Synthesis and pharmacological evaluation of novel N-aryl-cinnamoyl-hydrazone hybrids designed as neuroprotective agents for the treatment of Parkinson's disease.

Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.

Metabolic syndrome accentuates post-traumatic stress disorder-like symptoms and glial activation.

The relationship between individuals with post-traumatic stress disorder (PTSD) and the development of metabolic syndrome (MS) is well understood, but the relationship between individuals with preexisting MS and the development of PTSD is not yet known. Therefore, we evaluated the course of PTSD development in preexisting MS rats and we quantified the glial fibrillary acidic protein (GFAP) and ionized the calcium binding adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental animals. Male Wistar rats were divided into two groups: control or 10 % fructose for 5 weeks. After 5 weeks of MS induction, a group of animals was used to characterize MS. In another group, after 5 weeks of MS induction, animals were exposed to or not exposed to inescapable footshocks, followed by social isolation. After 14 days of a retention interval, the animals were re-exposed to the inescapable footshocks box, and the freezing time was evaluated. Over the following days, the animals were tested using the open field, social interaction and forced swimming tests, respectively. In another group of animals, after induction of MS and PTSD as previously described, elevated plus maze and object recognition tests were performed. Our results demonstrate that fructose solution for 5 weeks was able to induce MS, and animals with MS had more pronounced PTSD-like symptoms and a greater increase in GFAP and Iba-1 in the hippocampus and prefrontal cortex. In conclusion, MS accentuated PTSD-like symptoms that may be related to increased glial activation. This study helps reveal factors that may predispose individuals to the development of PTSD, such as metabolic disorders.

Anxiolytic-like effect of Sonchus oleraceus L. in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sonchus oleraceus L. has been used as a general tonic in Brazilian folk medicine. Nevertheless, available scientific information regarding this species is scarce; there are no reports related to its possible effect on the central nervous system. AIM OF THE STUDY: This study was conducted to establish the anxiolytic effect of extracts from the aerial parts of Sonchus oleraceus. MATERIALS AND METHODS: This study evaluated the effect of hydroethanolic and dichloromethane extracts of Sonchus oleraceus in mice submitted to the elevated plus-maze and open-field tests. Clonazepam was used as the standard drug. RESULTS: In the elevated plus-maze test, the Sonchus oleraceus extracts increased the percentage of open arm entries (P<0.05) and time spent in the open-arm portions of the maze (P<0.05). The extracts induce an anti-thigmotactic effect, evidenced by increased locomotor activity into the central part of the open field set-up (P<0.05). The extracts administered at 30-300 mg/kg, p.o. had a similar anxiolytic effect to clonazepam (0.5 mg/kg, p.o.). CONCLUSION: These data indicate that Sonchus oleraceus extract exerts an anxiolytic-like effect on mice.