l-carnitine modulates autophagy, oxidative stress and inflammation in trazodone induced testicular toxicity.

BACKGROUND: Trazadone is an antidepressant and may affect reproductive hormones and spermatogenesis. l-carnitine is an amino acid that exhibits antioxidant actions. This study was designed to investigate the potential protective effects of l-carnitine against trazadone-induced testicular toxicity in male rats and the possible underlying mechanisms such as oxidative stress, inflammation and autophagy. METHODS: thirty-two male Wistar rats were divided randomly into four equal groups (n = 8). Testicular damage was induced by oral administration of Trazadone (TRZ, 20 mg/kg/day, p.o.) for four weeks (TRZ group). l-carnitine (LC, 200 mg/kg/day, p.o.) was applied for four weeks (LC group). LC + TRZ group administered the same doses of LC and TRZ concomitantly. The control group received distilled water (as vehicle). RESULTS: the protective treatment with LC attenuated the decline of sperm count and motility resulted from trazadone administration. Moreover, LC ameliorated trazadone increased lipid peroxidation (MDA) and reduction of total thiol and catalase activity. LC modulated the elevation in tumor necrosis factor- α (TNF-α), and increased the expression of autophagy related genes Becline-1, ATG 5 and ATG-12 in rat testes. Serum level of FSH, LH and total testosterone were increased significantly (p < 0.001) in LC + TRZ group. Histopathological findings further supported the protective effects of LC against trazadone -induced testicular injury by increasing free sperms within the lumen of spermatogenic cells and improving testicular degeneration. CONCLUSION: These findings supported the protective effects of l-carnitine on rat testes due to suppression of oxidative stress, inflammation and enhancing autophagy. l-carnitine may be recommended as adjuvant therapy to trazadone treatment.

Whole organism high content screening identifies stimulators of pancreatic beta-cell proliferation.

Inducing beta-cell mass expansion in diabetic patients with the aim to restore glucose homeostasis is a promising therapeutic strategy. Although several in vitro studies have been carried out to identify modulators of beta-cell mass expansion, restoring endogenous beta-cell mass in vivo has yet to be achieved. To identify potential stimulators of beta-cell replication in vivo, we established transgenic zebrafish lines that monitor and allow the quantification of cell proliferation by using the fluorescent ubiquitylation-based cell cycle indicator (FUCCI) technology. Using these new reagents, we performed an unbiased chemical screen, and identified 20 small molecules that markedly increased beta-cell proliferation in vivo. Importantly, these structurally distinct molecules, which include clinically-approved drugs, modulate three specific signaling pathways: serotonin, retinoic acid and glucocorticoids, showing the high sensitivity and robustness of our screen. Notably, two drug classes, retinoic acid and glucocorticoids, also promoted beta-cell regeneration after beta-cell ablation. Thus, this study establishes a proof of principle for a high-throughput small molecule-screen for beta-cell proliferation in vivo, and identified compounds that stimulate beta-cell proliferation and regeneration.

The four-plates test: anxiolytic or analgesic paradigm?

The four-plates test (FPT) is an animal model of anxiety in which the exploration of the novel surroundings is suppressed by the delivery of a mild electric foot shock. The anti-nociceptive system has been reported to be activated by a variety of stressful stimuli such as footshock. The present study was thus designed to compare effects of drugs in the FPT and in the hot-plate test (an animal model of pain), in order to disambiguate the drug-induced anti-punishment effects obtained in the FPT from alterations in pain sensitivity. Various compounds, known to be implicated in anxiety states as well as nociception, have been studied. Although morphine induced a strong anti-nociceptive effect, it did not modify the number of shocks received in the FPT. Alprazolam and diazepam induced an anxiolytic-like effect in the FPT, at doses that did not induce any effect in the hot-plate test. The antidepressants previously reported anxiogenic (desipramine, maprotiline) in the FPT were found to be analgesic at the same doses. Milnacipran, venlafaxine and paroxetine did not modify the pain threshold, whereas they have previously been shown to induce anxiolytic-like effects in the FPT. The dopaminergic antidepressant agent nomifensine was without effect on both tests. Our results suggest that the reported drug-induced anti-punishment effects in the FPT are not related to modifications of pain threshold but to a pure anxiolytic-like effect.

Evaluation of nefazodone as a serotonin uptake inhibitor and a serotonin antagonist in vivo.

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl- 2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.

Chronic fluoxetine treatment reduces hypothalamic vasopressin secretion in vitro.

Patients with obsessive-compulsive disorder (OCD) hypersecrete the arousal producing neurohormone arginine vasopressin (AVP) into the cerebrospinal fluid and plasma. Because OCD responds preferentially to potent serotonin uptake inhibitors, we compared the effect of chronic fluoxetine treatment to that of other antidepressants (trazodone and desipramine) on AVP release from rat hypothalamic organ culture and showed that only fluoxetine significantly reduced in vitro AVP release.

Behavioral screen for antidepressants: the effects of drugs and electroconvulsive shock on performance under a differential-reinforcement-of-low-rate schedule.

Those antidepressant drugs that are in wide clinical use decrease response rate and increase reinforcement rate when administered to rats performing on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Drugs that are not antidepressants do not have this effect. In this experiment, the following were examined for their effects on a DRL 72-s schedule: trazodone, zimelidine, fluoxetine, and bupropion (atypical antidepressants); electroconvulsive shock (ECS, which is an effective treatment for depression); and haloperidol and clozapine (antipsychotic drugs). Trazodone (3.12-25.00 mg/kg), fluoxetine (10-20 mg/kg), and ECS decreased response rate and increased reinforcement rate. Zimelidine (20 mg/kg) increased reinforcement rate and nonsignificantly decreased response rate. At doses between 2.5 and 40 mg/kg, bupropion had no effect on reinforcement rate or response rate, but at 60 mg/kg response rate was increased and reinforcement rate was nonsignificantly decreased. At the higher dose, the effects of bupropion resemble those of a psychomotor stimulant. Haloperidol (0.04 mg/kg) and clozapine (2.5-10.0 mg/kg) decreased response rate and reinforcement rate. These results suggest that the DRL 72-s schedule may be useful for testing the antidepressant potential of new drugs.

Comparative effects of trazodone and tricyclic antidepressants on uptake of selected neurotransmitters by isolated rat brain synaptosomes.

The effect of trazodone, a new antidepressant agent, on uptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) by crude synaptosome preparations from rat hypothalamus was compared with imipramine, desipramine, and clomipramine. Trazodone was determined to be a very selective inhibitor of the 5-HT uptake mechanism with IC50 values of 5.67 X 10(-7), 3.54 X 10(-5), and 5.25 X 10(-5 M, for 5-HT, NE, and DA uptake, respectively. Clomipramine, the only other selective inhibitor of 5-HT uptake studied, had IC50 values of 7.59 X 10(-9), 1.12 X 10(-7), and 2.51 X 10(-7) M, for 5-HT, NE, and DA, respectively. Although less potent, trazodone was 4 +/- 0.6 times more selective than clomipramine in its ability to inhibit synaptosomal uptake of 5-HT with respect to NE. This selectivity for the 5-HT uptake mechanism is consistent with the clinical antidepressant efficacy of trazodone.