Methanolic Extract and Brominated Compound from the Brazilian Marine Sponge Aplysina fulva Are Neuroprotective and Modulate Inflammatory Profile of Microglia.

Neurodegenerative diseases involve neuroinflammation and a loss of neurons, leading to disability and death. Hence, the research into new therapies has been focused on the modulation of the inflammatory response mainly by microglia/macrophages. The extracts and metabolites of marine sponges have been presented as anti-inflammatory. This study evaluated the toxicity of an extract and purified compound from the Brazilian marine sponge Aplysina fulva as well as its neuroprotection against inflammatory damage associated with the modulation of microglia response. PC12 neuronal cells and neonatal rat microglia were treated with the methanolic extract of A. fulva (AF-MeOH, 0.1-200 µg/mL) or with its purified dimethyl ketal of 3,5-dibromoverongiaquinol (AF-H1, 0.1-100 µM). Cytotoxicity was determined by MTT tetrazolium, Trypan blue, and propidium iodide; microglia were also treated with the conditioned medium (CM) from PC12 cells in different conditions. The microglia phenotype was determined by the expression of Iba-1 and CD68. AF-MeOH and AF-H1 were not toxic to PC12 or the microglia. Inflammatory damage with Escherichia coli lipopolysaccharide (LPS, 5 µg/mL) was not observed in the PC12 cells treated with AF-MeOH (1-10 µg/mL) or AF-H1 (1-10 µM). Microglia subjected to the CM from PC12 cells treated with LPS and AF-MeOH or AF-H1 showed the control phenotype-like (multipolar, low-CD68), highlighting the anti-neuroinflammatory and neuroprotective effect of components of this marine sponge.

Effect of the Flavonoid Rutin on the Modulation of the Myenteric Plexuses in an Experimental Model of Parkinson's Disease.

Recent discoveries have shown that enteric glial cells play an important role in different neurodegenerative disorders, such as Parkinson's disease (PD), which is characterized by motor dysfunctions caused by the progressive loss of dopaminergic neurons in the substance nigra pars compacta and non-motor symptoms including gastrointestinal dysfunction. In this study, we investigated the modulatory effects of the flavonoid rutin on the behavior and myenteric plexuses in a PD animal model and the response of enteric glia. Adult male Wistar rats were submitted to stereotaxic injection with 6-hydroxydopamine or saline, and they were untreated or treated with rutin (10 mg/kg) for 14 days. The ileum was collected to analyze tissue reactivity and immunohistochemistry for neurons (HuC/HuD) and enteric glial cells (S100ß) in the myenteric plexuses. Behavioral tests demonstrated that treatment with rutin improved the motor capacity of parkinsonian animals and improved intestinal transit without interfering with the cell population; rutin treatment modulated the reactivity of the ileal musculature through muscarinic activation, reducing relaxation through the signaling pathway of nitric oxide donors, and increased the longitudinal contractility of the colon musculature in parkinsonian animals. Rutin revealed modulatory activities on the myenteric plexus, bringing relevant answers regarding the effect of the flavonoid in this system and the potential application of PD adjuvant treatment.

The Phytochemical Agathisflavone Modulates miR146a and miR155 in Activated Microglia Involving STAT3 Signaling.

MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the ß-amyloid peptide (Aß, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that ß-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-ß, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aß, as well as inflammatory cytokines IL1-ß, IL-6, and NOS2. In cells stimulated with Aß, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD.

Neuroprotective Effect of Flavonoid Agathisflavone in the Ex Vivo Cerebellar Slice Neonatal Ischemia.

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 µM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10+ oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.

Aminochrome Induces Neuroinflammation and Dopaminergic Neuronal Loss: A New Preclinical Model to Find Anti-inflammatory and Neuroprotective Drugs for Parkinson's Disease.

Studies have suggested aminochrome as an endogenous neurotoxin responsible for the dopaminergic neuron degeneration in Parkinson's disease (PD). However, neuroinflammation, an important alteration in PD pathogenesis, has been strictly induced in vitro by aminochrome. The aim of this study was to characterize the neuroinflammation induced in vivo by aminochrome. Wistar rats (male, 250-270 g) received a unilateral single dose by stereotaxic injection of saline into three sites in the striatum in the negative control group, or 32 nmol 6-hydroxydopamine (6-OHDA) in the positive control, or 6 nmol aminochrome. After 14 days, histological and molecular analyses were performed. We observed by immunofluorescence that aminochrome, as well as 6-OHDA, induced an increase in the number of Iba-1+ cells and in the number of activated (Iba-1+/ CD68+) microglia. An increase in the number of S100b+ cells and in the GFAP expression were also evidenced in the striatum and the SNpc of animals from aminochrome and positive control group. Dopaminergic neuronal loss was marked by reduction of TH+ cells and confirmed with reduction in the number of Nissl-stained neurons in the SNpc of rats from aminochrome and positive control groups. In addition, we observed by qPCR that aminocrhome induced an increase in the levels of IL-1ß, TNF-α, NLRP3, CCL5 and CCR2 mRNA in the SNpc. This work provides the first evidence of microgliosis, astrogliosis and neuroinflammation induced by aminochrome in an in vivo model. Since aminochrome is an endogenous molecule derived from dopamine oxidation present in the targeted neurons in PD, these results reinforce the potential of aminochrome as a useful preclinical model to find anti-inflammatory and neuroprotective drugs for PD. Aminochrome induced dopaminergic neuronal loss, microglial activation, astroglial activation and neuroinflammation marked by an increase in NLRP3, IL1ß, TNF-α, CCL2, CCL5 and CCR2.

Structural Design, Synthesis and Antioxidant, Antileishmania, Anti-Inflammatory and Anticancer Activities of a Novel Quercetin Acetylated Derivative.

Quercetin (Q) is a bioflavonoid with biological potential; however, poor solubility in water, extensive enzymatic metabolism and a reduced bioavailability limit its biopharmacological use. The aim of this study was to perform structural modification in Q by acetylation, thus, obtaining the quercetin pentaacetate (Q5) analogue, in order to investigate the biological potentials (antioxidant, antileishmania, anti-inflammatory and cytotoxicity activities) in cell cultures. Q5 was characterized by FTIR, 1H and 13C NMR spectra. The antioxidant potential was evaluated against the radical ABTS•+. The anti-inflammatory potential was evaluated by measuring the pro-inflammatory cytokine tumor necrosis factor (TNF) and the production of nitric oxide (NO) in peritoneal macrophages from BALB/c mice. Cytotoxicity tests were performed using the AlamarBlue method in cancer cells HepG2 (human hepatocarcinoma), HL-60 (promyelocytic leukemia) and MCR-5 (healthy human lung fibroblasts) as well as the MTT method for C6 cell cultures (rat glioma). Q and Q5 showed antioxidant activity of 29% and 18%, respectively, which is justified by the replacement of hydroxyls by acetyl groups. Q and Q5 showed concentration-dependent reductions in NO and TNF production (p < 0.05); Q and Q5 showed higher activity at concentrations > 40µM when compared to dexamethasone (20 µM). For the HL-60 lineage, Q5 demonstrated selectivity, inducing death in cancer cells, when compared to the healthy cell line MRC-5 (IC50 > 80 µM). Finally, the cytotoxic superiority of Q5 was verified (IC50 = 11 µM), which, at 50 µM for 24 h, induced changes in the morphology of C6 glioma cells characterized by a round body shape (not yet reported in the literature). The analogue Q5 had potential biological effects and may be promising for further investigations against other cell cultures, particularly neural ones.

Design, synthesis and cytotoxicity of the antitumor agent 1-azabicycles for chemoresistant glioblastoma cells.

Twelve multi-functional pyrrolizidinones, indolizidinones and pyrroliazepinones were prepared from formal aza-[3 + 2] and aza-[3 + 3] cycloadditions of five- to seven-membered heterocyclic enaminones as diverse ambident electrophiles. The antitumor activity of these alkaloid-like compounds was investigated through an initial screening performed on human glioblastoma multiform (GBM) cell lines (GL-15, U251), on murine glioma cells line (C6) and on normal glial cells. Of the compounds tested, the new pyrrolo[1,2a]azepinone, [ethyl (3-oxo-1,2-diphenyl-6,7,8,9-tetrahydro-3H-pyrrolo[1,2a]azepin-9a(5H)-yl)acetate] or (Compound-13) exhibited selective cytotoxic effects on GBM-temozolomide resistant cells. Compound-13 exerted dose-dependent cytotoxic activity by promoting arrest of cells in the G0/G1 phase of the cell cycle in the first 24 h. The apoptotic effect observed was in a time-dependent manner. Anti-migratory effect promoted by the treatment with compound-13 was also observed. Moreover, healthy mixed glial cell cultures from rat brain exhibited no cytotoxicity effect upon exposure to compound-13. Thus, the present study paves the way for the use of compound-13 as novel antitumor scaffold candidate for glioma cell therapy.

The flavonoid rutin and its aglycone quercetin modulate the microglia inflammatory profile improving antiglioma activity.

Microglia cells are the immune effector in the Central Nervous System (CNS). However, studies have showed that they contribute more to glioma progression than to its elimination. Rutin and its aglycone quercetin are flavonoids present in many fruits as well as plants and have been demonstrated to bear anti-inflammatory, antioxidant and antitumor properties also to human glioblastoma cell lines. Previous studies also demonstrated that rutin, isolated from the Brazilian plant Dimorphandra mollis Bent., presents immunomodulatory effect on astrocytes and microglia. In this study, we investigate the antitumor and immunomodulatory properties of rutin and its aglycone quercetin on the viability of glioma cells alone and under direct and indirect interaction with microglia. Flavonoid treatment of rat C6 glioma cells induced inhibition of proliferation and migration, and also induced microglia chemotaxis that was associated to the up regulation of tumor necrosis factor (TNF) and the down regulation of Interleukin 10 (IL-10) at protein and mRNA expression levels, regulation of mRNA expression for chemokines CCL2, CCL5 and CX3CL1, and Heparin Binding Growth Factor (HDGF), Insulin-like growth factor (IGF) and Glial cell-derived neurotrophic factor (GDNF) growth factors. Treatment of human U251 and TG1 glioblastoma cells with both flavonoids also modulated negatively the expression of mRNA for IL-6 and IL-10 and positively the expression of mRNA for TNF characterizing changes to the immune regulatory profile. Treatment of microglia and C6 cells either in co-cultures or during indirect interaction, via conditioned media from glioma cells treated with flavonoids or via conditioned media from microglia treated with flavonoids reduced proliferation and migration of glioma cells. It also directed microglia towards an inflammatory profile with increased expression of mRNA for IL-1ß, IL-6, IL-18 and decreased expression of mRNA for nitric oxide synthase 2 (NOS2) and prostaglandin-endoperoxide synthase 2 (PTGS2), arginase and transforming growth factor beta (TGF-ß), as well as Insulin-like growth factor (IGF). Treatment of U251 cells with flavonoids also reduced tumorigenesis when the cells were xenotransplanted in rat brains, and directed microglia and also astrocytes in the microenvironment of tumor cell implantation as well as in the brain parenchyma to a not favorable molecular inflammatory profile to the glioma growth, as observed in cultures. Together these results demonstrate that the flavonoid rutin and its aglycone quercetin present antiglioma effects related to the property of modulating the microglial inflammatory profile and may be considered for molecular and preclinical studies as adjuvant molecules for treatment of gliomas.

The flavonoid agathisflavone modulates the microglial neuroinflammatory response and enhances remyelination.

Myelin loss is the hallmark of the demyelinating disease multiple sclerosis (MS) and plays a significant role in multiple neurodegenerative diseases. A common factor in all neuropathologies is the central role of microglia, the intrinsic immune cells of the central nervous system (CNS). Microglia are activated in pathology and can have both pro- and anti-inflammatory functions. Here, we examined the effects of the flavonoid agathisflavone on microglia and remyelination in the cerebellar slice model following lysolecithin induced demyelination. Notably, agathisflavone enhances remyelination and alters microglial activation state, as determined by their morphology and cytokine profile. Furthermore, these effects of agathisflavone on remyelination and microglial activation were inhibited by blockade of estrogen receptor α. Thus, our results identify agathisflavone as a novel compound that may act via ER to regulate microglial activation and enhance remyelination and repair.

Amburana cearensis: Pharmacological and Neuroprotective Effects of Its Compounds.

Amburana cearensis A.C. Smith is an endemic tree from Northeastern Brazil used in folk medicine as teas, decocts and syrups for the treatment of various respiratory and inflammatory diseases, since therapeutic properties have been attributed to compounds from its stem bark and seeds. Numerous pharmacological properties of semi-purified extracts and isolated compounds from A. cearensis have been described in several biological systems, ranging from antimicrobial to anti-inflammatory effects. Some of these activities are attributed to coumarins and phenolic compounds, the major compounds present in A. cearensis seed extracts. Multiple lines of research demonstrate these compounds reduce oxidative stress, inflammation and neuronal death induced by glutamate excitotoxicity, events central to most neuropathologies, including Alzheimer's disease (AD) and Parkinson's Disease (PD). This review focuses on the botanical aspects, folk medicine use, biological effects and pharmacological activities of A. cearensis compounds and their potential as novel non-toxic drugs for the treatment of neurodegenerative diseases.

Alkene lactones from Persea fulva (Lauraceae): Evaluation of their effects on tumor cell growth in vitro and molecular docking studies.

The new alkene lactone, (3E)-5,6-dihydro-5-(hydroxymethyl)-3-docdecylidenefuran-3(4H)-one (1), named majoranolide B, and three alkene lactones known as majorenolide (2), majoranolide (3) and majorynolide (4) were obtained from the aerial parts of Persea fulva (Lauraceae). The structures were elucidated in light of extensive spectroscopic analysis, including 1D, 2D NMR (1H, 13C, 1H-1H-COSY, HMBC and HSQC) and HR-ESI-MS. These compounds were screened for their in vitro antiproliferative activity in rat C6 glioma and astrocyte cells using MTT assay and in silico by molecular docking against targets that play a central role in controlling glioma cell cycle progression. Majoranolide (3) is the most active compound with IC50 6.69 µM against C6 glioma cells, followed by the compounds 1 (IC50 9.06 µM), 2 (IC50 12.04 µM) and 4 (IC50 41.90 µM). The alkene lactones 1-3 exhibited lower toxicity in non-tumor cells when compared to glioma cells. Molecular docking results showed that majoranolide establishes hydrogen bonds with all targets through its α,ß-unsaturated-γ-lactone moiety, whereas the long-chain alkyl group binds by means of several hydrophobic bonds. In the present study, it can be concluded from the anti-proliferative activity of isolates against C6 glioma cells that lactone constituents from P. fulva could have a great potential for the control of C6 glioma cells.

In vitro ovicidal and larvicidal activities of some saponins and flavonoids against parasitic nematodes of goats.

This study assessed the anthelmintic activity of plant-derived compounds against gastrointestinal nematodes of goats using the egg hatch and larval motility assays. The compounds tested were saponins (digitonin and aescin) and their respective sapogenins (aglycones), hecogenin acetate and flavonoids (catechin, hesperidin, isocordoin and a mixture of isocordoin and cordoin). Additionally, cytotoxicity of active substances was analysed on Vero cell through 3-4,5-dimethylthiazol-2-yl,2,5diphenyltetrazolium bromide (MTT) and propidium iodide (PI) tests. Significant reduction on the egg hatching (P 90%). Nevertheless, higher cytotoxicity was observed in the MTT assay, with IC50 of 0.20 mg mL-1 (aescin) and 0.0074 mg mL-1 (digitonin). Aescin and digitonin have a pronounced in vitro anthelmintic effect and the glycone portion of these saponins plays an important role in this activity.

Research on the Scientific Evolution of the Flavonoid Agathisflavone.

PURPOSE: Flavonoids are a group of secondary metabolites of the polyphenols class present in several plant species. Among them, the biflavonoid agathisflavone is of interest since it bears several biological effects that include: antiviral, antitumoral, antiprotozoal and neurogenic actions. In this sense, this study aims to use the important tool of scientific prospecting to assess the level of research development concerning the flavonoid agathisflavone. METHODS: The experimental design was carried out through strategic reach with keywords on the PubMed (National Center for Biotechnology Information - NCBI) and Science Direct platforms. The articles were compiled and exported to Microsoft Office Excel 2007, where they were analyzed, stored and distributed in charts organized as to different countries, year of publication of scientific articles and journals RESULTS: The prospective research resulted in the identification of 81 scientific productions, published in several journals, submitted by different countries, in several areas of medical domain and in different years of publication over the last 50 years (1965 - 2018). It was also possible to investigate the advances in the study of agathisflavone for the development of new therapeutics. CONCLUSION: Although agathisflavone has been known in the literature since at least 1969, only 23 of the eligible articles found evaluated its possible therapeutic effects. The demonstrated biological activities of agathisflavone range from antiprotozoal to neurogenesis and neuroprotection, however, the molecule needs to be better studied at the in vivo and human level.

Flavonoids modulate the proliferation of Neospora caninum in glial cell primary cultures.

Neospora caninum (Apicomplexa; Sarcocystidae) is a protozoan that causes abortion in cattle, horses, sheep, and dogs as well as neurological and dermatological diseases in dogs. In the central nervous system of dogs infected with N. caninum, cysts were detected that exhibited gliosis and meningitis. Flavonoids are polyphenolic compounds that exhibit antibacterial, antiparasitic, antifungal, and antiviral properties. In this study, we investigated the effects of flavonoids in a well-established in vitro model of N. caninum infection in glial cell cultures. Glial cells were treated individually with 10 different flavonoids, and a subset of cultures was also infected with the NC-1 strain of N. caninum. All of the flavonoids tested induced an increase in the metabolism of glial cells and many of them increased nitrite levels in cultures infected with NC-1 compared to controls and uninfected cultures. Among the flavonoids tested, 3',4'-dihydroxyflavone, 3',4',5,7-tetrahydroxyflavone (luteolin), and 3,3',4',5,6-pentahydroxyflavone (quercetin), also inhibited parasitophorous vacuole formation. Taken together, our findings show that flavonoids modulate glial cell responses, increase NO secretion, and interfere with N. caninum infection and proliferation.

In vitro anti-parasitic effect of the alkaloids harmaline and piperine on Toxoplasma gondii.

Toxoplasma gondii is a coccidian protozoan of zoonotic importance that causes toxoplasmosis. Although the current treatments for toxoplasmosis may be associated with adverse effects and limited efficacy for different biological forms of the parasite, evidence suggests that alkaloid molecules such as harmaline and piperine exhibit antiparasitic effects against protozoa parasites. This investigation aimed to evaluate the in vitro effect of harmaline and piperine against T. gondii tachyzoites in infected Vero cell cultures. After 24 hours of host cell infection, the cultures were treated with harmaline or piperine (0.49 to 15.63 µg/mL). Negative and positive controls were RPMI/DMSO (0.1%) and sulfadiazine (200 µg/mL). Harmaline significantly reduced parasite multiplication by 20% compared to the negative control, while piperine decreased between 55.56% and 88.89% in a dose-dependent manner. According to an intracellular parasite proportion scale, it was observed that the Vero cells with low or moderate parasitic proliferation were more prevalent after the alkaloid treatment. The study demonstrated that the alkaloids had antiparasitic effects on T. gondii, with piperine being the most effective. Additional studies must be carried out to clarify other aspects of the action of the alkaloids on parasites.

Flavonoid Rutin Presented Anti-Glioblastoma Activity Related to the Modulation of Onco miRNA-125b Expression and STAT3 Signaling and Impact on Microglia Inflammatory Profile.

Glioblastoma (GBM) is the most aggressive and treatment-resistant brain tumor. In the GBM microenvironment, interaction with microglia is associated with the dysregulation of cytokines, chemokines, and miRNAs, contributing to angiogenesis, proliferation, anti-apoptosis, and chemoresistance. The flavonoid rutin can inhibit glioma cell growth associated with microglial activation and production of pro-inflammatory mediators by mechanisms that are still poorly understood. The present study investigated the effect of rutin on viability, regulation of miRNA-125b, and the STAT3 expression in GBM cells, as well as the effects on the modulation of the inflammatory profile and STAT3 expression in microglia during indirect interaction with GBM cells. Human GL15-GBM cells and human C20 microglia were treated or not with rutin for 24 h. Rutin (30-50 µM) significantly reduced the viability of GL15 cells; however, it did not affect the viability of microglia. Rutin (30 µM) significantly reduced the expression of miRNA-125b in the cells and secretome and STAT3 expression. Microglia submitted to the conditioned medium from GBM cells treated with rutin showed reactive morphology associated with reduced expression of IL-6, TNF, and STAT3. These results reiterate the anti-glioma effects of the flavonoid, which may also modulate microglia towards a more responsive anti-tumor phenotype, constituting a promising molecule for adjuvant therapy to GBM.

Differential Interactions of Flavonoids with the Aryl Hydrocarbon Receptor In Silico and Their Impact on Receptor Activity In Vitro.

The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR's activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (-13.14 to -15.31), while agathisflavone showed low scores (-0.57 and -5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin's newly described antagonistic potential. It underscores the importance of understanding flavonoid's molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules.

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by resting tremor, bradykinesia, rigidity, and postural instability that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) is the primary neurotransmitter involved in this disease, but cholinergic imbalance has also been implicated. Current intervention in PD is focused on replenishing central DA, which provides remarkable temporary symptomatic relief but does not address neuronal loss and the progression of the disease. It has been well established that neuronal nicotinic cholinergic receptors (nAChRs) can regulate DA release and that nicotine itself may have neuroprotective effects. Recent studies identified nAChRs in nonneuronal cell types, including glial cells, where they may regulate inflammatory responses. Given the crucial role of neuroinflammation in dopaminergic degeneration and the involvement of microglia and astrocytes in this response, glial nAChRs may provide a novel therapeutic target in the prevention and/or treatment of PD. In this review, following a brief discussion of PD, we focus on the role of glial cells and, specifically, their nAChRs in PD pathology and/or treatment.

Impact of Plant-Derived Compounds on Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal illness characterized by progressive motor neuron degeneration. Conventional therapies for ALS are based on treatment of symptoms, and the disease remains incurable. Molecular mechanisms are unclear, but studies have been pointing to involvement of glia, neuroinflammation, oxidative stress, and glutamate excitotoxicity as a key factor. Nowadays, we have few treatments for this disease that only delays death, but also does not stop the neurodegenerative process. These treatments are based on glutamate blockage (riluzole), tyrosine kinase inhibition (masitinib), and antioxidant activity (edaravone). In the past few years, plant-derived compounds have been studied for neurodegenerative disorder therapies based on neuroprotection and glial cell response. In this review, we describe mechanisms of action of natural compounds associated with neuroprotective effects, and the possibilities for new therapeutic strategies in ALS.

The Flavonoid Agathisflavone Directs Brain Microglia/Macrophages to a Neuroprotective Anti-Inflammatory and Antioxidant State via Regulation of NLRP3 Inflammasome.

Agathisflavone, purified from Cenostigma pyramidale (Tul.) has been shown to be neuroprotective in in vitro models of glutamate-induced excitotoxicity and inflammatory damage. However, the potential role of microglial regulation by agathisflavone in these neuroprotective effects is unclear. Here we investigated the effects of agathisflavone in microglia submitted to inflammatory stimulus in view of elucidating mechanisms of neuroprotection. Microglia isolated from cortices of newborn Wistar rats were exposed to Escherichia coli lipopolysaccharide (LPS, 1 µg/mL) and treated or not with agathisflavone (1 µM). Neuronal PC12 cells were exposed to a conditioned medium from microglia (MCM) treated or not with agathisflavone. We observed that LPS induced microglia to assume an activated inflammatory state (increased CD68, more rounded/amoeboid phenotype). However, most microglia exposed to LPS and agathisflavone, presented an anti-inflammatory profile (increased CD206 and branched-phenotype), associated with the reduction in NO, GSH mRNA for NRLP3 inflammasome, IL1-ß, IL-6, IL-18, TNF, CCL5, and CCL2. Molecular docking also showed that agathisflavone bound at the NLRP3 NACTH inhibitory domain. Moreover, in PC12 cell cultures exposed to the MCM previously treated with the flavonoid most cells preserved neurites and increased expression of ß-tubulin III. Thus, these data reinforce the anti-inflammatory activity and the neuroprotective effect of agathisflavone, effects associated with the control of NLRP3 inflammasome, standing out it as a promising molecule for the treatment or prevention of neurodegenerative diseases.