No abstract

Alzheimer's disease (AD), a neurodegenerative disorder exhibiting a gradual decline in cognitive function, is characterized by the presence of neuritic plaques composed of neurofibrillary tangles and amyloid-β (Aβ) peptide. Available drugs for AD therapy have small effect sizes and do not alter disease progression. Several studies have been shown that resveratrol is associated with anti-amyloidogenic properties, but therapeutic application of its beneficial effects is limited. Here we compared the neuroprotective effects of free resveratrol treatment with those of resveratrol-loaded lipid-core nanocapsule treatment against intracerebroventricular injection of Aβ1-42 in rats. Animals received a single intracerebroventricular injection of Aβ1-42 (2 nmol), and 1 day after Aβ infusion, they were administered either free resveratrol (RSV) or resveratrol-loaded lipid-core nanocapsules (5 mg/kg, each 12 h, intraperitoneally), for 14 days. Aβ1-42-infused animals showed a significant impairment on learning memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels. Furthermore, animals exhibited activated astrocytes and microglial cells, as well as disturbance in c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3β (GSK-3β) activation, beyond destabilization of β-catenin levels. Our results clearly show that by using lipid-core nanocapsules, resveratrol was able to rescue the deleterious effects of Aβ1-42 while treatment with RSV presented only partial beneficial effects. These findings might be explained by the robust increase of resveratrol concentration in the brain tissue achieved by lipid-core nanocapsules. Our data not only confirm the potential of resveratrol in treating AD but also offer an effective way to improve the efficiency of resveratrol through the use of nanodrug delivery systems.

Neuroinflammation, characterized by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of Alzheimer's disease (AD). Epidemiological studies suggesting that nonsteroidal anti-inflammatory drugs decrease the risk of developing AD have encouraged further studies elucidating the role of inflammation in AD. Nanoparticles have become an important focus of neurotherapeutic research because they are an especially effective form of drug delivery. Here, we investigate the potential protective effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNCs) against cell damage and neuroinflammation induced by amyloid beta (Aβ)1-42 in AD models. Our results show that IndOH-LNCs attenuated Aβ-induced cell death and were able to block the neuroinflammation triggered by Aβ1-42 in organotypic hippocampal cultures. Additionally, IndOH-LNC treatment was able to increase interleukin-10 release and decrease glial activation and c-jun N-terminal kinase phosphorylation. As a model of Aβ-induced neurotoxicity in vivo, animals received a single intracerebroventricular injection of Aβ1-42 (1 nmol/site), and 1 day after Aβ1-42 infusion, they were administered either free IndOH or IndOH-LNCs (1 mg/kg, intraperitoneally) for 14 days. Only the treatment with IndOH-LNCs significantly attenuated the impairment of this behavior triggered by intracerebroventricular injection of Aβ1-42. Further, treatment with IndOH-LNCs was able to block the decreased synaptophysin levels induced by Aβ1-42 and suppress glial and microglial activation. These findings might be explained by the increase of IndOH concentration in brain tissue attained using drug-loaded lipid-core NCs. All these findings support the idea that blockage of neuroinflammation triggered by Aβ is involved in the neuroprotective effects of IndOH-LNCs. These data provide strong evidence that IndOH-LNC treatment may represent a promising approach for treating AD.

Resveratrol, a natural polyphenolic compound, has attracted considerable interest for its anti-inflammatory and neuroprotective properties. However, the biological effects of resveratrol appear strongly limited because it is photosensitive, easily oxidized, and has unfavorable pharmacokinetics. The present study aimed to elucidate the effect of resveratrol on Abeta-triggered neuroinflammation by comparing the effects of free resveratrol (RSV) treatment with those of treatment with resveratrol-loaded lipid-core nanocapsules (RSV-LNC). Organotypic hippocampal cultures were stimulated by Abeta1-42 with or without different concentrations of RSV or RSV-LNC. We found that Abeta triggered a harmful neuroinflammation process in organotypic hippocampal cultures. Pre- and co-treatments with RSV-LNC were able to protect cultures against ROS formation and cell death induced by Abeta, possibly through sustained blocking of TNF-alpha, IL-1beta, and IL-6 release. Furthermore, RSV-LNC was able to increase IL-10 release even in the presence of Abeta and prevent or decrease both glial and JNK activation. On the other hand, both pre- and co-treatment with RSV exhibited a lower ability to prevent or decrease neuroinflammation, ROS formation, and cell death, and failed to increase IL-10 release. Our findings suggest that modulation of neuroinflammation through a combination of resveratrol and a lipid-core nanocapsule-based delivery system might represent a promising approach for preventing or delaying the neurodegenerative process triggered by Abeta. The results open new vistas to the interplay between inflammation and amyloid pathology.

These results reinforce the neuroprotective effects of curcumin on Abeta toxicity and add some evidence that its mechanism may involve beta-catenin and PI3K signaling pathway in organotypic hippocampal slice culture.