Depressive-like behaviour induced by an intracerebroventricular injection of streptozotocin in mice: the protective effect of fluoxetine, antitumour necrosis factor-α and thalidomide therapies.

Information on the effect of an intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) on noncognitive behaviour in rodents such as depression states is scarce. Thus, the aim of this study was to examine the depressive-like effect of STZ injected by the i.c.v. route in mice and the potential protective effect of fluoxetine, antitumour necrosis factor-α (anti-TNF-α) and thalidomide. Our results indicated that a single injection of STZ (0.1 mg/site) promoted depressive-like behaviour in the tail suspension and sucrose preference tests without altering either locomotor activity or plasma glucose levels. We also showed that STZ increased TNF-α levels in the hippocampus of mice. Fluoxetine (32 mg/kg, intraperitoneally. 30 min before STZ injection), and the anti-TNF-α antibody (0.1 pg/site, i.c.v.) and thalidomide (3 mg/kg, subcutaneously), coadministered with STZ, prevented these effects. This is the first study to report depressive-like effects of STZ using the i.c.v. route in mice. We concluded that fluoxetine, anti-TNF-α antibody and thalidomide were effective in preventing depressive-like behaviour and the increase in TNF-α levels in the hippocampus of mice induced by an i.c.v. injection of STZ, reinforcing the involvement of TNF-α in the pathophysiology of depression. This model and the mechanisms studied may contribute towards the development of new antidepressant drugs and enhance the options for studying depression.

Neuroprotective effect of physical exercise in a mouse model of Alzheimer's disease induced by ß-amyloid1₋40 peptide.

This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid1₋40 (Aß1₋40) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aß1₋40 administration (400 pmol/animal; 3 µl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aß1₋40 administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aß1₋40. Also, Aß1₋40 inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex-alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aß1₋40-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aß1₋40 in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.

Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice.

The present study investigated a possible antidepressant-like activity of hesperidin using two predictive tests for antidepressant effect in mice: the forced swimming test (FST) and the tail suspension test (TST). Results demonstrated that hesperidin (0.1, 0.3 and 1 mg/kg, intraperitoneal, i.p.) decreased the immobility time in the FST and TST without affecting the locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) on the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (pCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) and WAY100635 (0.1 mg/kg, subcutaneous, s.c., a selective 5-HT(1A) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a ß-adrenoceptor antagonist), AMPT (100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist) or MDL72222 (1 mg/kg, i.p., a 5-HT(3) receptor antagonist) did not block the antidepressant-like effect of hesperidin (0.3 mg/kg, i.p.) in the TST. Administration of hesperidin (0.01 mg/kg, i.p.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. The antidepressant-like effect caused by hesperidin in mice in the TST was dependent on an interaction with the serotonergic 5-HT(1A) receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like property and may be of interest source for therapeutic agent for the treatment of depressive disorders.

Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test.

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1 mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3 mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1 mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1 mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1 mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3 mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, a selective µ-opioid receptor antagonist) or caffeine (3 mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01 mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1 mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, µ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.

In vitro antioxidant activity and in vivo antidepressant-like effect of α-(phenylselanyl) acetophenone in mice.

In this study, the antioxidant and antidepressant-like effects of α-(phenylselanyl) acetophenone (PSAP), an organoselenium compound, were investigated. To assess the in vitro antioxidant properties, PSAP was evaluated in four test systems (DPPH, ABTS, FRAP and inhibition of lipid peroxidation). PSAP (100-500 µM) showed potent antioxidant activity and protected against lipid peroxidation. Additionally, we investigated whether PSAP, when administered in mice (100, 200 and 400mg/kg, per oral, p.o.), could cause acute toxicity. Our results demonstrated that PSAP did not cause the death of any animal, significantly reduce body weight or cause any oxidative tissue stress following treatment. This study also evaluated the effect of PSAP (0.1-10 mg/kg, p.o) on mice in a forced swim test (FST) and tail suspension test (TST), assays that are predictive of depressant activity and motor activity in the open-field. PSAP (5-10 mg/kg) significantly reduced immobility time in the FST and TST without affecting motor activity. In addition, the antidepressant-like effect caused by PSAP (5m/kg, p.o) in mice during the TST was dependent on an interaction with the serotonergic system (5-HT(1A) receptors), but not with the noradrenergic, dopaminergic or adenosinergic system. Together, these results suggest that PSAP possesses antioxidant and antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.