The Antidepressant-like Activity, Effects on Recognition Memory Deficits, Bioavailability, and Safety after Chronic Administration of New Dual-Acting Small Compounds Targeting Neuropsychiatric Symptoms in Dementia.

This study aimed to extend the body of preclinical research on prototype dual-acting compounds combining the pharmacophores relevant for inhibiting cyclic nucleotide phosphodiesterase 10 (PDE10A) and serotonin 5-HT1A/5-HT7 receptor (5-HT1AR/5-HT7R) activity into a single chemical entity (compounds PQA-AZ4 and PQA-AZ6). After i.v. administration of PQA-AZ4 and PQA-AZ6 to rats, the brain to plasma ratio was 0.9 and 8.60, respectively. After i.g. administration, the brain to plasma ratio was 5.7 and 5.3, respectively. An antidepressant-like effect was observed for PQA-AZ6 in the forced swim test, after chronic 21-day treatment via i.p. administration with 1 mg/kg/day. Both compounds revealed an increased level of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus and prefrontal cortex. Moreover, PQA-AZ4 and PQA-AZ6 completely reversed (+)-MK801-induced memory disturbances comparable with the potent PDE10 inhibitor, compound PQ-10. In the safety profile that included measurements of plasma glucose, triglyceride, and total cholesterol concentration, liver enzyme activity, the total antioxidant activity of serum, together with weight gain, compounds exhibited no significant activity. However, the studied compounds had different effects on human normal fibroblast cells as revealed in in vitro assay. The pharmacokinetic and biochemical results support the notion that these novel dual-acting compounds might offer a promising therapeutic tool in CNS-related disorders.

The Comparison of In Vitro Photosensitizing Efficacy of Curcumin-Loaded Liposomes Following Photodynamic Therapy on Melanoma MUG-Mel2, Squamous Cell Carcinoma SCC-25, and Normal Keratinocyte HaCaT Cells.

The research focused on the investigation of curcumin encapsulated in hydrogenated soy phosphatidylcholine liposomes and its increased photoactive properties in photodynamic therapy (PDT). The goal of this study was two-fold: to emphasize the role of a natural photoactive plant-based derivative in the liposomal formulation as an easily bioavailable, alternative photosensitizer (PS) for the use in PDT of skin malignancies. Furthermore, the goal includes to prove the decreased cytotoxicity of phototoxic agents loaded in liposomes toward normal skin cells. Research was conducted on melanoma (MugMel2), squamous cell carcinoma (SCC-25), and normal human keratinocytes (HaCaT) cell lines. The assessment of viability with MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) evaluated cell death after exposure to blue light irradiation after 4 h of pre-incubation with free and encapsulated curcumin. Additionally, the wound healing assay, flow cytometry, and immunocytochemistry to detect apoptosis were performed. The malignant cells revealed increased phototoxicity after the therapy in comparison to normal cells. Moreover, liposome curcumin-based photodynamic therapy showed an increased ratio of apoptotic and necrotic cells. The study also demonstrated that nanocurcumin significantly decreased malignant cell motility following PDT treatment. Acquired results suggest that liposomal formulation of a poor soluble natural compound may improve photosensitizing properties of curcumin-mediated PDT treatment in skin cancers and reduce toxicity in normal keratinocytes.

Azacarbazole n-3 and n-6 polyunsaturated fatty acids ethyl esters nanoemulsion with enhanced efficacy against Plasmodium falciparum.

Alternative therapies are necessary for the treatment of malaria due to emerging drug resistance. However, many promising antimalarial compounds have poor water solubility and suffer from the lack of suitable delivery systems, which seriously limits their activity. To address this problem, we synthesized a series of azacarbazoles that were evaluated for antimalarial activity against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. The most active compound, 9H-3-azacarbazole (3), was encapsulated in a novel o/w nanoemulsion consisting of ethyl esters of polyunsaturated fatty acids n-3 and n-6 obtained from flax oil as the oil phase, Smix (Tween 80 and Transcutol HP) and water. This formulation was further analyzed using transmission electron microscopy, dynamic light scattering and in vitro and in vivo studies. It was shown that droplets of the 3-loaded nanosystem were spherical, with satisfactory stability, without cytotoxicity towards fibroblasts and intestinal cell lines at concentrations corresponding to twice the IC50 for P. falciparum. Moreover, the nanoemulsion with this type of oil phase was internalized by Caco-2 cells. Additionally, pharmacokinetics demonstrated rapid absorption of compound 3 (tmax = 5.0 min) after intragastric administration of 3-encapsulated nanoemulsion at a dose of 0.02 mg/kg in mice, with penetration of compound 3 to deep compartments. The 3-encapsulated nanoemulsion was found to be 2.8 and 4.2 times more effective in inhibiting the D10 and W2 strains of the parasite, respectively, compared to non-encapsulated 3. Our findings support a role for novel o/w nanoemulsions as delivery vehicles for antimalarial drugs.