André Meneghetti

Free and nanoencapsulated curcumin suppress β-amyloid-induced cognitive impairments in rats: involvement of BDNF and Akt/GSK-3β signaling pathway.

Alzheimers disease (AD), a neurodegenerative disorder exhibiting progressive loss of memory and cognitive functions, is characterized by the presence of neuritic plaques composed of neurofibrillary tangles and β-amyloid (Aβ) peptide. Drug delivery to the brain still remains highly challenging for the treatment of AD. Several studies have been shown that curcumin is associated with anti-amyloidogenic properties, but therapeutic application of its beneficial effects is limited. Here we investigated possible mechanisms involved in curcumin protection against Aβ(1-42)-induced cognitive impairment and, due to its poor bioavailability, we developed curcumin-loaded lipid-core nanocapsules in an attempt to improve the neuroprotective effect of this polyphenol. Animals received a single intracerebroventricular injection of Aβ(1-42) and they were administered either free curcumin or curcumin-loaded lipid-core nanocapsules (Cur-LNC) intraperitoneally for 10days. Aβ(1-42)-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 BDNF expression and Akt/GSK-3β signaling pathway, beyond tau hyperphosphorylation. Our findings demonstrate that administration of curcumin was effective in preventing behavioral impairments, neuroinflammation, tau hyperphosphorylation as well as cell signaling disturbances triggered by Aβ in vivo. Of high interest, Cur-LNC in a dose 20-fold lower presented similar neuroprotective results compared to the effective dose of free curcumin. Considered overall, the data suggest that curcumin is a potential therapeutic agent for neurocognition and nanoencapsulation of curcumin in LNC might constitute a promising therapeutic alternative in the treatment of neurodegenerative diseases such as AD.

Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models

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.

The curry spice curcumin attenuates beta-amyloid-induced toxicity through beta-catenin and PI3K signaling in rat organotypic hippocampal slice culture

Abstract Objective: Accumulating evidence indicates that curcumin potently protects against beta-amyloid (Abeta) due to its oxygen free radicals scavenging and anti-inflammatory properties. However, cellular mechanisms that may underlie the neuroprotective effect of curcumin in Abeta-induced toxicity are not fully understood yet. The present study was undertaken to investigate the mechanisms involved in neuroprotective effects of curcumin, particularly involving Wnt/beta-catenin and PI3K pathways. Methods: Organotypic hippocampal slice cultures were treated with curcumin and exposed to Abeta1–42 for 48 hours. Synaptic dysfunction, cell death, ROS formation, neuroinflammation and beta-catenin, Akt, and GSK-3beta phosphorylation were measured to determine the effects of curcumin against Abeta toxicity. Results: Curcumin significantly attenuated Abeta-induced cell death, loss of synaptophysin, and ROS generation. Furthermore, curcumin was able to decrease IL-6 release and increase IL-10 release, and prevented glial activation. The phosphorylation of beta-catenin was avoided and the levels of free beta-catenin were increased by curcumin to promote cell survival upon treatment with Abeta. Curcumin, in the presence of Abeta, activated Akt which in turn phosphorylates GSK-3beta, and resulted in the inhibition of GSK-3beta. The presence of LY294002, an inhibitor of PI3K pathway, blocked the pro-survival effect of curcumin. Discussion: 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.

Incorporation of resveratrol into lipid-core nanocapsules improves its cerebral bioavailability and reduces the Aβ-induced toxicity

vitro, BQCA increased carbachol potency approx. 90-fold at 10 ÂmM (n 1⁄4 6). In vivo, a maximal brain level of 270 nM was observed 40 min after i.p. administration at 10 mg/kg. Based on in vitro experiments, at level BQCA should produce about 3-fold increase of the agonist potency; it reduced a scopolamine-induced hyper locomotion. Further, BQCA reversed a deficit observed in the two models of memory impairment. Moreover, BQCA showed no side effect at 10 mg/kg and above in spontaneous locomotion as well as in the salivation test. Conclusions: Altogether, these data suggest that theM1 PAMBQCAmay be of interest for the treatment of memory deficits observed in Alzheimer’s disease.

Questionário Virtual Para o Ensino de Probabilidade

As the concept of probability is fundamental to the individual formation due to its form of reasoning,to its applicability and to the professional field, we present a proposal that suggests, first, a problematization then the definition of the probability jargon. It follows that methodology, since the history occurs in this order: first the problems arise, then the concepts and definitions. So, we use the technology in two virtual and interactive quizzes to be solved by students, since playing has an important role during the constrution of the concepts and definitions, the student becomes easily closer to the whole subject.

Involvement of PI3-K pathway and β-catenin signaling in curcumin protecting against Aβ1-42-induced neurotoxicity

Alzheimer’s disease (AD) is the most prevalent form of dementia. New treatments to manage this complex illness will require full understanding of the pathophysiological mechanisms involved, which include amyloid β (Aβ)-induced toxicity. Substantial evidence indicates that curcumin has neuroprotective properties in AD; however, the molecular mechanisms involved in this process remain poorly understood. The aim of this study was investigate whether curcumin possesses a neuroprotective effect against Aβ-induced toxicity organotypic hippocampal cultures. Slices were exposed to Aβ, curcumin and/or LY294002, an inhibitor of phosphoinositide-3-kinase (PI3-K) pathway. Cell death was measured by propidium iodide uptake and some cell signaling pathways were investigated by Western blot assay. Moreover, we measured the synaptophysin expression, involved in the regulation of synaptic plasticity. Our results show that Aβ caused about 30% of cell damage in hippocampal slices, a significant increase when compared to controls cultures. The treatments with 5 and 10 μM of curcumin decreased the cell death significantly. The curcumin treatment prevented the decreased in synaptophysin expression after exposure to Aβ peptide. Aβ treatment increased the phosphorylated (Ser45) β-catenin and decreased βcatenin immunocontent, and the curcumin treatment prevented this β-catenin destabilization. Additionally, the curcumin neuroprotection was prevented by LY294002 and curcumin induced the phosphorylation/activation of Akt and the phosphorylation/inactivation of glycogen synthase kinase-3β (GSK-3β). These results reinforce the neuroprotective effect of curcumin and add some evidence that its mechanism may involve the PI3-K pathway and β-catenin signaling, a key transducer of the Wnt signaling pathway.