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1.
Drug Des Devel Ther ; 18: 1613-1625, 2024.
Article En | MEDLINE | ID: mdl-38774484

Purpose: Remimazolam, an ultra-short-acting and fast-metabolized sedative, has only been sporadically investigated in children. This study was performed to determine the beneficial effects of intranasal remimazolam or dexmedetomidine on preoperative anxiety in children undergoing general surgeries. Patients and Methods: Ninety children were randomly and equally assigned to Group R (intranasal remimazolam 1.5mg kg-1), Group D (intranasal dexmedetomidine 2 mcg kg-1), and Group C (intranasal distilled water). The primary outcomes were the preoperative anxiety scores using the modified Yale preoperative anxiety scale (m-Ypas). The secondary outcomes included the cooperation behaviour of intranasal drug application, preoperative sedation levels, parental separation anxiety scores (PSAS), and mask acceptance scores (MAS). Results: Group R showed a significant low anxiety at 10 min after intranasal premedication (vs group C, P=0.010; vs group D, P = 0.002) and at anaesthesia induction (vs group C, P = 0.004). Group D showed a significantly low anxiety score only prior to anaesthesia induction (vs group C, P = 0.005). Most children in group R achieved mild sedation at 10 min (vs group C, P < 0.001; vs group D, P < 0.001), with a few progressing to deep sedation afterwards, while group D tended toward deep sedation. Compared to Group C, patients in Group R performed significantly better on the MAS (P = 0.014) and PSAS (P = 0.008). However, remimazolam did cause poor cooperation behavior to the intranasal application due to its mucosal irritation (vs group C, P = 0.001; vs group D, P = 0.010). Conclusion: Both intranasal remimazolam and dexmedetomidine can effectively alleviate preoperative anxiety in children. While intranasal remimazolam has a rapid onset, it produces only mild sedation and causes substantial nasal irritation. Trial Registration: NCT04720963, January 22, 2021, ClinicalTrials.Gov.


Administration, Intranasal , Anti-Anxiety Agents , Anxiety , Dexmedetomidine , Hypnotics and Sedatives , Humans , Dexmedetomidine/administration & dosage , Dexmedetomidine/pharmacology , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacology , Male , Female , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/pharmacology , Child , Child, Preschool , Anxiety/drug therapy , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Double-Blind Method
2.
Sci Rep ; 14(1): 11519, 2024 05 21.
Article En | MEDLINE | ID: mdl-38769131

Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-D-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.


Anti-Anxiety Agents , Dextran Sulfate , Disease Models, Animal , Enterococcus faecalis , Animals , Mice , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Dextran Sulfate/toxicity , Male , Anxiety/drug therapy , Lipopolysaccharides , Corticosterone/blood , Prefrontal Cortex/metabolism , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/microbiology , Mice, Inbred C57BL
3.
Bull Exp Biol Med ; 176(5): 581-584, 2024 Mar.
Article En | MEDLINE | ID: mdl-38724817

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.


Analgesics , Animals , Mice , Rats , Male , Analgesics/pharmacology , Diclofenac/pharmacology , Tramadol/pharmacology , Psychotropic Drugs/pharmacology , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Anti-Anxiety Agents/pharmacology , Bradykinin B1 Receptor Antagonists/pharmacology , Rats, Wistar , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Pain Measurement/drug effects , Pain Measurement/methods
4.
Nutrients ; 16(10)2024 May 18.
Article En | MEDLINE | ID: mdl-38794765

In the process of validating the elevated zero maze, a common test of anxiety-like behavior, in our laboratory, we demonstrated an anxiolytic-like effect of castor oil and its primary component, ricinoleic acid. We tested the effects of vehicle and chlordiazepoxide in male mice in the elevated zero maze following a 30-min pretreatment time. Chlordiazepoxide is a United States Food and Drug Administration-approved drug that was previously shown to exert anxiolytic-like effects in both the elevated zero maze and elevated plus maze. Chlordiazepoxide was administered at doses of 5 or 10 mg/kg. We used 5% polyoxyl 35 castor oil (Kolliphor® EL) and saline as treatment vehicles and found that the effect of chlordiazepoxide on open zone occupancy and open zone entries was blunted when 5% Kolliphor was used as the vehicle. These tests demonstrated that chlordiazepoxide increased open zone occupancy and entries in the elevated zero maze more effectively when saline was used as the treatment vehicle and that Kolliphor dampened the anxiolytic-like effect of chlordiazepoxide when it was used as the treatment vehicle. Notably, 5% Kolliphor alone slightly increased baseline open zone occupancy and entries. Given that Kolliphor is a derivative of castor oil, we next tested the effect of 5% castor oil and 5% ricinoleic acid, which is a major component of castor oil. We found that both castor oil and ricinoleic acid increased open zone occupancy but not entries compared with saline. Altogether, our findings demonstrate that Kolliphor, castor oil, and ricinoleic acid may exert anxiolytic-like effects in male mice in the elevated zero maze. This potential anxiolytic-like effect of castor oil is consistent with its well-established beneficial effects, including anti-inflammatory, antioxidant, antifungal, and pain-relieving properties.


Anti-Anxiety Agents , Anxiety , Castor Oil , Ricinoleic Acids , Animals , Ricinoleic Acids/pharmacology , Anti-Anxiety Agents/pharmacology , Male , Mice , Anxiety/drug therapy , Behavior, Animal/drug effects , Chlordiazepoxide/pharmacology , Maze Learning/drug effects , Exploratory Behavior/drug effects
5.
Pak J Pharm Sci ; 37(2): 349-356, 2024 Mar.
Article En | MEDLINE | ID: mdl-38767102

Evidence suggests that surgical procedures can effect the central nervous system and lead to changes in mood and behavior, rarely understood about the role of acute inflammation in promoting acute anxiety postoperatively. This study was designed to explore the possible mechanism of dexmedetomidine (DEX, a2-adrenergic receptor agonist) for reducing acute postoperative anxiety, which may be related to the activation of nuclear factor kappa B (NF-κB) and downstream signal pathway in the hippocampus. Experiments were conducted with rat, the elevated plus-maze and open field test were performed to evaluate anxiety-like behavior. Inhibit DEX with Atipamezole (AT, α2-adrenergic receptor antagonist) and inhibit NF-κB with Pyrrolidinedithiocarbamate (PDTC, inhibit phosphorylation of IκB, prevent the activation of NF-κB), the level of interleukin-6 (IL-6), IL-1ß, IL-10 and Tumor necrosis factor-α (TNF-α); the nuclear translocation of NF-κB in the hippocampus and anxiety-like behavior were measured. Rats exhibited anxiety-like behavior at 6h and 12h after surgery. Preoperative administration of DEX significantly alleviated postoperative anxiety-like behavior. DEX premedication inhibited the nuclear translocation of NF-κB alleviate acute postoperative anxiety. These findings are the first to show that acute postoperative anxiety may be related to NF-κB nuclear translocation in the hippocampus in rats, which can be alleviated by DEX premedication.


Anxiety , Dexmedetomidine , Hippocampus , NF-kappa B , Rats, Sprague-Dawley , Signal Transduction , Animals , Dexmedetomidine/pharmacology , NF-kappa B/metabolism , Male , Anxiety/drug therapy , Anxiety/psychology , Signal Transduction/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Rats , Adrenergic alpha-2 Receptor Agonists/pharmacology , Behavior, Animal/drug effects , Anti-Anxiety Agents/pharmacology , Cytokines/metabolism , Disease Models, Animal , Imidazoles
6.
Sci Rep ; 14(1): 11174, 2024 05 15.
Article En | MEDLINE | ID: mdl-38750129

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14-3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.


Anti-Anxiety Agents , Anxiety , Behavior, Animal , Larva , Mitogen-Activated Protein Kinase 8 , Signal Transduction , Zebrafish , Animals , Anxiety/drug therapy , Anxiety/metabolism , Mitogen-Activated Protein Kinase 8/metabolism , Mitogen-Activated Protein Kinase 8/genetics , Larva/drug effects , Mice , Signal Transduction/drug effects , Behavior, Animal/drug effects , Anti-Anxiety Agents/pharmacology , Phenotype , Antidepressive Agents/pharmacology , Disease Models, Animal , Brain/metabolism , Brain/drug effects , Proto-Oncogene Proteins c-akt/metabolism
7.
Pak J Pharm Sci ; 37(1): 53-63, 2024 Jan.
Article En | MEDLINE | ID: mdl-38741400

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.


Anxiety , Ascorbic Acid , Behavior, Animal , Oxidative Stress , Sorghum , Tramadol , Animals , Tramadol/pharmacology , Oxidative Stress/drug effects , Male , Ascorbic Acid/pharmacology , Anxiety/prevention & control , Anxiety/chemically induced , Anxiety/drug therapy , Rats , Behavior, Animal/drug effects , Antioxidants/pharmacology , Brain/drug effects , Brain/metabolism , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Rats, Wistar , Analgesics, Opioid/pharmacology , Anti-Anxiety Agents/pharmacology , Maze Learning/drug effects
8.
Pak J Pharm Sci ; 37(1): 129-137, 2024 Jan.
Article En | MEDLINE | ID: mdl-38741409

Stress is described as a noxious stimulus that affects the health of an individual and alters body homeostasis resulting in changes the individual behavioural and metabolic condition. Synthesis of drug from plants has main interest due the significant medicinal values. The recent investigation was designed to examine the pharmacological impacts of Ficus carica leaves extract on stress. In this experiment, the rodents were randomly distributed as (n=6) control rats were kept at standard condition, second group of rats were exposed with different stressors and Third group of rodents was exposed to stress and treated with extract of ficus carica leaves at the dose of 100 mg/kg. Acute behavioural alteration was observed after 7 days and prolonged impact was monitored after the 28 days. The current finding showed that administration of Ficus carica leaves extract produced anxiolytic behaviours and decreased depression like symptoms in CUMS treated rats. It also increased stimulatory, ambulatory, locomotor activity and enhanced spatial working memory and recognition memory in CUMS exposed rats. So, it can be concluded from recent study that leaves of Ficus carica can be utilized as secure drug for curing physiological stress with less side effect profile.


Behavior, Animal , Disease Models, Animal , Ficus , Plant Extracts , Plant Leaves , Stress, Psychological , Animals , Ficus/chemistry , Plant Extracts/pharmacology , Behavior, Animal/drug effects , Stress, Psychological/drug therapy , Male , Rats , Rats, Wistar , Anti-Anxiety Agents/pharmacology , Depression/drug therapy
9.
J Ethnopharmacol ; 331: 118332, 2024 Sep 15.
Article En | MEDLINE | ID: mdl-38735421

ETHNOPHARMACOLOGICAL RELEVANCE: Citri Reticulata Pericarpium Viride (also known Qing-Pi or QP) is a plant in the Rutaceae family, QP is a traditional Qi-regulating medicine in Chinese medicine that is compatible with other Chinese medicine components and has extensive clinical practice in treating anxiety and depression. Reports on the pharmacological effects of QP have demonstrated its neuroprotective effects and antioxidant capacities. Numerous pharmacological benefits of QP are attributed to its antioxidant abilities. Anxiety disorders are a broadly defined category of mental illnesses. Oxidative stress and an imbalance in the antioxidant defense system are typical pathological features of these disorders. AIM OF THE STUDY: The aim of this study was to evaluate the effects of QP essential oil on anxiety using animal models and investigate the underlying neurobiological mechanisms. MATERIALS AND METHODS: This study aimed to develop an animal model of anxiety using chronic restraint stress and investigate the effects of inhalation of Citri Reticulata Pericarpium Viride essential oil on anxiety-like behavior, olfactory function, and olfactory bulb neurogenesis in mice with anxiety. RESULTS: The results showed that long-term chronic restraint stimulation caused a decrease in olfactory function, significant anxiety-like behavior, and a notable reduction in the number of neurons in the olfactory bulb. However, inhalation of Citri Reticulata Pericarpium Viride essential oil reversed these effects, improving the olfactory function, neuro-stimulating effect, alleviating anxiety-like behavior, and regulating theta (4-12Hz) oscillation in the hippocampus DG area. These effects were associated with changes in the expression levels of glutamate receptor NMDAR and NeuN in olfactory bulb. CONCLUSIONS: The study revealed that mice with anxiety induced by chronic restraint stress exhibited significant olfactory dysfunction, providing strong evidence for the causal relationship between anxiety disorders and olfactory dysfunction. Moreover, QP essential oil has the potential to be developed as a therapeutic drug for anxiety disorders, in addition to its role as a complementary anxiolytic.


Anti-Anxiety Agents , Anxiety , Oils, Volatile , Olfactory Bulb , Receptors, N-Methyl-D-Aspartate , Animals , Oils, Volatile/pharmacology , Oils, Volatile/isolation & purification , Male , Anxiety/drug therapy , Mice , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Anti-Anxiety Agents/isolation & purification , Receptors, N-Methyl-D-Aspartate/metabolism , Behavior, Animal/drug effects , Glutamic Acid/metabolism , Neurogenesis/drug effects , Disease Models, Animal , Stress, Psychological/drug therapy
10.
Neurosci Biobehav Rev ; 161: 105648, 2024 Jun.
Article En | MEDLINE | ID: mdl-38565340

This narrative review describes the research on the effects of the association between environmental context and medications, suggesting the benefit of specific design interventions in adjunction to pharmacotherapy. The literature on Evidence-Based Design (EBD) studies and Neuro-Architecture show how contact with light, nature, and specific physical features of urban and interior architecture may enhance the effects of analgesic, anxiolytics, and antidepressant drugs. This interaction mirrors those already known between psychedelics, drugs of abuse, and setting. Considering that the physical feature of space is a component of the complex placebo configuration, the aim is to highlight those elements of built or natural space that may help to improve drug response in terms of efficacy, tolerability, safety, and compliance. Ecocebo, the integration of design approaches such as EBD and Neuro-Architecture may thus contribute to a more efficient, cost-sensitive, and sustainable pharmacotherapy.


Antidepressive Agents , Humans , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Analgesics/pharmacology , Environment
11.
Sci Rep ; 14(1): 9799, 2024 04 29.
Article En | MEDLINE | ID: mdl-38684743

This study investigated the potential anxiolytic properties of flavan-3-ols and aromatic resins through a combined computational and experimental approach. Network pharmacology techniques were utilized to identify potential anxiolytic targets and compounds by analyzing protein-protein interactions and KEGG pathway data. Molecular docking and simulation studies were conducted to evaluate the binding interactions and stability of the identified targets. Behavioral tests, including the elevated plus maze test, open field test, light-dark test, actophotometer, and holeboard test, were used to assess anxiolytic activity. The compound-target network analysis revealed complex interactions involving 306 nodes and 526 edges, with significant interactions observed and an average node degree of 1.94. KEGG pathway analysis highlighted pathways such as neuroactive ligand-receptor interactions, dopaminergic synapses, and serotonergic synapses as being involved in anxiety modulation. Docking studies on EGCG (Epigallocatechin gallate) showed binding energies of -9.5 kcal/mol for MAOA, -9.2 kcal/mol for SLC6A4, and -7.4 kcal/mol for COMT. Molecular dynamic simulations indicated minimal fluctuations, suggesting the formation of stable complexes between small molecules and proteins. Behavioral tests demonstrated a significant reduction in anxiety-like behavior, as evidenced by an increased number of entries into and time spent in the open arm of the elevated plus maze test, light-dark test, open field center activity, hole board head dips, and actophotometer beam interruptions (p < 0.05 or p < 0.01). This research provides a comprehensive understanding of the multi-component, multi-target, and multi-pathway intervention mechanisms of flavan-3-ols and aromatic resins in anxiety treatment. Integrated network and behavioral analyses collectively support the anxiolytic potential of these compounds and offer valuable insights for future research in this area.


Anti-Anxiety Agents , Anxiety , Catechin , Catechin/analogs & derivatives , Flavonoids , Molecular Docking Simulation , Animals , Flavonoids/chemistry , Flavonoids/pharmacology , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/chemistry , Anxiety/drug therapy , Catechin/pharmacology , Catechin/chemistry , Molecular Dynamics Simulation , Male , Network Pharmacology , Monoamine Oxidase/metabolism , Monoamine Oxidase/chemistry , Behavior, Animal/drug effects , Catechol O-Methyltransferase/metabolism , Catechol O-Methyltransferase/chemistry , Mice , Protein Binding
12.
Behav Pharmacol ; 35(4): 156-160, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38651975

Exposure to chronic caffeine during adolescence has been shown to produce decreased anxiety-like behaviors in rats as well as decreased immobility in the forced swim test (FST) suggesting an antidepressant-like effect. The effects of chronic caffeine on anxiety, however, have been found to be test-dependent and sexually dimorphic. In addition, decreased immobility in the FST has been argued to reflect a shift toward active coping behavior as opposed to an antidepressant-like effect. In order to further characterize the effects of adolescent caffeine exposure, the present experiment assessed the effects of caffeine on marble burying behavior in a two-zone marble burying task. There was no difference in the amount of time rats spent in the two zones failing to support a shift in coping strategy. Caffeine-exposed rats spent less time engaged in marble burying activity and buried slightly fewer marbles, suggesting an anxiolytic effect of caffeine. In addition, caffeine treated rats spent less time engaged in nondirected burying and slightly more time actively engaging with the marbles; however, these effects appeared to be sexually dimorphic as they were driven by larger changes in the females. Overall, these results support an anxiolytic effect of adolescent caffeine, with female behavior appearing to be more affected by caffeine than males.


Anxiety , Behavior, Animal , Caffeine , Animals , Caffeine/pharmacology , Caffeine/administration & dosage , Male , Anxiety/drug therapy , Female , Rats , Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Anti-Anxiety Agents/pharmacology , Rats, Sprague-Dawley , Motor Activity/drug effects
13.
J Ethnopharmacol ; 331: 118271, 2024 Sep 15.
Article En | MEDLINE | ID: mdl-38688356

ETHNOPHARMACOLOGICAL RELEVANCE: The use of medicinal plants for central nervous system (CNS)-related ailments, such as epilepsy and anxiety, is prevalent in South Africa. Plants from the Lamiaceae family are commonly used for their therapeutic benefits. Leonotis leonurus (L.) R.Br. has been reported in ethnobotanical literature to have anticonvulsant and anxiolytic effects through the inhalation of pyrolysis products obtained by combustion of the aerial parts. AIM AND OBJECTIVES: To explore the chemical profiles and CNS activity of the smoke extract and isolated constituents of L. leonurus in zebrafish larvae, through anticonvulsive and anxiolytic activity assays. MATERIALS AND METHODS: The smoke extract of L. leonurus was obtained through the combustion of the aerial parts of the plant using a custom-built smoke recovery apparatus. The chemical profile of the smoke constituents was determined using Ultra-Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS). Targeted compounds were subjected to preparative High-Performance Liquid Chromatography for separation before structure elucidation using Nuclear Magnetic Resonance (NMR). The maximum tolerated concentrations, as well as the anxiolytic activity of the smoke extract were determined in five days post fertilisation zebrafish larvae. Reverse-thigmotaxis and locomotor activity of larvae in the light/dark transition assay were used to determine anxiolytic activity. Zebrafish larvae at six days post fertilisation (dpf) were subjected to several concentrations of the smoke constituents of L. leonurus. The baseline locomotor activity of the larvae was tracked for 30 min, prior to addition of pentylenetetrazole (PTZ) to induce seizure-like behaviour in the larvae, after which the locomotor activity of the larvae was once again tracked for an additional 30 min. RESULTS: The UPLC-MS profiles of the smoke extract revealed the presence of two main compounds, leoleorin A and leoleorin B, which were targeted and isolated. Upon subjection to NMR spectroscopy for structure elucidation, the compounds were confirmed to be labdane diterpenoids. Both leoleorin A and leoleorin B, and the smoke extract displayed suppression of the PTZ induced seizure-like behaviour in zebrafish larvae. Under light and dark conditions, the smoke extract and compounds displayed potential anxiolytic activity at different concentrations. CONCLUSION: Our results suggest that the smoke constituents of L. leonurus may exert anticonvulsant and anxiolytic effects which align with the traditional indications and the mode of administration.


Anti-Anxiety Agents , Anticonvulsants , Plant Extracts , Seizures , Smoke , Zebrafish , Animals , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/isolation & purification , Anti-Anxiety Agents/chemistry , Smoke/adverse effects , Plant Extracts/pharmacology , Plant Extracts/chemistry , Anticonvulsants/pharmacology , Anticonvulsants/isolation & purification , Seizures/drug therapy , Seizures/chemically induced , Larva/drug effects , Lamiaceae/chemistry , Pentylenetetrazole , Plant Components, Aerial/chemistry , South Africa , Behavior, Animal/drug effects
14.
Int J Neuropsychopharmacol ; 27(4)2024 Apr 01.
Article En | MEDLINE | ID: mdl-38577951

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.


Anti-Anxiety Agents , Anxiety , Carbon Dioxide , Placebo Effect , Humans , Carbon Dioxide/administration & dosage , Carbon Dioxide/pharmacology , Male , Female , Adult , Young Adult , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/administration & dosage , Administration, Inhalation , Anxiety/drug therapy , Anxiety/chemically induced , Lorazepam/pharmacology , Lorazepam/administration & dosage , Double-Blind Method
15.
Pharmacol Biochem Behav ; 239: 173770, 2024 Jun.
Article En | MEDLINE | ID: mdl-38636813

The population of most countries in the world is increasing and understanding risk factors that can influence the health of the older population is critical. Older adults consume alcohol often in a risky, binge manner. Previous work has demonstrated that aged rats are more sensitive to many of the effects of acute ethanol. In the current project aged, adult, and adolescent female and male rats were tested on the elevated plus maze and open field following either a 1.0 g/kg alcohol injection or a saline injection. We report sex- and age-dependent effects whereas aged female rats, but not aged male rats, showed an increased anxiolytic effect of alcohol in the elevated plus maze while aged male rats, but not aged female rats, showed increased stimulatory movement in the open field. In addition, significant age effects were found for both female and male rats. It is proposed that the sex- and age-dependent effects reported in the current studies may be due to differential levels of alcohol-induced allopregnanolone for the anxiolytic effects and differential levels of alcohol-induced dopamine for the stimulatory effects. The current work provides insights into factors influencing alcohol consumption in older adults.


Aging , Anti-Anxiety Agents , Ethanol , Motor Activity , Animals , Male , Female , Rats , Ethanol/administration & dosage , Ethanol/pharmacology , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/administration & dosage , Aging/psychology , Motor Activity/drug effects , Behavior, Animal/drug effects , Anxiety/psychology , Anxiety/drug therapy , Age Factors , Sex Characteristics , Maze Learning/drug effects , Sex Factors
16.
Physiol Behav ; 277: 114506, 2024 Apr 01.
Article En | MEDLINE | ID: mdl-38432442

The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.


Anti-Anxiety Agents , Cannabinoids , Mice , Animals , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Cytidine Diphosphate Choline , Receptor, Cannabinoid, CB1 , Anxiety/etiology , Anxiety/chemically induced , Cannabinoids/pharmacology
17.
Exp Brain Res ; 242(4): 913-920, 2024 Apr.
Article En | MEDLINE | ID: mdl-38451318

Self-care behavior covers individual's health, life and well-being to maintain the necessary activities. The aim of this study is to examine the self-care and possible anxiolytic effects of high-intensity interval exercise (HIIT). Eight-week-old Wistar Albino male rats were divided into Control (n = 8), and Exercise (n = 8). Rat exercised for 38 min a day, 5 days a week, for 8 weeks The animals were then subjected to open field test and splash test, and the behaviors were video recorded. Student t test and Shapiro-Wilk test were used as statistical tests. In the exercise group, spray-induced grooming behavior increased significantly in terms of duration and frequency (p < 0.05), but no significant difference was observed in the latency of grooming (p > 0.05). In the open-field test, the total distance traveled, which is a locomotor activity parameter, did not change between the groups. Anxiolytic-like behaviors such as total rearing behavior, unsupported rearing, central time, and central region entries increased remarkably in the exercise group vs. control (p < 0.0001). Freezing as an anxiogenic behavior decreased in the exercise group positively (p < 0.0001). Intermittent high-intensity exercise improved and increased self-care behaviors. Further, the present study shows that HIIT has beneficial effects on different aspects of behaviors such as exploratory behaviors, increasing anxiolytic behaviors, and reducing anxiogenic behavior. The present study is a preclinical study that will pave the way for new studies.


Anti-Anxiety Agents , High-Intensity Interval Training , Rats , Animals , Humans , Anti-Anxiety Agents/pharmacology , Rats, Wistar , Self Care , Anxiety/therapy
18.
Molecules ; 29(6)2024 Mar 21.
Article En | MEDLINE | ID: mdl-38543047

Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.


Anti-Anxiety Agents , Nitric Oxide , Humans , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Anxiety Disorders/drug therapy , Anxiety/drug therapy , Anxiety/etiology , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use
19.
J Agric Food Chem ; 72(12): 6189-6202, 2024 Mar 27.
Article En | MEDLINE | ID: mdl-38501577

The hexapeptide YPVEPF with strong sleep-enhancing effects could be detected in rat brain after a single oral administration as we previously proved. In this study, the mechanism and molecular effects of YPVEPF in the targeted stress-induced anxiety mice were first investigated, and its key active structure was further explored. The results showed that YPVEPF could significantly prolong sleep duration and improve the anxiety indexes, including prolonging the time spent in the open arms and in the center. Meanwhile, YPVEPF showed strong sleep-enhancing effects by significantly increasing the level of the GABA/Glu ratio, 5-HT, and dopamine in brain and serum and regulating the anabolism of multiple targets, but the effects could be blocked by bicuculline and WAY100135. Moreover, the molecular simulation results showed that YPVEPF could stably bind to the vital GABAA and 5-HT1A receptors due to the vital structure of Tyr-Pro-Xaa-Xaa-Pro-, and the electrostatic and van der Waals energy played dominant roles in stabilizing the conformation. Therefore, YPVEPF displayed sleep-enhancing and anxiolytic effects by regulating the GABA-Glu metabolic pathway and serotoninergic system depending on distinctive self-folding structures with Tyr and two Pro repeats.


Anti-Anxiety Agents , Sleep Initiation and Maintenance Disorders , gamma-Aminobutyric Acid/analogs & derivatives , Rats , Mice , Animals , Caseins/metabolism , Receptors, GABA-A/metabolism , Serotonin , Anti-Anxiety Agents/pharmacology , Anxiety
20.
Neurosci Lett ; 826: 137723, 2024 Mar 15.
Article En | MEDLINE | ID: mdl-38467272

Cannabidiol (CBD), a non-psychoactive compound derived from the cannabis plant, has been confirmed to induce anxiolytic-like and antipsychotic-like effects. However, the exact mechanisms remain unclear. This study substantiated CBD's interaction with the 5-HT1A receptor (5-HT1AR) in vitro (CHO cells expressing human 5-HT1AR) and in vivo (rat lower lip retraction test, LLR test). We then assessed the impact of CBD in mice using the stress-induced hyperthermia (SIH) model and the phencyclidine (PCP)-induced negative symptoms of schizophrenia model, respectively. Concurrently, we investigated whether WAY-100635, a typical 5-HT1AR antagonist, could attenuate these effects. Furthermore, the neurotransmitter changes through high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were studied. Results revealed that CBD exhibits selective 5-HT1AR agonists-mediated effects in the rat lower lip retraction test, aligning with the robust agonistic (EC50 = 1.75 µM) profile observed in CHO cells. CBD at 3 mg/kg significantly reduced SIH (ΔT), a response that WAY-100635 abolished. Chronic administration of CBD at 100 mg/kg mitigated the increase in PCP-induced immobility time in the forced swim test (FST) and tail suspension test (TST). Moreover, it induced significant alterations in gamma-aminobutyric acid (GABA) and norepinephrine (NE) levels within the hippocampus (HPC). Thus, we concluded that the 5-HT1AR mediates CBD's anxiolytic-like effects. Additionally, CBD's effects on the negative symptoms of schizophrenia may be linked to changes in GABA and NE levels in the hippocampus. These findings offer novel insights for advancing the exploration of CBD's anxiolytic-like and antipsychotic-like effects.


Anti-Anxiety Agents , Antipsychotic Agents , Cannabidiol , Cricetinae , Mice , Rats , Humans , Animals , Antipsychotic Agents/pharmacology , Anti-Anxiety Agents/pharmacology , Cannabidiol/pharmacology , Serotonin , Cricetulus , Chromatography, Liquid , Tandem Mass Spectrometry , gamma-Aminobutyric Acid
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