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Microglia are the resident macrophages in the central nervous system (CNS) and play essential roles in neuronal homeostasis and neuroinflammatory pathologies. Recently, microglia have been shown to contribute decisively to neuropathologic processes after ischemic stroke. Furthermore, natural compounds have been reported to attenuate inflammation and pathologies associated with neuroinflammation. Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) is a phytoalkaloid with known anti-inflammatory effects in cells. In present study, the authors confirmed middle cerebral artery occlusion (MCAO) injury triggers the activation of microglia in brain tissue, and investigated whether tryptanthrin influences the function of mouse murine BV2 microglia under LPS-induced inflammatory conditions in vitro. It was found tryptanthrin protected BV2 microglia cells against LPS-induced inflammation and inhibited the induction of M1 phenotype microglia under inflammatory conditions. In addition, tryptanthrin reduced the production of pro-inflammatory cytokines in BV2 microglia cells via nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling and NF-ΚB signaling. The authors suggest that tryptanthrin might alleviate the progress of neuropathologies by controlling microglial functions under neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Dopamine replacement with levodopa (Ɩ-DOPA) represents the mainstay of Parkinson's disease (PD) therapy. Nevertheless, this well established therapeutic intervention loses efficacy with the progression of the disease and patients develop invalidating side effects, known in their complex as Ɩ-DOPA-induced dyskinesia (LID). Unfortunately, existing therapies fail to prevent LID and very few drugs are available to lessen its severity, thus representing a major clinical problem in PD treatment. D2-like receptor (D2R) agonists are a powerful clinical option as an alternative to Ɩ-DOPA, especially in the early stages of the disease, being associated to a reduced risk of dyskinesia development. D2R agonists also find considerable application in the advanced stages of PD, in conjunction with Ɩ-DOPA, which is used in this context at lower dosages, to delay the appearance and the extent of the motor complications. In advanced stages of PD, D2R agonists are often effective in delaying the appearance and the extent of motor complications. Despite the great attention paid to the family of D2R agonists, the main reasons underlying the reduced risk of dyskinesia have not yet been fully characterized. Here we show that the striatal NMDA/AMPA receptor ratio and the AMPA receptor subunit composition are altered in experimental parkinsonism in rats. Surprisingly, while Ɩ-DOPA fails to restore these critical synaptic alterations, chronic treatment with pramipexole is associated not only with a reduced risk of dyskinesia development but is also able to rebalance, in a dose-dependent fashion, the physiological synaptic parameters, thus providing new insights into the mechanisms of dyskinesia. [ABSTRACT FROM AUTHOR]

Inflammation significantly impacts the progression of Huntington's disease (HD) and the mutant HTT protein determines a pro-inflammatory activation of microglia. Mesenchymal stem/stromal cells (MSC) from the amniotic membrane (hAMSC), and their conditioned medium (CM-hAMSC), have been shown to possess protective effects in vitro and in vivo in animal models of immune-based disorders and of traumatic brain injury, which have been shown to be mediated by their immunomodulatory properties. In this study, in the R6/2 mouse model for HD we demonstrate that mice treated with CM-hAMSC display less severe signs of neurological dysfunction than saline-treated ones. CM-hAMSC treatment significantly delayed the development of the hind paw clasping response during tail suspension, reduced deficits in rotarod performance, and decreased locomotor activity in an open field test. The effects of CM-hAMSC on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal atrophy and the formation of striatal neuronal intranuclear inclusions. In addition, while no significant increase was found in the expression of BDNF levels after CM-hAMSC treatment, a significant decrease of microglia activation and inducible nitric oxide synthase levels were observed. These results support the concept that CM-hAMSC could act by modulating inflammatory cells, and more specifically microglia., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Cognitive impairment is common in multiple sclerosis (MS). Unfortunately, the synaptic and molecular mechanisms underlying MS-associated cognitive dysfunction are largely unknown. We explored the presence and the underlying mechanism of cognitive and synaptic hippocampal dysfunction during the remission phase of experimental MS. Experiments were performed in a chronic-relapsing experimental autoimmune encephalomyelitis (EAE) model of MS, after the resolution of motor deficits. Immunohistochemistry and patch-clamp recordings were performed in the CA1 hippocampal area. The hole-board was utilized as cognitive/behavioural test. In the remission phase of experimental MS, hippocampal microglial cells showed signs of activation, CA1 hippocampal synapses presented an impaired long-term potentiation (LTP) and an alteration of spatial tests became evident. The activation of hippocampal microglia mediated synaptic and cognitive/behavioural alterations during EAE. Specifically, LTP blockade was found to be caused by the reactive oxygen species (ROS)-producing enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We suggest that in the remission phase of experimental MS microglia remains activated, causing synaptic dysfunctions mediated by NADPH oxidase. Inhibition of microglial activation and NADPH oxidase may represent a promising strategy to prevent neuroplasticity impairment associated with active neuro-inflammation, with the aim to improve cognition and counteract MS disease progression.

17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson's disease.