Amelioration of Pentylenetetrazole-Induced Seizures by Modulators of Sigma, N-Methyl-D-Aspartate, and Ryanodine Receptors in Mice.

BACKGROUND: Sigma receptors, N-methyl-D-aspartate (NMDA) antagonist, and modulators of intracellular calcium may be useful for seizure control. Therefore, we aimed to evaluate the antiepileptic effects of opipramol, a sigma receptor agonist, against pentylenetetrazole (PTZ)-induced seizures in mice and assess ketamine and caffeine interaction with the antiepileptic effects of opipramol. METHODS: PTZ (100 mg/kg) was used for the induction of seizure in 72 male albino Swiss strain of mice (n=8). Opipramole (10, 20, and 50 mg/kg), ketamine (50 mg/kg), caffeine (200 mg/kg), opipramole (20 mg/kg) plus ketamine (50 mg/kg), opipramole (20 mg/kg) plus caffeine (200 mg/kg), diazepam (5 mg/kg as a positive control), and the vehicle were administered interaperitoneally 30 minutes before the injection of PTZ. The latency was recorded for the clonic, tonic-clonic seizures, and death of animals after the injection of PTZ. Kruskal-Wallis test followed by Dunn's test was used for the analysis of data. Statistical analysis was performed with the SPSS software version 23.0 and P<0.05 was considered as the significant level. RESULTS: Opipramol (20 mg/kg) increased the latency for the PTZ-induced clonic (44%, P=0.021) and tonic-clonic (130.80%, P=0.043) seizures compared with the vehicle-treated group. Animals treated with opipramol (20 mg/kg) plus caffeine (200 mg/kg) had a significantly higher onset of PTZ-induced clonic and tonic-clonic seizures compared with the control (P=0.046 and <0.001, respectively). Ketamine combined with opipramol increased the onset of tonic-clonic seizure compared with the vehicle-treated groups (P<0.001). CONCLUSION: Opipramol attenuated the seizures induced by the PTZ. Ketamine and caffeine had no effect on the anticonvulsant activity of opipramol.

Implication of Rac1 GTPase in molecular and cellular mitochondrial functions.

Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as a fundamental regulator of actin cytoskeleton. Signal transduction by Rac1 occurs through interaction with multiple effector proteins, and its activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The small protein is mainly anchored to the inner side of the plasma membrane but it can be found in endocellular compartments, notably endosomes and cell nuclei. The protein localizes also into mitochondria where it contributes to the regulation of mitochondrial dynamics, including both mitobiogenesis and mitophagy, in addition to signaling processes via different protein partners, such as the proapoptotic protein Bcl-2 and chaperone sigma-1 receptor (σ-1R). The mitochondrial form of Rac1 (mtRac1) has been understudied thus far, but it is as essential as the nuclear or plasma membrane forms, via its implication in regulation of oxidative stress and DNA damages. Rac1 is subject to diverse post-translational modifications, notably to a geranylgeranylation which contributes importantly to its mitochondrial import and its anchorage to mitochondrial membranes. In addition, Rac1 contributes to the mitochondrial translocation of other proteins, such as p53. The mitochondrial localization and functions of Rac1 are discussed here, notably in the context of human diseases such as cancers. Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here.

Erratum: Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study.

[This corrects the article DOI: 10.3389/fnbeh.2021.788708.].

Consecutive Controlled Case Series on Effectiveness of Opipramol in Severe Sleep Bruxism Management-Preliminary Study on New Therapeutic Path.

BACKGROUND: Sleep bruxism (SB) management aims to reduce the number and magnitude of bruxism episodes per hour of a patient's sleep and, therefore, reduce the potentially negative clinical consequences. Opipramol belongs to the group of tricyclic antidepressants (TCAs) and is considered as an atypical TCA, as it acts primarily as a sigma receptor agonist. This study aimed to preliminarily determine the effectiveness of opipramol in the management of severe SB. METHODS: A total of 19 otherwise healthy participants with severe SB diagnosed during stage I video polysomnography (vPSG) were subjected to an 8-week pharmacotherapy trial with a 100 mg bedtime daily dose of opipramol and were then analyzed by control stage II vPSG. RESULTS: The participants included 14 females and 5 males, aged 20-47 years (mean ± standard deviation: 32.32 ± 8.12). A comparison of stage I and II vPSG recordings showed a decrease in all the studied SB parameters in 78.85% of participants. Only in a small group of participants (15.53%) was a non-significant increase of SB parameters observed. CONCLUSIONS: A single 100 mg dose of opipramol at bedtime seems to positively affect the reduction of SB in otherwise healthy individuals diagnosed with severe SB. However, the subject requires further research on a larger population including a control group.

Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study.

Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

Interaction of sigma-1 receptor modulators with seizure development in pentylenetetrazole-induced kindled mice.

This study aimed to investigate the effects of sigma receptor modulators, opipramol and BD-1063, on epileptogenesis in pentylenetetrazole (PTZ)-kindling model of epilepsy. Mice (n = 6/group) were received PTZ (30 mg/kg), PTZ plus opipramol (5 or 10 mg/kg), PTZ plus opipramol (5 mg/kg) plus BD-1063 (5 mg/kg, a selective sigma-1 receptor antagonist), and PTZ plus BD-1063 on alternate days for 15 days. Opipramol (5 and 10 mg/kg) + PTZ groups became fully kindled and had higher seizure scores compared to the PTZ group. In contrast, the PTZ plus BD-1063 and the PTZ plus opipramol (5 mg/kg) plus BD-1063 group did not show full kindling. These findings indicate that opipramol has a pro-convulsant effect, which is possibly mediated through activation of sigma-1 receptors.

Mania induced by opipramol.

Antidepressants have propensity to induce manic switch in patients with bipolar disorder. Opipramol is an atypical anxiolytic and antidepressant drug which predominantly acts on sigma receptors. Although structurally resembles tricyclic antidepressant imipramine it does not have inhibitory action on the reuptake of norepinephrine/serotonin and hence it is not presumed to cause manic switch in bipolar depression. Here, we describe a case of mania induced by opipramol, in a patient with bipolar affective disorder who was treated for moderate depressive episode with lithium and opipramol and we discuss neurochemical hypothesis of opipramol-induced mania.

Spectroscopic investigation (FT-IR, FT-Raman and SERS), vibrational assignments, HOMO-LUMO analysis and molecular docking study of Opipramol.

FT-IR and FT-Raman spectra of Opipramol were recorded and analyzed. SERS spectrum was recorded in silver colloid. The vibrational wave numbers were computed using DFT quantum chemical calculations. The data obtained from wave number calculations are used to assign vibrational bands obtained in infrared and Raman spectra as well as in SERS of the studied molecule. Potential energy distribution was done using GAR2PED program. The geometrical parameters (DFT) of the title compound are in agreement with the XRD results. The presence of CH2 stretching modes in the SERS spectrum indicates the close of piperazine ring with the metal surface and the interaction of the silver surface with this moiety. NBO analysis, HOMO-LUMO, first hyperpolarizability and molecular electrostatic potential results are also reported. The inhibitor Opipramol forms a stable complex with P4502C9 as is evident from the ligand-receptor interactions and a -9.0 kcal/mol docking score and may be an effective P4502C9 inhibitor if further biological explorations are carried out.

Introduction of sustained release opipramol dihydrochloride matrix tablets as a new approach in the treatment of depressive disorders.

Opipramol 2-HCl (OP) is used for therapy of general somatoform and anxiety disorders. Conventional tablets in the market contain 50 mg OP to be used once or up to three times a day in effective treatment of depression in mild. In case of serious depressive disorders, OP may be administired up to 300 mg a day. Decrease in frequency of high dose administration via sustained drug release would reduce incidence of symptoms of intoxication in long-term use of OP. With this aim, OP matrix tablets containing 100 mg were prepared by direct compression method to be used once a day to provide patient compliance and constant blood level, consequently to decrease side effects. Two concentrations of polymers (10% and 20%): hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), sodium alginate (NaAlg), xanthan gum (XG) and Carbopol(®)941 (C941) were used in preparation of matrix tablets. Drug release study were performed in distilled water, pH1.2 HCl buffer and pH7.4 phosphate buffer solutions according to the Method II in USP 29. Two commercial tablets containing 50 mg OP available in Turkish market were used for comparison. Kinetic models of release patterns from tablets were evaluated. Drug release was displayed slower to faster pattern in order of formulations containing C941, HPMC and HPC. Drug release was significantly faster in tablets of 10% polymers than those of 20%. NaAlg and XG were insufficient to sustain drug release. The most sustaining drug release effect at the lowest polymer concentration was obtained with C941. Drug release from matrix tablets containing 10% C941 was determined as 58.2%, 52.4 and 57.0% in related dissolution mediums above after 8 hours, respectively. However, HPMC and HPC sustained drug release at 20% concentration. As a result, Carbopol® 941, HPMC and HPC can be suggested as suitable to prepare matrix tablets of OP.