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The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1-42 and in mice injected with Aβ 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions.

Blood-brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus Infection of HBMEC with B. abortus induced the secretion of IL-6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC, but to a greater extent. Although B. abortus-infected glial cells secreted IL-1β and TNF-α, activation of HBMEC was dependent on IL-1β because CS from B. abortus-infected astrocytes and microglia deficient in caspase-1 and apoptosis-associated speck-like protein containing a CARD failed to induce HBMEC activation. Consistently, treatment of CS with neutralizing anti-IL-1β inhibited HBMEC activation. Both absent in melanoma 2 and Nod-like receptor containing a pyrin domain 3 are partially required for caspase-1 activation and IL-1β secretion, suggesting that multiple apoptosis-associated speck-like protein containing CARD-dependent inflammasomes contribute to IL-1β-induced activation of the brain microvasculature. Inflammasome-mediated IL-1β secretion in glial cells depends on TLR2 and MyD88 adapter-like/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1β-dependent fashion, and the infiltration of neutrophils into the brain parenchyma upon intracranial injection of B. abortus was diminished in the absence of Nod-like receptor containing a pyrin domain 3 and absent in melanoma 2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to the activation of the blood-brain barrier in neurobrucellosis and IL-1β mediates this phenomenon., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Context: Pereskia aculeata Miller (Cactaceae) is a cactus distributed from south to northeast of Brazil, where its leaves are commonly used as a vegetable, in skin wound healing, and to treat inflammation., Objectives: The objective of this study was to perform the chemical characterization and to evaluate the antinociceptive activity of the hydromethanolic fraction obtained from the methanol extract of P. aculeata leaves., Materials and Methods: Chemical characterization was performed by UPLC-MS analysis. The antinociceptive activity was evaluated by the acetic acid-induced writhing, formalin, and tail-flick tests in mice, administering the single oral doses of 100, 200, and 300 mg/kg 1 h before each test., Results: Tryptamine, abrine, mescaline, hordenine, petunidin, di-tert-butylphenol isomers, and quercetin were identified. The antinociceptive activity was inversely proportional to the administered doses in the acetic acid test, as the dose of 100 mg/kg reduced by 78% the number of writhings, while the doses of 200 and 300 mg/kg reduced by 64% and 41%, respectively. In the formalin test, the dose of 300 mg/kg inhibited by 50% and 86% the licking paw time in the first and second phases, respectively, while the doses of 200 mg/kg (45% and 62%, respectively) and 100 mg/kg (15% and 48%, respectively) were less effective. The sample did not respond to the tail-flick test. Those results suggested a peripheral and central antinociception devoid of an opioid effect., Conclusion: Pereskia aculeata not only is a plant food with high nutritional value but also presents analgesic potential. It is the first time that this bioactivity is reported for this species.

Cecropia pachystachya is widely used in the traditional medicine as anti-inflammatory, antitusive, expectorant, antiasthmatic and hypoglycemic. It is also commercially available to treat skin cancer. To validate some of the popular uses of this species, its methanol leaves extract (CPM) was tested for anti-inflammatory, antinociceptive and cytotoxic effects. The anti-inflammatory activity was evaluated by croton oil-induced ear edema test. When used orally, the anti-inflammatory effect of CPM at 300 mg/kg was similar to that of indomethacin with 53% inhibition of the ear edema. Also, results on topical treatment were similar to that of dexamethasone with 83% inhibition of the edema. To evaluate the antinociceptive activity, acetic acid-induced writhing and formalin-induced pain tests were employed. CPM (100 and 300 mg/kg) reduced the number of writhing by 61% and 67%, respectively. In both doses, the activity was comparable to the reference drug, indomethacin. The oral administration of CPM was ineffective in the first phase of formalin test but exhibited great effects on the second phase decreasing the licking time by 85% at 300 mg/kg. The cytotoxic potential of CPM was also investigated against HL60, HL60.bcl2 and Jurkat tumor cell lines and showed an inhibition of more than 50% of cell proliferation. The flavones orientin and isoorientin were detected in CPM., (Copyright © 2012 John Wiley & Sons, Ltd.)