Neurobehavioral effects of vigabatrin and its ability to induce DNA damage in brain cells after acute treatment in rats.

RATIONALE: Vigabatrin (VGB) is a drug indicated mostly for the treatment of spasms in childhood and West's syndrome patients. This drug inhibits irreversibly the enzyme GABA-transaminase (GABA-T), increasing GABA concentrations and enhancing GABAergic neurotransmission in the brain, which is known to induce behavioral changes. OBJECTIVES: The aims of this study were to evaluate the effects of VGB in the short-term memory (STM), long-term memory (LTM), motivation, locomotion, and exploratory behavior tests and to detect deleterious or protective effects on DNA in target tissues of the drug. METHODS: Male Wistar rats were treated with a single dose of VGB (100, 250, or 500 mg/kg) or saline solution before the inhibitory avoidance and open-field tasks. DNA damage was evaluated using the alkaline comet assay in peripheral blood, cerebral cortex, and hippocampus after behavioral testing. RESULTS: There was no significant difference in the inhibitory avoidance task between the treated groups and the saline group. In all tested doses, VGB reduced the number of rearings in the open-field task. Besides, VGB 500 mg/kg affected locomotion, though it was not able to induce any DNA damage. CONCLUSIONS: VGB did not affect STM and LTM, but the drug impaired the exploration and locomotion likely associated with its sedative effect. In addition, no DNA damage in cortex and hippocampus was detected after behavioral testing, when brain GABA levels are already increased.

Behavioral and genotoxic evaluation of rosmarinic and caffeic acid in acute seizure models induced by pentylenetetrazole and pilocarpine in mice.

The goal of this study was to investigate the effects of rosmarinic acid (RA) and caffeic acid (CA) in the acute pentylenetetrazole (PTZ) and pilocarpine (PIL) seizure models. We also evaluated the effect of RA and CA on the diazepam (DZP)-induced sleeping time test and its possible neuroprotective effect against the genotoxic damage induced by PTZ and PIL. Mice were treated intraperitoneally (i.p.) with saline, RA (2 or 4 mg/kg), or CA (4 or 8 mg/kg) alone or associated to low-dose DZP. After, mice received a single dose of PTZ (88 mg/kg) or PIL (250 mg/kg) and were monitored for the percentage of seizures and the latency to first seizure (LFS) >3 s. Vigabatrin and DZP were used as positive controls. In the DZP-induced sleeping time test, mice were treated with RA and CA and 30 min after receiving DZP (25 mg/kg, i.p.). The alkaline comet assay was performed after acute seizure tests to evaluate the antigenotoxic profiles of RA and CA. The doses of RA and CA tested alone did not reduce the occurrence of seizures induced by PTZ or PIL. The association of 4 mg/kg RA + low-dose DZP was shown to increase LFS in the PTZ model, compared to the group that received only the DZP. In the DZP-induced sleeping time test, the latency to sleep was reduced by 4 mg/kg RA and 8 mg/kg CA. The PTZ-induced genotoxic damage was not prevented by RA or CA, but the PIL-induced genotoxic damage was decreased by pretreatment with 4 mg/kg RA (in cortex) and 4 mg/kg CA (in hippocampus). In conclusion, RA and CA presented neuroprotective effect against PIL-induced genotoxic damage and reduced the latency to DZP-induced sleep. Of the rosmarinic acid, 4 mg/kg enhanced the DZP effect in the increase of latency to clonic PTZ-induced seizures.

Genotoxic, mutagenic and antigenotoxic effects of Cecropia pachystachya Trécul aqueous extract using in vivo and in vitro assays.

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia pachystachya is a medicinal plant native to South and Central Americas used to treat asthma and diabetes. AIM OF THE STUDY: In this study, we evaluated the genotoxic, mutagenic and antigenotoxic effects of crude aqueous extract of C. pachystachya (CAE-Cp) leaves. MATERIAL AND METHODS: CAE-Cp was analyzed by the Folin-Ciocalteu method to determine total phenolic and tannin contents. High performance liquid chromatography (HPLC) was used to identify major compounds. Distinct tissues from female and male adult mice were treated with 500-2000mg/kg of CAE-Cp by gavage for the comet assay and micronucleus test analyses. In addition, peripheral blood slides of the group treated with 2000mg/kg CAE-Cp were analyzed 3, 6, and 24h after treatment and were exposed to hydrogen peroxide (ex vivo) to evaluate the genotoxic effect using the comet assay. The Salmonella/microsome assay was carried out against to TA100, TA98, TA97a, TA102, and TA1535 strains in presence and absence of the S9 mix. RESULTS: HPLC showed the presence of chlorogenic acid, isoorientin, orientin, and isovitexin as major compounds. Total phenolic and tannin contents were, respectively, 305.6±0.80 and 144.6±19.04mg of gallic acid equivalent/g of extract. Brain DNA damage was observed in all groups treated with CAE-Cp. The H2O2 challenge indicated genotoxic effect only 6h after the administration of the extract. No increase was detected in micronucleus frequency for any group treated with the extract. Mutagenic effects were detected by Salmonella/microsome assay only in TA102 strain without S9 mix at higher doses. CONCLUSION: The results obtained indicate that CAE-Cp was genotoxic to brain tissue. This result is supported by other papers, showing that compounds present in this extract can cross the blood-brain barrier and act on central nervous system.

Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice.

AIMS: Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. MAIN METHODS: Male CF-1 mice were treated once every three days during 16days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2',7'-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). KEY FINDINGS: Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. SIGNIFICANCE: Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo.