Effects of memantine, a non-competitive N-methyl-D-aspartate receptor antagonist, on genomic stability.

Memantine is an aminoadamantane drug useful in neurodegenerative diseases, with beneficial effects on cognitive functions. Some studies have shown that memantine protects brain cells, thereby decreasing glutamate excitotoxicity. This study evaluated the genotoxic/antigenotoxic and mutagenic effects of memantine in CF-1 mice, following standardized protocols. Memantine was administered i.p. at 7.5, 15 or 30 mg/kg for three consecutive days. Blood and brain samples were collected to assess DNA damage using the alkaline comet assay. The mutagenic effect was assessed using the bone marrow micronucleus test. In addition, possible antioxidant effects were evaluated measuring the survival of Saccharomyces cerevisiae yeast strains [wild-type (WT) and isogenic mutants lacking superoxide dismutase] to cotreatment of memantine plus hydrogen peroxide. Memantine decreased DNA oxidative damage mainly in brain tissue. This antigenotoxic effect corroborated an increase observed in the survival of S. cerevisiae WT strain against hydrogen peroxide-induced damage. Furthermore, memantine did not increase the micronucleus frequency. The overall results indicate that memantine showed no mutagenic activity, did not cause DNA damage in the blood and brain tissues and showed antigenotoxic effects in brain tissue.

Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models.

Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake, used in the treatment of major depression. It has been recognized that some antidepressants can affect memory in humans, but there is not study that report the duloxetine effect on memory using the inhibitory avoidance. The aim of this work was to investigate the effect of duloxetine on short- and long-term memory (STM and LTM) in the inhibitory avoidance task in mice. Duloxetine (10 and 20 mg/kg; i.p.) administered before or after the inhibitory avoidance training was not able to produce effects on STM e LTM (p>0.05). The group that received MK-801 (0.0625 mg/kg), an NMDA receptor antagonist, showed an impairment in STM and LTM (p<0.01). These effects were not reversed by duloxetine administration (p=0.114 and p=0.06, respectively). Duloxetine effect on memory 5 days after i.p. administration was also investigated. After this treatment both duloxetine doses used were unable to affect STM or LTM in the inhibitory avoidance task (p=0.371 and p=0.807, respectively). DNA damages were evaluated in brain tissues and blood by the comet assay, after subacute treatment (10 or 20 mg/kg by 5 days). Duloxetine did not induce genotoxic effects. However, when the cells were treated ex vivo hydrogen peroxide, a pro-oxidant effect on brain tissue from treated animals was observed with significantly higher DNA damage in comparison to untreated animals, suggesting increased susceptibility to injuries by reactive oxygen species in brain after treatment with duloxetine. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.

Effects of gamma-decanolactone on seizures induced by PTZ-kindling in mice.

Gamma-decanolactone is a monoterpene compound, and its psychopharmacological evaluation in mice revealed that it has a dose-dependent effect on the central nervous system, with hypnotic, anticonvulsant, and hypothermic activity. The aim of the present study was to investigate the effect of gamma-decanolactone on pentylenetetrazole (PTZ)-kindling in mice. Phenobarbital, an antiepileptic drug, was also tested for the purpose of comparison. After the behavioral procedures had been undertaken, the animals were killed and brain tissue was sampled to evaluate DNA damage in the brain using comet assay. The data reported here suggest that the administration of phenobarbital (10 mg/kg) and gamma-decanolactone at 0.3 g/kg, but not at 0.1 g/kg, impairs both the severity and the progression of seizures in the PTZ-kindling model. DNA damage to brain tissue decreased in gamma-decanolactone-treated kindling animals (similar to phenobarbital) as compared to nontreated animals. The results suggest that gamma-decanolactone has dose-dependent anticonvulsant properties, and may also have antiepileptogenic and neuroprotective effects in the PTZ-kindling model.