOI: 10.1080/10408398.2023.2296991 -
Cannabis and Cannabinoid Research Sep 2023Cannabis and its primary psychoactive constituent delta-9-tetrahydrocannabinol (D9-THC) produce biphasic, dose-dependent effects on anxiety. In addition to D9-THC,...
Cannabis and its primary psychoactive constituent delta-9-tetrahydrocannabinol (D9-THC) produce biphasic, dose-dependent effects on anxiety. In addition to D9-THC, cannabis contains other "minor" cannabinoids and terpenes with purported therapeutic potential for the treatment of anxiety. Empirical data on potential therapeutic effects of these compounds is limited. The current study evaluated the effects of selected minor cannabinoids and terpenes in a battery of tests sensitive to anxiolytic and anxiogenic drugs. In Experiment 1, adult male Sprague Dawley rats (=7-8/group) were administered acute oral doses of one of five minor cannabinoids: delta-8-tetrahydrocannabinol (D8-THC; 10 mg/kg), tetrahydrocannabivarin (32 mg/kg), cannabidiolic acid (32 mg/kg), cannabidivarin (32 mg/kg), and cannabigerol (100 mg/kg), or one of five terpenes: D-limonene (17 mg/kg), ⍺-pinene (100 mg/kg), ⍺-terpineol (10 mg/kg), bisabolol (100 mg/kg), and β-caryophyllene (17 mg/kg), or vehicle (medium-chain triglycerides [MCT] oil). Ethyl alcohol was tested as an active comparator. Thirty minutes post-administration, the marble burying test, the three-chamber social interaction test, and the novelty-induced hypophagia test were completed; motor activity was assessed throughout testing. Experiment 2 examined the potential anxiolytic effects of minor cannabinoids when administered chronically; rats administered MCT oil or minor cannabinoids in Experiment 1 continued receiving once-daily doses for 21 days and were assessed using the same test battery after 7, 14, and 21 days of administration. When compared to vehicle, acute administration of bisabolol and D-limonene increased the amount of food consumed and bisabolol-, D-limonene-, ⍺-pinene-, and β-caryophyllene decreased percent time spent in the outer zone in the novelty-induced hypophagia test, suggestive of an anxiolytic effect. Only ethanol increased social interaction. After acute administration, anxiogenic effects in the marble burying test were observed for D8-THC, but not for other minor cannabinoids and terpenes. Throughout chronic administration, only D8-THC displayed anxiogenic effects in the novelty-induced hypophagia test. The other cannabinoids did not show anxiolytic or anxiogenic effects in any of the tests at the doses or times tested. The minor cannabinoids and terpenes did not impair or stimulate general motor activity. These data provide a foundation for future studies investigating cannabinoid/terpene interactions.
Topics: Male; Rats; Animals; Terpenes; Anti-Anxiety Agents; Limonene; Rats, Sprague-Dawley; Hallucinogens; Cannabis; Cannabinoid Receptor Agonists; Administration, Oral; Turpentine; Calcium Carbonate; Cannabinoids
PubMed: 37721993
DOI: 10.1089/can.2023.0083 -
Expert Review of Neurotherapeutics May 2024Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many... (Review)
Review
INTRODUCTION
Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many patients continue to suffer due to incomplete symptom resolution and side effects.
AREAS COVERED
This manuscript examines Vortioxetine's role in Major Depressive Disorder (MDD) treatment, highlighting its potential to reshape therapeutic strategies due to its unique Multimodal action and proven broad-spectrum efficacy in multiple depressive domains. A detailed examination of Vortioxetine's pharmacological aspects, including indications, dosage, pharmacodynamics, and pharmacokinetics, is provided, emphasizing its safety and effectiveness. The discussion extends to Vortioxetine's role in acute-phase treatment and maintenance of MDD and its profound impact on specialized depression domains.
EXPERT OPINION
Vortioxetine is distinguished for its novel multimodal serotonin modulation mechanism, showcasing significant promise as an innovative treatment for MDD. Its efficacy, which is dose-dependent, along with a commendable tolerability profile, positions it as a potential leading option for initial treatment strategies. The discourse on dosage titration, particularly the strategy of initiating treatment at lower doses followed by gradual escalation, underscores the approach toward minimizing initial adverse effects while optimizing therapeutic outcomes, aligning with the principles of personalized medicine in psychiatric care.
Topics: Antidepressive Agents; Anxiety; Cognitive Dysfunction; Depressive Disorder, Major; Emotions; Escitalopram; Post-Acute COVID-19 Syndrome; Precision Medicine; Selective Serotonin Reuptake Inhibitors; Serotonin; Vortioxetine; Humans; Neurotransmitter Agents; Animals
PubMed: 38536761
DOI: 10.1080/14737175.2024.2333394 -
Molecules (Basel, Switzerland) Jul 2023The negative impact on worldwide social well-being by the increasing rate of psychiatric diseases has led to a continuous new drug search. Even though the current... (Review)
Review
The negative impact on worldwide social well-being by the increasing rate of psychiatric diseases has led to a continuous new drug search. Even though the current therapeutic options exert their activity on multiple neurological targets, these have various adverse effects, causing treatment abandonment. Recent research has shown that offers a rich source of metabolites, mainly terpenes and flavonoids, as useful agents against central nervous system disorders, with remarkable in vitro and in vivo activities on models related to these pathologies. Furthermore, studies have revealed that some compounds exhibit a chemical interaction with γ-aminobutyric acid, 5-hydroxytryptamine, and N-methyl-D-aspartate receptors, which are key components in the pathophysiology associated with psychiatric and neurological diseases. The current clinical evaluations of standardized extracts of are scarce; however, one or more of its compounds represents an area of opportunity to test the efficacy of the plant as an anxiolytic, antidepressant, antiepileptic, or sleep enhancer. For this, the aim of the review was based on the pharmacological activities offered by the compounds identified and isolated from coriander and the processes involved in achieving their effect. In addition, lines of technological research, like molecular docking and nanoparticles, are proposed for the future development of phytomedicines, based on the bioactive molecules of , for the treatment of psychiatric and neurological disorders addressed in the present study.
Topics: Humans; Coriandrum; Molecular Docking Simulation; Anti-Anxiety Agents; Antidepressive Agents; Mental Disorders; Plant Extracts
PubMed: 37513187
DOI: 10.3390/molecules28145314 -
Stroke and Vascular Neurology Dec 2023Poststroke depression and anxiety, independent predictor of poor functional outcomes, are common in the acute phase of stroke. Up to now, there is no fast-onset...
BACKGROUND
Poststroke depression and anxiety, independent predictor of poor functional outcomes, are common in the acute phase of stroke. Up to now, there is no fast-onset antidepressive and anxiolytic agents suitable for the management of acute stroke. ZL006-05, a dual-target analgesic we developed, dissociates nitric oxide synthase from postsynaptic density-95 while potentiates α2-containing γ-aminobutyric acid type A receptor. This study aims to determine whether ZL006-05 can be used as an antistroke agent with fast-onset antidepressant and anxiolytic effects.
METHODS
Photothrombotic stroke and transient middle cerebral artery occlusion were induced in rats and mice. Infarct size was measured by TTC(2,3,5-Triphenyltetrazolium chloride) staining or Nissl staining. Neurological defects were assessed by four-point scale neurological score or modified Neurological Severity Scores. Grid-walking, cylinder and modified adhesive removal tasks were conducted to assess sensorimotor functions. Spatial learning was assessed using Morris water maze task. Depression and anxiety were induced by unpredictable chronic mild stress. Depressive behaviours were assessed by tail suspension, forced swim and sucrose preference tests. Anxiety behaviours were assessed by novelty-suppressed feeding and elevated plus maze tests. Pharmacokinetics, toxicokinetics and long-term toxicity studies were performed in rats.
RESULTS
Administration of ZL006-05 in the acute phase of stroke attenuated transient and permanent ischaemic injury and ameliorated long-term functional impairments significantly, with a treatment window of 12 hours after ischemia, and reduced plasminogen activato-induced haemorrhagic transformation. ZL006-05 produced fast-onset antidepressant and anxiolytic effects with onset latency of 1 hour in the normal and CMS mice, had antidepressant and anxiolytic effects in stroke mice. ZL006-05 crossed the blood-brain barrier and distributed into the brain rapidly, and had a high safety profile in toxicokinetics and long-term toxicological studies.
CONCLUSION
ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy, safety and targeting of clinical issues.
Topics: Rats; Mice; Animals; Anti-Anxiety Agents; Antidepressive Agents; Brain; Anxiety; Stroke
PubMed: 37185136
DOI: 10.1136/svn-2022-002156 -
Peptides Dec 2023Pain, a worldwide problem with a high incidence and complex pathogenesis, has attracted the attention of pharmaceutical enterprises for the development of safer and more...
Pain, a worldwide problem with a high incidence and complex pathogenesis, has attracted the attention of pharmaceutical enterprises for the development of safer and more effective drugs. Extensive experimental and clinical evidence has demonstrated the analgesic effects of two endogenous peptides: endomorphin-2 (EM-2) and salmon calcitonin (sCT). However, EM-2 has limitations, such as poor ability to cross the blood-brain barrier (BBB) and little therapeutic effect in chronic pain due to rapid in vivo proteolysis. Herein, we propose the design of a novel hybrid peptide TEM2CT by combining EM-2, sCT, and the cell-penetrating peptide HIV-1 trans-activator protein (TAT) with the aim of enhancing their analgesic effects. TEM2CT treatment attenuated nociceptive behavior in both acute and chronic pain mouse models, exhibiting increased anti-allodynic and anti-anxiety effects compared to sCT treatment. Furthermore, TEM2CT also regulated the excitability of pyramidal neurons in the anterior cingulate cortex (ACC) in spared nerve injury (SNI) model mice. The improved efficacy of this hybrid peptide provides a promising strategy for developing analgesic drugs.
Topics: Mice; Animals; Anti-Anxiety Agents; Chronic Pain; Hyperalgesia; Analgesics; Cell-Penetrating Peptides
PubMed: 37778465
DOI: 10.1016/j.peptides.2023.171108 -
British Journal of Clinical Pharmacology Aug 2023Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based...
AIMS
Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PK) and pharmacodynamic (PD) modelling to further examine the underlying mechanisms of anxiety treatment and addiction.
METHODS
Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The physiologically based PK models for alprazolam were developed using PK-Sim software and PD models were implemented with the MonolixSuite 2021R platform.
RESULTS
After single administrations, peak unbound interstitial brain concentrations range from 4 to 33 nM for 0.25-2 mg-doses of the immediate-release form and 3-54 nM for 0.5-10-mg doses of the extended-release form. With repetitive administrations, peak concentration is 59 nM for a 2-mg alprazolam immediate-release dose and 122 nM for a 10-mg extended-release dose. Potentiation of EC GABA-gated currents from recombinant GABA Rs composed of α1β2γ2, α2β3γ2 and α5β3γ2 subunit combinations is 92, 150 and 75%, respectively, for an alprazolam concentration of 59 nM. The 10-90% rise times for the brain concentration-time profile following a single 1-mg immediate-release administration is 22.8 min and 3.8 h for a 3-mg extended-release administration.
CONCLUSION
Unbound interstitial brain concentration-time profiles of alprazolam corresponded to changes in β rhythm activity, peak saccade velocity, mood improvement, cognitive speed slowing and digit symbol substitution test scores. PD models for these endpoints suggest that alprazolam immediate-release maximal effects on cognitive slowing, cognitive impairment, sedation and mood improvement occur sequentially following the brain concentration-time profile.
Topics: Humans; Alprazolam; Anti-Anxiety Agents; Substance-Related Disorders; Anxiety; gamma-Aminobutyric Acid
PubMed: 36946233
DOI: 10.1111/bcp.15719 -
European Archives of Psychiatry and... Oct 2023There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric... (Review)
Review
There is need for novel fast acting treatment options in affective disorders. 3α-reduced neurosteroids such as allopregnanolone are powerful positive allosteric modulators of GABA receptors and target also extrasynaptic receptors. Their synthesis is mediated by the translocator protein 18 kDa (TSPO). TSPO ligands not only promote endogenous neurosteroidogenesis, but also exert a broad spectrum of functions involving modulation of mitochondrial activity and acting as anti-inflammatory and neuroregenerative agents. Besides affective symptoms, in depression cognitive impairment can be frequently observed, which may be ameliorated through targeting of extrasynaptic GABA receptors either via TSPO ligands or exogenously administered 3α-reduced neurosteroids. Interestingly, recent findings indicate an enhanced activation of the complement system, e.g., enhanced expression of C1q, both in depression and dementia. It is of note that benzodiazepines have been shown to reduce long-term potentiation and to cause cognitive decline. Intriguingly, TSPO may be crucial in mediating the effects of benzodiazepines on synaptic pruning. Here, we discuss how benzodiazepines and TSPO may interfere with synaptic pruning. Moreover, we highlight recent developments of TSPO ligands and 3α-reduced neurosteroids as therapeutic agents. Etifoxine is the only clinically available TSPO ligand so far and has been studied in anxiety disorders. Regarding 3α-reduced neurosteroids, brexanolone, an intravenous formulation of allopregnanolone, has been approved for the treatment of postpartum depression and zuranolone, an orally available 3α-reduced neurosteroid, is currently being studied in major depressive disorder and postpartum depression. As such, 3α-reduced neurosteroids and TSPO ligands may constitute promising treatment approaches for affective disorders.
Topics: Humans; Female; Neurosteroids; Anti-Anxiety Agents; Pregnanolone; Ligands; Depression; Depression, Postpartum; Depressive Disorder, Major; Neurotransmitter Agents; Receptors, GABA-A; Benzodiazepines; Carrier Proteins; Neuronal Plasticity; Cognition; gamma-Aminobutyric Acid; Receptors, GABA
PubMed: 36574032
DOI: 10.1007/s00406-022-01532-3 -
Journal of Ethnopharmacology Feb 2024Central nervous system (CNS) diseases can be diverse and usually present with comorbidity, as in the case of depression and anxiety. Despite alternatives like Psilocybe...
ETHNOPHARMACOLOGY RELEVANCE
Central nervous system (CNS) diseases can be diverse and usually present with comorbidity, as in the case of depression and anxiety. Despite alternatives like Psilocybe mushrooms for mental health there is no basic research to evidence their CNS benefits.
AIM OF THE STUDY
To evaluate the anxiolytic- and antidepressant-like effects, as well as the acute toxicity of P. cubensis mushroom.
MATERIAL AND METHODS
First, the acute toxicity (LD) of P. cubensis (2000 mg/kg) was determined after the esophageal (p.o.) and intraperitoneal (i.p.) route of administration. The rota-rod test and electroencephalogram (EEG) were included to assess CNS toxicity in free moving mice. Anxiolytic (ambulatory or exploratory and rearing behaviors) and antidepressant behavioral responses were assayed in the open-field, plus-maze, and forced swimming test, respectively, after administration of 1000 mg/kg, p.o., of the whole P. cubensis mushroom or the polar aqueous (AQ) or methanolic (MeOH) extractions (1, 10, and/or 100 mg/kg, i.p.) in comparison to the reference drugs buspirone (4 mg/kg, i.p.), fluoxetine and/or imipramine (10 mg/kg, s.c. and i.p., respectively). A chemical analysis of the AQ and MeOH extractions was performed to detect psilocybin and/or psilocin by using UHPLC.
RESULTS
Neurotoxic effects of P. cubensis mushroom administered at high doses were absent in mice assessed in the rota-rod test or for EEG activity. A LD > 2000 mg/kg was calculated by p.o. or i.p. administration. While significant and/or dose-response antidepressant-like effects were produced with the whole P. cubensis mushroom, p.o., and after parenteral administration of the AQ or MeOH extractions resembling the effects of the reference drugs. Behavioral responses were associated with an anxiolytic-like effect in the open-field as corroborated in the plus-maze tests. The presence of psilocybin and psilocin was mainly characterized in the AQ extraction.
CONCLUSION
Our results provide preclinical evidence of the anxiolytic- and antidepressant-like effects of the P. cubensis mushroom without producing neurotoxicity after enteral or parenteral administration, where psilocybin and psilocin were identified mainly after AQ extraction. This study reinforces the benefits of the P. cubensis mushroom in mental health and therapy for anxiety and depression.
Topics: Animals; Mice; Agaricales; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Methanol; Models, Theoretical; Psilocybe; Psilocybin
PubMed: 37977425
DOI: 10.1016/j.jep.2023.117415