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- Pre-clinical study of 21 approved drugs in the mdx mouse. [In Vitro, Journal Article, Research Support, Non-U.S. Gov't]
- Neuromuscul Disord 2011 May; 21(5):313-27.
Duchenne muscular dystrophy, a genetic disease caused by the absence of functional dystrophin, remains without adequate treatment. Although great hopes are attached to gene and cell therapies, identification of active small molecules remains a valid option for new treatments. We have studied the effect of 20 approved pharmaceutical compounds on the muscles of dystrophin-deficient mdx5Cv mice. These compounds were selected as the result of a prior screen of 800 approved molecules on a dystrophin mutant of the invertebrate animal model Cænorhabditis elegans. Drugs were administered to the mice through maternal feeding since 2weeks of life and mixed in their food after the 3rd week of life. The effects of the drugs on mice were evaluated both at 6weeks and 16weeks. Each drug was tested at two concentrations. Prednisone was added to the molecule list as a positive control. To investigate treatment efficiency, more than 30 histological, biochemical and functional parameters were recorded. This extensive study reveals that tricyclics (Imipramine and Amitriptyline) are beneficial to the fast muscles of mdx mice. It also highlights a great variability of responses according to time, muscles and assays.
- Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. [Journal Article, Research Support, Non-U.S. Gov't]
- Cell Death Differ 1998 Jan; 5(1):29-37.
Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K.
- The effect of imipramine after single and repeated administration on the apomorphine response in the acoustic startle reflex in rats. [Journal Article]
- Pol J Pharmacol Pharm 1992 Jul-Aug; 44(4):347-53.
The paper presents the results of studies into the effects of single and repeated (2 or 10 mg/kg po, twice daily for 14 days) administration of imipramine (IMI) on the behavior of male Wistar rats in an acoustic startle response test. Statistically significant attenuation of the animal reactivity was observed after 8 or 14 days administration of IMI in a dose of 10 mg/kg. Apomorphine APO (1.0 mg/kg, ip) enhanced the animals reactivity after repeated (but not single) administration of IMI in a dose of 2 mg/kg. The obtained results confirm the hypothesis about an increase of the dopaminergic system reactivity under the influence of repeated administration of tricyclic antidepressants.
- Long-term effects of imipramine on striatal dopamine autoreceptor function: involvement of both noradrenergic and serotonergic systems. [In Vitro, Journal Article, Research Support, Non-U.S. Gov't]
- Gen Pharmacol 1992 May; 23(3):397-401.
1. The effects of apomorphine (APO) administration on DA system activity were assessed by measuring dopamine metabolite levels (HVA) in several circumstances. 2. Pretreatment with IMI reduced the effect of APO on HVA levels. 3. Pretreatments with either IDE or DMI did not reduce the effect of APO on HVA levels. 4. Reductions of either NE and 5-HT levels after DSP4 and pCPA restored the effect of APO after IMI pretreatment.
- Cardiogenic shock with imipramine. [Journal Article]
- Indian J Psychiatry 1990 Oct; 32(4):364-5.
A 35 years old physically healthy individual, being treated far depression with imipramine and electroplexy, developed cardiogenic shock which was managed successfully with inotropic support. The case is presented to highlight a rare and potentially fatal side effect of tricyclic anti-depressants.
- Different effects of short- and long-term treatment with imipramine on the apomorphine- and food-induced place preference conditioning in rats. [Journal Article]
- Pharmacol Biochem Behav 1988 Aug; 30(4):889-93.
The effect of imipramine (IMI) on the rewarding properties of pharmacological and natural reinforcers was studied with a place preference paradigm. The pairing of distinctive environmental stimuli with either injection of different doses of apomorphine (APO) or presentation of food to hungry rats resulted in a conditioned preference for those stimuli. The development of APO- and food-induced place preference was prevented by short-term administration of IMI. In contrast, long-term pretreatment with IMI significantly potentiated the APO- and food-induced conditioned effect. In separate experiments aversive properties of IMI by itself were also found, as the conditioned avoidance response to the environmental stimuli paired with administration of single doses of IMI was demonstrated. The results indicate an enhancing effect of the long-term IMI administration on the dopamine-mediated reward functions and the rewarding value of natural reinforcers.
- Species differences in hepatic microsomal drug-metabolizing enzymes. [Comparative Study, Journal Article]
- Pol J Pharmacol Pharm 1988 Jul-Aug; 40(4):351-6.
The activity of some metabolizing enzymes was assessed in the liver microsomes of Acomys cahirinus, mice and rats. The enzymatic studies were followed by the determination of cerebral level of apomorphine (APO), imipramine (IMI) and its metabolite desipramine (DMI) of animals treated with a single dose of APO or IMI. It was found that the level of cytochrome P-450 and the activity of IMI demethylase and glucuronyltransferase in the liver microsomes of rats was significantly higher than those in the liver microsomes of Acomys and mice. The brain levels of APO, IMI and DMI were different in investigated species and IMI and DMI levels in the brain of Acomys, mice and rats corresponded to the activity of IMI demethylase in the liver microsomes of these species.
- Long-term administration of (-)deprenyl (selegiline), a compound which facilitates dopaminergic tone in the brain, leaves the sensitivity of dopamine receptors to apomorphine unchanged. [Journal Article]
- Arch Int Pharmacodyn Ther 1986 Dec; 284(2):255-66.
The effect of repeated administration of the MAO-B enzyme blocker (-)deprenyl on the apomorphine (APO) sensitivity of dopamine (DA) receptors was investigated in rats, and compared to the effect of other drugs influencing the dopaminergic system. APO was given either in a high dose (0.1-0.6 mg/kg), which induces stereotyped behaviour or in a smaller one (0.02 mg/kg) causing sedation. Repeated administration of all the other drugs investigated (except (-)deprenyl), i.e. haloperidol, d-amphetamine, (1 mg/kg s.c., respectively) and the MAO-A blocker clorgyline (0.25 mg/kg s.c.) altered the efficiency of APO on the stereotypy. Haloperidol, clorgyline (0.5 mg/kg s.c.) and imipramine (10 mg/kg i.p.) attenuated the APO-sedation. The long-lasting administration of (-)deprenyl (0.25 mg/kg s.c., daily for 42 days) however, left the effects of APO unchanged, demonstrating that (-)deprenyl facilitates the dopaminergic tone in the rat brain without altering the sensitivity of DA receptors.
- Behavioural pharmacology of imidazole, a potential antidepressant agent. [Journal Article, Research Support, Non-U.S. Gov't]
- Arch Int Pharmacodyn Ther 1985 Oct; 277(2):303-12.
Imidazole (IMID) inhibited (+/-) N-n-propylnorapomorphine (NPA) and BHT-920 induced penile erections (PE) and stretching and yawning (SY) in rats as well as apomorphine (APO) induced hypothermia in mice, enhanced shock-elicited aggressiveness in rats and antagonized sleep induced by clonidine in chicks. IMID moreover displayed activity in behavioural tests used in specific screening for antidepressants, potentiating yohimbine toxicity in mice and antagonizing immobility time in the despair test, with a potency in some cases equal to imipramine. IMID per se, depressed motor activity in both mice and rats. The possible mechanism of action and receptors involved are briefly discussed as well as IMID's profile as an antidepressant drug.
- Striatal dopamine autoreceptors uninfluenced by chronic administration of antidepressants. [Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.]
- Eur J Pharmacol 1982 Aug 27; 82(3-4):173-8.
Dopamine (DA) receptor sensitivity to apomorphine (APO) was assessed in the rat nigrostriatal system following chronic antidepressant treatment. Imipramine (IMI), iprindole (IPR) or vehicle was administered to rats for 10 days (10 mg/kg i.p., b.i.d.). Two and a half days after the last injection 3,4-dihydroxyphenylacetic acid (DOPAC) levels were measured in rat striata following injection of APO (50 or 100 micrograms/kg s.c.) or vehicle. In contrast with rats receiving chronic vehicle injections, rats chronically treated with IMI or IPR failed to exhibit a significant APO-induced fall in striatal DOPAC levels. Antidepressant-treated animals, however, exhibited significantly lower basal DOPAC levels than vehicle-treated rats. In an effort to localize the diminished APO response, DA autoreceptor sensitivity to APO was assessed in drug- and vehicle-treated animals. Employing gamma-butyrolactone (GBL) and a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor to elevate striatal DOPA, the APO-induced reversal of DOPA elevation was used as an index of DA autoreceptor sensitivity. This GBL-stimulated in vivo tyrosine hydroxylation was similarly reversed by APO (125, 250 or 500 micrograms/kg i.p.) in IMI-, IPR- and vehicle-treated animals. In view of these findings, we propose that the blunted biochemical response to APO observed in animals pretreated with antidepressants does not originate as a result of alterations in the sensitivity of DA autoreceptors located on the striatal presynaptic nerve terminal.