A Proline Derivative-Enriched Fraction from Sideroxylon obtusifolium Protects the Hippocampus from Intracerebroventricular Pilocarpine-Induced Injury Associated with Status Epilepticus in Mice.

The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle per os, po) and NMP-treated groups (Pilo 300 µg/1 µL icv, followed by 100 or 200 mg/kg po). The treatments started one day after the Pilo injection and continued for 15 days. The effects of NMP were assessed by characterizing the preservation of cognitive function in both the Y-maze and object recognition tests. The hippocampal cell viability was evaluated by Nissl staining. Additional markers of damage were studied-the glial fibrillary acidic protein (GFAP) and the ionized calcium-binding adaptor molecule 1 (Iba-1) expression using, respectively, immunofluorescence and western blot analyses. We also performed molecular docking experiments revealing that NMP binds to the γ-aminobutyric acid (GABA) transporter 1 (GAT1). GAT1 expression in the hippocampus was also characterized. Pilo induced cognitive deficits, cell damage, increased GFAP, Iba-1, and GAT1 expression in the hippocampus. These alterations were prevented, especially by the higher NMP dose. These data highlight NMP as a promising candidate for the protection of the hippocampus, as shown by the icv Pilo model.

(-)-α-bisabolol prevents neuronal damage and memory deficits through reduction of proinflammatory markers induced by permanent focal cerebral ischemia in mice.

The pathophysiology of ischemic stroke involves multiple events such as inflammation and oxidative stress which will lead to neuronal death and cognitive deficits. The (-)-α-bisabolol is a monocyclic sesquiterpene alcohol found in various plants and mainly in Matricaria chamomilla, which exerts antioxidant, anti-inflammatory, and anti-apoptotic activities. The aim of this work was to investigate the neuroprotective effects of (-)-α-bisabolol in mice underwent permanent occlusion of the middle cerebral artery (pMCAO). Animals were treated with (-)-α-bisabolol (50, 100 and 200 mg/kg/day, orally) or vehicle (3% tween 80) one day before and 1 h after pMCAO and the treatment continued once daily for the following five days. The treatment with (-)-α-bisabolol (100 and 200 mg/kg) significantly reduced the infarcted area and neurological deficits caused by pMCAO. (-)-α-bisabolol at the 200 mg/kg dose increased cell viability and decreased neuronal degeneration, as evaluated by cresyl violet and Fluoro-Jade C stainings, respectively. (-)-α-bisabolol also increased the locomotor activity which was reduced by cerebral ischemia and improved pMCAO-induced working, spatial, object recognition, and aversive memories deficits. (-)-α-bisabolol (200 mg/kg) significantly prevented the increase of myeloperoxidase (MPO) activity, TNF-α immunoreactivity in the temporal cortex, and the increase of iNOS both in the temporal cortex and in the striatum. (-)-α-bisabolol treatment also prevented astrogliosis in these areas. These data showed that (-)-α-bisabolol provides neuroprotective action probably due to its anti-inflammatory activity, although other mechanisms cannot be discarded.

Effect of the signaling lymphocytic activation molecule (SLAM) in the modulation of T cells in immune response to Leishmania braziliensis in vitro / Efeito da molécula de sinalização para ativação linfocítica (SLAM) na modulação de células T na resposta imune à Leishmania braziliensis in vitro

Introduction: Signaling lymphocyte activation molecule (SLAM) is a self-ligand receptor on the surface of activated T- and B-lymphocytes, macrophages, and DC. Studies have shown PBMC from healthy individuals exposed to Leishmania differ in IFN-γ production. Objective: We investigated the role of SLAM signaling pathway in PMBC from high (HP) and low (LP) IFN-γ producers exposed to L. braziliensis in vitro. Methods: PBMC from 43 healthy individuals were cultured with or without antigen, α-SLAM, rIL-12 and rIFN-γ. The cytokines production was evaluated by ELISA, and SLAM expression by flow cytometry. Results: L. braziliensis associated with rIFN-γ or rIL-12 reduced early SLAM but did not modify this response later in HP. α-SLAM did not alter CD3+SLAM+ expression, and not affected IFN-γ and IL-13 production, in both groups, but increased significantly IL-10 in HP. Leishmania associated with α-SLAM and rIL-12 increased IFN-γ in LP, as well as IL-13 in HP. LP group presented low IFN-γ and IL-13 production, and low SLAM expression. Conclusion: Collectively, these findings suggest that when PBMC from healthy individuals are sensitized with L. braziliensis in vitro, SLAM acts in modulating Th1 response in HP individuals and induces a condition of immunosuppression in LP individuals. (AU)

Introdução: A molécula de sinalização para ativação linfocítica (SLAM) é um receptor autoligante na superfície de linfócitos T e B ativados, macrófagos e DC. Estudos têm mostrado que PBMC de indivíduos saudáveis expostos à Leishmania diferem na produção de IFN-γ. Objetivo: Nós investigamos o papel da via de sinalização de SLAM em PMBC de altos produtores de IFN-γ (AP) e baixos (BP) expostos à L. braziliensis in vitro. Métodos: PBMC de 43 indivíduos saudáveis foram cultivadas com ou sem antígeno, α-SLAM, rIL-12 e rIFN-γ. Foi avaliada a produção de citocinas por ELISA e expressão de SLAM por citometria de fluxo. Resultados: L. braziliensis associado a rIFN-γ ou rIL-12 reduziu a expressão inicial de SLAM, mas não modificou esta resposta mais tarde em AP. α-SLAM não alterou a expressão de CD3+SLAM+, e não afetou a produção de IFN-γ e IL-13, em ambos os grupos, mas aumentou significativamente IL-10 em AP. Leishmania associada a α-SLAM e rIL-12 aumentou IFN-γ em BP, assim como IL-13 em AP. BP apresentaram baixa produção de IFN-γ e IL-13 e baixa expressão de SLAM. Conclusão: Coletivamente, esses achados sugerem que quando PBMC de indivíduos saudáveis são sensibilizados por L. braziliensis in vitro, SLAM atua na modulação da resposta Th1 em indivíduos AP e induz uma condição de imunossupressão em indivíduos BP. (AU)

Neuroinflammatory response to experimental stroke is inhibited by eriodictyol.

BACKGROUND: Cerebral ischemia is a common disease and one of the most common causes of death and disability worldwide. The lack of glucose and oxygen in neuronal tissue leads to a series of inflammatory events, culminating in neuronal death. Eriodictyol is a flavonoid isolated from the Chinese herb Dracocephalum rupestre that has been proven to have anti-inflammatory properties. HYPOTHESIS/PURPOSE: Thus, the present study was designed to explore whether eriodictyol has neuroprotective effects against the neuronal damage, motor and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice. STUDY DESIGN: Animals were orally treated with eriodictyol (1, 2 and 4mg/kg) or vehicle (saline) 30min before pMCAO, 2h after, and then once daily for the following five days. METHODS: The parameters studied were neuronal viability, brain infarcted area; sensorimotor deficits; exploratory activity; working and aversive memory; myeloperoxidase (MPO) activity; TNFα, iNOS and GFAP immunoreactivity. RESULTS: The treatment with eriodictyol prevented neuronal death, reduced infarct area and improved neurological and memory deficits induced by brain ischemia. The increase of MPO activity and TNF-α, iNOS and GFAP expression were also reduced by eriodictyol treatment. CONCLUSION: These findings demonstrate that eriodictyol exhibit promising neuroprotection effects against the permanent focal ischemia cerebral injury in the mice experimental model and the underlying mechanisms might be mediated through inhibition of neuroinflammation.