Involvement of the serotoninergic system in the anxiolytic action mechanism of a liposomal formulation containing nimodipine (NMD-Lipo).

In the search for anxiolytic drugs with fewer adverse effects, calcium blockers were proposed as a benzodiazepines (BZDs) alternative. In this context, the anxiolytic effect of nimodipine has been demonstrated. However, its low bioavailability and solubility could be improved by using nanostructured drug delivery systems such as liposomes. In this way, liposomal formulation containing nimodipine (NMD-Lipo) was developed. The NMD-lipo is a formulation capable of improving the kinetic characteristics of the drug, as well as the anxiolytic effect of nimodipine. In this work, the serotonergic system participation in the anxiolytic mechanism of the liposomal formulation containing nimodipine (NMD-Lipo) was investigated. A possible 5-HT1A receptor mediation on the NMD-Lipo anxiolytic effect was demonstrated by using WAY 100635 (5-HT1A receptor antagonist) since the antagonist reversed the NMD-Lipo anxiolytic effect in the light/dark test and elevated plus maze test. The results demonstrated that the NMD-Lipo administration had anxiolytic activity through 5-HT1A receptors without causing sedation or compromising the motor coordination of the tested animals.

Citrinin against breast cancer: A cytogenotoxicological study.

Breast cancer is one of the most lethal types of cancer and a leading cause of mortality among Women worldwide. Citrinin (CIT), a polyketide extracted from the fungus Penicillium citrinum, exhibits a wide range of biological activities such as antibacterial, antifungal, and cytotoxic effects. The aim of the current study was to evaluate the antitumoral effects of CIT against 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinoma in Swiss mice For this, CIT, DMBA and the standard cyclophosphamide (CPA) induced behavioral changes in experimental animals, and these changes were screened by using the rota rod and open field tests. Additionally, hematological, biochemical, immuno-histochemical, and histopathological analyses were carried out. Results suggest that CIT did not alter behavioral, hematological, and biochemical parameters in mice. DMBA induced invasive mammary carcinoma and showed genotoxic effects in the breasts, bone marrow, lymphocytes, and hepatic cells. It also caused mutagenic effects in the formation of micronuclei, bridges, shoots, and binucleate cells in bone marrow and liver. CIT and CPA genotoxic effects were observed after 3 weeks of therapy, where CIT exhibited a repair capacity and induced significant apoptotic damage in mouse lymphocytes. In conclusion, CIT showed antitumoral effects in Swiss mice, possibly through induction of apoptosis.

Pegylated nanoparticles for the oral delivery of nimodipine: Pharmacokinetics and effect on the anxiety and cognition in mice.

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments.

Antidepressant-like activity of liposomal formulation containing nimodipine treatment in the tail suspension test, forced swim test and MAOB activity in mice.

Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca(2+) channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.

Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice.

Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD-Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity.

Development and evaluation of liposomal formulation containing nimodipine on anxiolytic activity in mice.

Nimodipine has been investigated in the treatment of anxiety. Its administration, however, presents a number of limitations, particularly by low bioavailability, low aqueous solubility and photosensitivity. These difficulties can be resolved by the use of nanometer-scale pharmaceutical carriers. The goal of the present study was thus to develop a liposomal formulation containing nimodipine (NMD-Lipo) and evaluate anxiolytic activity using models of anxiety (open-field, light and dark and elevated plus-maze test). The results suggest that administration of NMD-Lipo has no sedative or muscle relaxant effect in animals, since there was no reduction in the number of crossings, grooming and rearings. The increased residence time of the animals treated with NMD-Lipo in the bright field is a reflection of the anxiolytic-like activity of the formulation. Furthermore, the reduction in residence time of rodents treated with the combination of flumazenil and NMD-Lipo in the illuminated box suggests that NMD-Lipo acts on benzodiazepine receptors. The increase in the number of entries and length of stay in the open arms of mice treated with NMD-Lipo suggests that anxiolytic activity of formulation and reduction in number of entries and length of stay in open arms of rodents treated with a combination of flumazenil and NMD-Lipo suggest that NMD-Lipo act on benzodiazepine receptors.