B2 receptor blockage prevents Aß-induced cognitive impairment by neuroinflammation inhibition.

BACKGROUND AND PURPOSE: Aß-induced neuronal toxicity and memory loss is thought to be dependent on neuroinflammation, an important event in Alzheimer's disease (AD). Previously, we demonstrated that the blockage of the kinin B2 receptor (B2R) protects against the memory deficits induced by amyloid ß (Aß) peptide in mice. In this study, we aimed to investigate the role of B2R on Aß-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations. EXPERIMENTAL APPROACH: The selective kinin B2R antagonist HOE 140 (50 pmol/site) was given by intracerebroventricular (i.c.v.) route to male Swiss mice 2 h prior the i.c.v. injection of Aß(1-40) (400 pmol/site) peptide. Animals were sacrificed, at specific time points after Aß(1-40) injection (6 h, 1 day or 8 days), and the brain was collected in order to perform immunohistochemical analysis. Different groups of animals were submitted to behavioral cognition tests on day 14 after Aß(1-40) administration. KEY RESULTS: In this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited Aß-induced neuroinflammation in mice. B2R antagonism reduced microglial activation and the levels of pro-inflammatory proteins, including COX-2, iNOS and nNOS. Notably, these phenomena were accompanied by an inhibition of MAPKs (JNK and p38) and transcription factors (c-Jun and p65/NF-κB) activation. Finally, the anti-inflammatory effects of B2R antagonism provided significant protection against Aß(1-40)-induced synaptic loss and cognitive impairment in mice. CONCLUSIONS AND IMPLICATIONS: Collectively, these results suggest that B2R activation may play a critical role in Aß-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection.

The antinociceptive effects of the tetracyclic triterpene euphol in inflammatory and neuropathic pain models: The potential role of PKCε.

Evidences suggest protein kinase C epsilon (PKCε) activation is involved in both inflammatory and neuropathic pains. We have previously shown that tetracyclic triterpene euphol produces antinociception in different models of persistent pain, an action associated with its anti-inflammatory properties. Among these properties are the cannabinoid system activation and different PKC isozymes modulation. Herein, we sought to explore the potential role of PKCε modulation on euphol antinociceptive effect, in inflammatory and neuropathic pain models, in rodents. Also, we investigated further mechanisms associated with euphol effects. Oral treatment with euphol (30 mg/kg) prevented the putative effect of PGE2-induced acute and persistent mechanical hypersensitivity in mice and rats, respectively. In the PGE2-induced acute mechanical hypersensitivity euphol promoted an inhibitory effect similar to a PKCε inhibitor peptide. Likewise, in rats it prevented the mechanical hypersensitivity induced by a PKCε activator. Conversely, euphol effectiveness was not observed in a cAMP/PKA-induced mechanical hypersensitivity in mice. Single (1h prior) or repeated (twice daily during 3 or 13 days) treatments with euphol ameliorated painful peripheral neuropathy induced by paclitaxel and also the mechanical hypersensitivity induced by B16F10 melanoma cells injection, in mice. Additionally, in both inflammatory and neuropathic pain models, euphol consistently prevented PKCε up-regulation, as well as, inhibited the up-regulation of PKCε-activated intracellular pathways; namely nuclear factor-κB (NF-κB), cyclic AMP response element binding protein (CREB) and cyclo-oxygenase-2 (COX-2). The present results suggest the antinociceptive effect on persistent pain caused by euphol is likely dependent on the inhibition of pro-inflammatory mediators modulated by PKCε.

Anxiolytic-like, stimulant and neuroprotective effects of Ilex paraguariensis extracts in mice.

Yerba-mate (Ilex paraguariensis St. Hil.) is the most used beverage in Latin America with approximately 426 thousand of tons consumed per year. Considering the broad use of this plant, we aimed to investigate the anxiety-like and stimulant activity of both the hydroethanolic (HE) and aqueous (AE) extracts from leaves of I. paraguariensis. Swiss mice were treated with I. paraguariensis HE or AE chronically or acutely, respectively, followed by evaluation in the elevated plus-maze (EPM; anxiety-like paradigm), open field (OF; locomotor activity) or the step-down avoidance task (memory assessment). Following behavioral protocols the brains were collected for evaluation of acetylcholinesterase (AChE) activity ex vivo. Chronic treatment with HE induced an anxiolytic-like effect and increased motor activity besides augmented AChE activity. Additionally, acute treatment with AE prevented the scopolamine-induced memory deficit in the step-down avoidance task. Overall, our results indicate the importance of the I. paraguariensis-induced CNS effects, since it is a widely used nutraceutical. We have reported anxiolytic, stimulant and neuroprotective effects for this plant species. These effects are potentially modulated by the cholinergic system as well as by caffeine.

The selective and competitive N-methyl-D-aspartate receptor antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid, prevents synaptic toxicity induced by amyloid-ß in mice.

The toxicity of amyloid ß (Aß) is highly associated with Alzheimer's disease (AD), which has a high incidence in elderly people worldwide. While the current treatment for moderate and severe AD includes blockage of the N-methyl-d-aspartate receptor (NMDAR), the molecular mechanisms of its effect are still poorly understood. Herein, we report that a single i.p. administration of the selective and competitive (NMDAR) antagonist LY235959 reduced Aß neurotoxicity by preventing the down-regulation of glial glutamate transporters (glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)), the decrease in glutamate uptake, and the production of reactive oxygen species (ROS) induced by Aß(1-40). Importantly, the blockage of NMDAR restored the Aß(1-40)-induced synaptic dysfunction and cognitive impairment. However, LY235959 failed to prevent the inflammatory response associated with Aß(1-40) treatment. Altogether, our data indicate that the acute administration of Aß promotes oxidative stress, a decrease in glutamate transporter expression, and neurotoxicity. Our results reinforce the idea that NMDAR plays a critical regulatory action in Aß toxicity and they provide further pre-clinical evidence for the potential role of the selective and competitive NMDAR antagonists in the treatment of AD.