The anxiolytic drug opipramol inhibits insulin-induced lipogenesis in fat cells and insulin secretion in pancreatic islets.

The antidepressant drug opipramol has been reported to exert antilipolytic effect in human adipocytes, suggesting that alongside its neuropharmacological properties, this agent might modulate lipid utilization by peripheral tissues. However, patients treated for depression or anxiety disorders by this tricyclic compound do not exhibit the body weight gain or the glucose tolerance alterations observed with various other antidepressant or antipsychotic agents such as amitriptyline and olanzapine, respectively. To examine whether opipramol reproduces or impairs other actions of insulin, its direct effects on glucose transport, lipogenesis and lipolysis were investigated in adipocytes while its influence on insulin secretion was studied in pancreatic islets. In mouse and rat adipocytes, opipramol did not activate triglyceride breakdown, but partially inhibited the lipolytic action of isoprenaline or forskolin, especially in the 10-100 µM range. At 100 µM, opipramol also inhibited the glucose incorporation into lipids without limiting the glucose transport in mouse adipocytes. In pancreatic islets, opipramol acutely impaired the stimulation of insulin secretion by various activators (high glucose, high potassium, forskolin...). Similar inhibitory effects were observed in mouse and rat pancreatic islets and were reproduced with 100 µM haloperidol, in a manner that was independent from alpha2-adrenoceptor activation but sensitive to Ca2+ release. All these results indicated that the anxiolytic drug opipramol is not only active in central nervous system but also in multiple peripheral tissues and endocrine organs. Due to its capacity to modulate the lipid and carbohydrate metabolisms, opipramol deserves further studies in order to explore its therapeutic potential for the treatment of obese and diabetic states.

Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. METHODS: A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. RESULTS: We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. INTERPRETATION: SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.

Gastroprotective and antioxidant effects of opipramol on indomethacin-induced ulcers in rats.

Tricyclic antidepressants are particularly useful in the treatment of endogenous depression. Since the 1950s, tricyclic antidepressants (TCAs) have also been used for the treatment of gastric ulcer disease. Many TCAs have been evaluated for their antiulcer effects, but there are presently no data in the literature specifically concerning the antidepressant opipramol. This study aimed to investigate the antiulcer effects of opipramol and to determine its potential relationship with oxidant and antioxidant systems. The antiulcer activities of 25, 50 and 100 mg/kg opipramol have been investigated on indomethacin-induced ulcers in rats. Compared with a control group (indomethacin alone), opipramol decreased indomethacin-induced ulcers significantly at all doses used (52%, 71% and 76% respectively). Opipramol also significantly increased the glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels in the stomach tissue, all of which were decreased in the control group given only indomethacin. All doses of opipramol also significantly decreased myeloperoxidase (MPO), malondialdehyde (MDA) and catalase (CAT) levels in stomach tissue compared to the control. In conclusion, the activation of enzymatic and non-enzymatic antioxidant mechanisms, as well as the inhibition of some toxic oxidant mechanisms, appear to play a role in the antiulcer effect of opipramol. This new indication for opipramol prompts a rethinking about the possible clinical application of opipramol, particularly for peptic ulcer patients also presenting depression.

Modeling malaria control intervention effect in KwaZulu-Natal, South Africa using intervention time series analysis.

The change of the malaria control intervention policy in South Africa (SA), re-introduction of dichlorodiphenyltrichloroethane (DDT), may be responsible for the low and sustained malaria transmission in KwaZulu-Natal (KZN). We evaluated the effect of the re-introduction of DDT on malaria in KZN and suggested practical ways the province can strengthen her already existing malaria control and elimination efforts, to achieve zero malaria transmission. We obtained confirmed monthly malaria cases in KZN from the malaria control program of KZN from 1998 to 2014. The seasonal autoregressive integrated moving average (SARIMA) intervention time series analysis (ITSA) was employed to model the effect of the re-introduction of DDT on confirmed monthly malaria cases. The result is an abrupt and permanent decline of monthly malaria cases (w0=-1174.781, p-value=0.003) following the implementation of the intervention policy. The sustained low malaria cases observed over a long period suggests that the continued usage of DDT did not result in insecticide resistance as earlier anticipated. It may be due to exophagic malaria vectors, which renders the indoor residual spraying not totally effective. Therefore, the feasibility of reducing malaria transmission to zero in KZN requires other reliable and complementary intervention resources to optimize the existing ones.

Neurochemical characterization of dopaminergic effects of opipramol, a potent sigma receptor ligand, in vivo.

Opipramol, a tricyclic antidepressant drug, potently interacted with sigma recognition sites labelled by [3H](+)-3-hydroxyphenyl)N-(1-propyl)piperidine [( 3H](+)-3-PPP) with a Ki value of 50 +/- 8 nM and with minimal affinity for phencyclidine receptors (Ki greater than 30,000 nM). Opipramol potently increased the metabolism of dopamine in the striatum, olfactory tubercle and pyriform cortex of the rat and increased the release of dopamine from the striatum of the mouse, as measured by increases in the levels of 3-methoxytyramine in vivo. Opipramol increased plasma prolactin in the rat, only at a dose as large as 50 mg/kg dose. Irreversible inactivation of dopamine receptors by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) did not affect the opipramol-induced increases in levels of dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat, indicating a predominant role of activation of sigma receptors in the dopaminergic effects of opipramol. However, pretreatment with the putative sigma ligand, rimcazole, markedly potentiated the ability of opipramol to increase the metabolism of release of DA in the striatum of the mouse in vivo. These results suggest that rimcazole and opipramol interact at two distinct receptors, the pharmacological significance of which is yet to be elucidated.

Opipramol, a potent sigma ligand, is an anti-ischemic agent: neurochemical evidence for an interaction with the N-methyl-D-aspartate receptor complex in vivo by cerebellar cGMP measurements.

Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not offer protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol.

A quantitative study of the anticholinergic action of several tricyclic antidepressants on the rat isolated fundal strip.

1. Investigations were carried out on the antagonism of the action of carbamylcholine chloride on the isolated fundus of the rat stomach by several tricyclic antidepressants.2. The anticholinergic potency of the compounds was in the order: GP 45437>amitriptyline>protriptyline>desmethylimipramine>opipramol. All of the antagonists were less effective than atropine.3. Statistical analysis was carried out to determine whether the theory of competitive antagonism would fit the data obtained.

Analysis of the inhibition of pethidine N-demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man.

1. N-Demethylation of pethidine was studied in microsomal suspensions from unstarved male rat liver and the N-demethylase identified as belonging to the class of hepatic microsomal mixed function oxidases.2. A study of the structure/action relationships of compounds inhibiting pethidine N-demethylase revealed that hydrazine derivatives including phenylhydrazine, methylphenylhydrazine and mebanazine were all potent competitive inhibitors.3. Pethidine N-demethylase was only slightly inhibited by histamine and amphetamine but not by adrenaline and ephedrine nor by several miscellaneous compounds including piperidine, N-ethylpiperidine, N-methylpiperidine, N-methylammonium, hydrallazine or pethidinic acid.4. Several psychotropic drugs were all found to be potent competitive inhibitors of pethidine N-demethylase. These included monoaminoxidase inhibitors (the most active being nialamide and phenoxypropazine [K(i)=0.01 mM]; the least active iproniazid [K(i)=1.05 mM]); the tranquillizers promazine, propiomazine and chlorpromazine and tricyclic antidepressants (opipramol [K(i)=0.01 mM], imipramine [K(i)=0.03 mM], desipramine [K(i)=0.03 mM] and amitryptyline [K(i)=0.03 mM]). Hydrocortisone [K(i)=0.3 mM], prednisolone [2.8 mM] and nalorphine [0.07 mM] were also inhibitors, whilst SKF 525A was the most active of all [K(i)=0.002 mM].5. These results are discussed in relation to the clinically observed drug interactions which may occur between monoamineoxidase inhibitors and pethidine. It is concluded that since many different groups of drugs, including monoamineoxidase inhibitors, tranquillizers, tricyclic antidepressants, steroids, nalorphine, SKF 525A and barbiturates compete for cytochrome P(450) reductase, it is possible that this mechanism may account, at least in part, for the observed interactions of these various drugs in man.

[Postsynaptic attack of tricyclic antidepressive agents in the circulatory system]. / Untersuchungen über den postsynaptischen Angriffspunkt trizyklischer Antidepressiva im Kreislaufsystem

Tricyclic antidepressives (TA) exert differential effects on the circulatory system, though all of them have one principle in common: inhibition of back resorption of noradrenaline in the adrenergic synapses. Of more importance, however, seems to be the dose rather than the type of substance used. Smaller doses were found to potentiate the pressoric effects of noradrenaline, while higher doses frequently had an inhibitory action. In rats pretreated with 6-OH-dopamine, only an inhibitory action has been established. It is concluded that the TA must have a postsynaptic influence that becomes effective either through the membrane receptors and/or other factors within the cell.

5-Hydroxytryptamine uptake and imipramine binding sites in neurotumor NCB-20 cells.

NCB-20 cells (neuroblastoma X fetal Chinese hamster brain hybrids) are equipped with a [3H]5-hydroxytryptamine [( 3H]5-HT) uptake system and [3H]imipramine recognition sites. Approximately 80% of the radioactivity taken up by cells incubated with [3H]5-HT was identified with 5-HT. [3H]5-HT uptake was temperature-dependent, partially sodium-dependent, saturable (Km = 7.3 +/- 0.6 microM; Vmax = 2.0 +/- 0.6 pmol/min/mg), and inhibited by clomipramine, imipramine, fluoxetine, and desipramine, but not by iprindole, mianserin, or opipramol. Lineweaver-Burk plots showed a competitive type of inhibition by imipramine and fluoxetine. [3H]5-HT uptake was not inhibited by nisoxetine or benztropine. [3H]Imipramine binding sites had a KD of 12 +/- 2 nM and a Bmax of 22 +/- 7 pmol/mg protein. The binding was sodium-sensitive although to a lesser extent than that found with brain membranes. Imipramine binding was displaced by tricyclic antidepressants with the following order of potency: clomipramine greater than imipramine greater than fluoxetine greater than desipramine much greater than iprindole = mianserin greater than opipramol. These results suggest that imipramine binding sites are present together with the 5-HT uptake sites in NCB-20 cells and that these sites interact functionally but are different biochemically.

On the central antiserotonin activity of benzoctamine and opipramol.

Benzoctamine inhibited the head twitch reaction induced by L-5-hydroxytryptophan (5-HTP) in mice and by 5-methoxytryptamine (5-MT) in rats pretreated with tranylcypromine. It also antagonized tryptamine (TRP)-induced clonic convulsions of forepaws in rats. Opipramol had no effect in the 5-MT test and appeared to be a weak antagonist in the 5-HTP and TRP tests. Both drugs, of which benzoctamine was a more potent antagonist, inhibited hyperthermia induced by LSD in rabbits. Benzoctamine abolished also LSD-or quipazine-induced stimulation of the flexor reflex in spinal rats; the above effect did not depend on noradrenolytic action of the drug. Opipramol was ineffective as an LSD or quipazine antagonist in this test. These results suggest that benzoctamine blocks the central postsynaptic serotonin receptors. This effect may contribute to the anxiolytic effect of the drug.

Some central effects of opipramol given repeatedly.

Some central effects of opipramol administered repeatedly (twice daily, 14 days) were studied in rats and mice. Repeated or acute treatment with opipramol did not change the locomotor activity of rats. Given repeatedly, but not in a single dose, opipramol increased the (+)-amphetamine-induced hyperactivity. The (+)-amphetamine-induced stereotypy was unchanged by acute or repeated treatment with opipramol. The aggressiveness induced by clonidine in mice was attenuated by a single dose of opipramol, but it was markedly enhanced after repeated treatment with this drug. The immobility time of rats (behavioral despair test) was prolonged by a single dose of opipramol; when given three times, opipramol reduced the immobility time. The obtained results seem to indicate that repeated treatment with opipramol leads to similar effects in the experimental models as those after repeated treatment with typical antidepressant drugs, i.e. enhancement of the responses mediated by dopamine receptors (probably in the limbic system, but not in the striatum) and alpha 1-adrenoceptors in the brain.

Specific modulation of sigma binding sites by the anxiolytic drug opipramol.

The atypical anxiolytic and antidepressive drug opipramol binds with high affinity to sigma1 and somewhat lower affinity to sigma2 sites. After subchronic treatment, opipramol significantly down-regulated sigma2 but not sigma1 sites. This effect was not seen for imipramine, citalopram, and reboxetine under similar conditions. On the other hand, only imipramine reduced the number of sigma1 sites. It is suggested that effects at sigma2 sites are involved in the anxiolytic properties of opipramol.