Stimulation Of Microglial Cells Research Articles

Effect of Natural Plant Products on Alzheimer's Disease.

Plants and their extracts like ginger, garlic, Curcuma, Salvia, and Ginkgo are best known for their anti-oxidative and anti-inflammatory responses. These plants have shown their anti-Alzheimer's properties in various in vivo and in vitro studies. Their diverse phytochemicals play a protective role against amyloid-beta-induced neurotoxicity and improve cognitive and learning impairments. These plants have a wide range of bioactive compounds, including alkaloids, flavonoids, phenols, glycosides, terpenoids, coumarins, and saponins. These chemicals scavenge the free radicals, lower the amyloid burden, improve memory dysfunction, and inhibit acetylcholinesterase activity. Some of the clinical trials and animal-based studies suggested the protective role of these plants and their extract mentioned in the literature. The articles for this review were majorly searched from popular search engines, viz, Google Scholar, PubMed, and Scopus. Medicinal plants improve cognitive and memory impairments by inhibiting acetylcholinesterase activity and scavenging free oxygen species by activating superoxide dismutase, catalase, and GSH activity. The plant extracts reduce amyloid insult by inactivating the beta-site amyloid precursor protein cleaving enzyme (BACE). The inactivation of Caspase 3 and 9 reduces apoptosis. Furthermore, the stimulation of microglial cells and astrocyte reduce inflammation by lowering chemokines and interleukins. The medicinal plants help to reduce AD pathogenesis by controlling different pathways and could be used as a therapeutic agent against the symptoms.

Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.

The S1P2 receptor regulates blood-brain barrier integrity and leukocyte extravasation with implications for neurodegenerative disease

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid which modulates vascular integrity through its receptors, S1P1–S1P5. Notably, S1P2 has been shown to mediate the disruption of cerebrovascular integrity in vitro and in vivo. However, the mechanism underlying this process has not been fully elucidated. We evaluated the role of S1P2 in blood-brain barrier (BBB) disruption induced by lipopolysaccharide (LPS)-mediated systemic inflammation and found that BBB disruption and neutrophil infiltration were significantly attenuated in S1pr2−/− mice relative to S1pr2+/− littermates. This is concomitant with attenuation of LPS-induced transcriptional activation of IL-6 and downregulation of occludin. Furthermore, S1pr2−/− mice had significantly reduced expression of genes essential for neutrophil infiltration: Sele, Cxcl1, and Cxcl2. Conversely, pharmacological agonism of S1P2 induced transcriptional activation of E-selectin in vitro and in vivo. Although S1P2 does not appear to be required for activation of microglia, stimulation of microglial cells with the S1P2 potentiated the response of endothelial cells to LPS. These results demonstrate that S1P2 promotes LPS-induced neutrophil extravasation by inducing expression of endothelial adhesion molecule gene, Sele, and potentiating microglial inflammation of endothelial cells. It is likely that S1P2 is a mediator of cerebrovascular inflammation and represents a potential therapeutic target for neurodegenerative disease such as vascular cognitive impairment.

Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells

Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis of E. coli K1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing of E. coli K1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections.

Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells

BackgroundToll-Like receptors (TLRs) belong to the family of pattern-recognition receptors with a crucial function of recognising pathogen-associated molecular patterns (PAMPs). Cryptococcal meningitis is a potentially fatal disease with a high mortality and risk of neurological sequelae.MethodsWe studied the ability of microglial cells to increase the phagocytosis of cryptococci after stimulation with agonists of TLR1/2, TLR3, TLR4 and TLR9.ResultsStimulation of murine microglial cells with these TLR agonists for 24 h increased the phagocytosis of encapsulated Cryptococcus neoformans. Stimulation increased the release of TNF-α, CXCL1 (KC), IL-6, IL-10 and MIP-2, which indicated the activation of microglial cells. Unstimulated and TLR agonist-stimulated MyD88-deficient cells showed a reduced ability to phagocytose cryptococci compared to their wild-type counterpart. Intracellular killing of cryptococci was also increased in TLR-stimulated cells compared to unstimulated microglial cells.ConclusionOur observation suggests that stimulation of microglial cells by TLR agonists can increase the resistance of the brain against CNS infections caused by Cryptococcus neoformans. This may be of interest when an immunocompromised patient is unable to eliminate Cryptococcus neoformans despite antifungal therapy.

Evaluation of the pathogenesis of meningitis caused by Streptococcus suis sequence type 7 using the infection of BV2 microglial cells

Streptococcus suis is an important agent of swine and human meningitis. Among several sequence types (STs) characterized within the S. suis strain population, ST7 has emerged only in China and has been reported to be the cause of the human outbreak caused by S. suis in 2005. S. suis ST7 was shown to be derived from S. suis ST1 through a single-nucleotide change in the housekeeping gene thyA. The virulence potential of S. suis ST7 is reported to be higher than that of the worldwide-studied pathogenic S. suis ST1. The pathogenesis of ST1 infection has been partially elucidated, but information on the pathogenesis of ST7 infections remains scarce. To improve our understanding of the mechanisms involved in the development of meningitis caused by ST7, this study compared the microglial inflammatory response induced by ST1 and ST7 strains. The data showed that S. suis ST7 possessed a higher ability to induce pro-inflammatory cytokine production and to activate mitogen-activated protein kinase pathways and several transcription factors. The stimulation of microglial cells by S. suis increased the expression levels of the nucleotide oligomerization domain 2 (Nod2) gene. Finally, the results indicated that signal transducer and activator of transcription 3 (STAT-3) was involved in the development of meningitis induced by S. suis ST7 infection.

Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 and Streptococcus pneumoniae R6 by microglial cells

The ability of microglial cells to phagocytose bacteria after stimulation with the endocannabinoid palmitoylethanolamide (PEA) was studied in vitro. PEA increased the phagocytosis of unencapsulated Streptococcus pneumoniae R6 and encapsulated Escherichia coli K1 by murine microglial cells significantly after 30min of microglial stimulation. This suggested that stimulation of microglial cells by PEA can increase the resistance of the brain against CNS infections.

S-Methylisothiourea Induces Apoptosis of Herpes Simplex Virus-1-Infected Microglial Cells

Our study showed that S-methylisothiourea (SMT) had anti-inflammatory effects in treating herpes simplex encephalitis in mice, and SMT also induced apoptosis of herpes simplex virus (HSV-1)-infected microglial cells. Both animal and cell models were employed in this study. Both models included the following five groups: a normal control group, a virus group (HSV-1 infected), an SMT group (HSV-1-infected + SMT (0.1mg/10g)), a dexamethasone group (HSV-1 infected + dexamethasone (2μg/10g)), and an APS group (HSV-1-infected + APS (0.8mg/10g)). ELISA was used to measure tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10, and Greiss method was used for measuring nitric oxide (NO) secretion. HE staining was performed for detecting changes in mice brain. Flow cytometry assay for caspase-3, caspase-8, caspase-9, and caspase-12 expressions was also carried out to assess apoptosis. Expressions of TNF-α, IL-1β, and NO were significantly elevated after stimulation of microglial cells with HSV-1. Following SMT intervention, TNF-α, IL-1β, and NO levels were significantly decreased. The inflammatory changes in HSV-1-infected murine brain tissues were also reduced. SMT induction of apoptosis of HSV-stimulated microglia seemed to be through three pathways: the death receptor, mitochondrially gated, and endoplasmic reticulum. SMT can reduce HSV-induced inflammatory insult to the brain. Its mechanism of action is most probably due to the induction of microglial cell apoptosis.

Anti-inflammatory and anti-oxidant activity of anionic dendrimer–N-acetyl cysteine conjugates in activated microglial cells

Dendrimers are emerging as potential intracellular drug delivery vehicles. Understanding and improving the cellular efficacy of dendrimer–drug conjugates, can lead to significant in vivo benefits. This study explores efficacy of anionic polyamidoamine (PAMAM–COOH) dendrimer–N-acetyl cysteine (NAC) conjugates for applications in neuroinflammation. The anti-oxidative and anti-inflammatory effects of PAMAM–(COOH) 46–(NAC) 18 conjugate is evaluated on microglial cells in vitro. Cell entry and localization of PAMAM–(COOH) 62–(FITC) 2 conjugate in BV-2 microglial cells were assessed using flow cytometry and confocal microscopy. ELISA assays were used to evaluate markers of oxidative stress (ROS, NO) and inflammation (TNF-α) after stimulation of microglial cells with lipopolysaccharides (LPS), following treatment with increasing doses of free N-acetyl- l-cysteine (NAC) or PAMAM–(COOH) 46–(NAC) 18 conjugate containing an equivalent molar concentration of NAC. Flow cytometry and confocal microscopy demonstrated the PAMAM–(COOH) 62–(FITC) 2 conjugate entered BV-2 cells rapidly with significant increase in fluorescence within 15 min and localized mostly in the cytoplasm. PAMAM–(COOH) 46–(NAC) 18 conjugate was non-toxic, and significantly reduced ROS, NO and TNF-α release by activated microglial cells after 24 h and 72 h stimulation of LPS following 3 h pre-treatment when compared to the same concentration of free NAC ( P < 0.05 or P < 0.01). Anionic PAMAM dendrimer–NAC conjugate was synthesized with a glutathione sensitive linker for intracellular release. The non-toxic conjugate is a more effective anti-oxidant and anti-inflammatory agent when compared to free NAC in vitro. The conjugate showed significant efficacy even at the lowest dose (0.5 mM NAC), where the activity was comparable or better than that of free drug at 8 mM (16× higher dosage). The improved efficacy of the conjugate, when combined with the intrinsic neuroinflammation-targeting ability of the PAMAM dendrimers, may provide new opportunities for in vivo applications.

Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia

Despite the pivotal role of microglia in immune system of the brain, a growing body of evidence suggests that the excessive microglial activation provokes neuronal and glial damages, leading to neurodegenerative and neuroinflammatory disorders. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have recently received much attention for their suppressive effects on inflammation in the central nervous system. In the current study, we have examined the statin-mediated inhibition of microglial function, especially that of chemokine production. Stimulation of microglial cells with interferon-β (IFN-β) resulted in the expression of CC chemokine ligand 5 (CCL5), a major chemoattractant of inflammatory cells. Microglial CCL5 response was synergistically potentiated by costimulation with IFN-β and tumor necrosis factor-α (TNF-α). The simvastatin treatment significantly diminished the microglial CCL5 expression induced by IFN-β alone or by IFN-β/TNF-α combination. In the presence of simvastatin, the IFN-β-induced activation of Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway was attenuated, although this compound had little or no effect on the TNF-α-evoked activation of nuclear factor κB and c-Jun N-terminal kinase pathways. In addition, chemical inhibitor of Jak-STAT signaling significantly diminished the IFN-β-induced expression of CCL5 in microglia. Taken together, these results suggest that simvastatin suppresses the IFN-β-induced expression of CCL5 via down-regulation of Jak-STAT signaling pathway.

HIV-infection of the central nervous system: the tightrope walk of innate immunity

Infection of the central nervous system (CNS) by HIV is a frequent and sometimes very early event in the course of HIV pathogenesis. Possible consequences are diverse symptoms of neurological dysfunction, but also the establishment of a lifelong latent viral reservoir in the brain. Whereas in the periphery innate and adaptive immunity are equal partners, the blood–brain barrier (BBB) with its restricted access of peripheral immune effectors shifts this balance in favour of the local innate immunity. Four main elements of cerebral innate immunity are discussed in the present article, including two cell types with immunological functions and two soluble immune systems: (1) the stimulation of microglial cells as the predominant brain-resident immune cell and the main local reservoir for the virus; (2) the reaction of astrocytes in response to viral infection; (3) the activation of the local complement system as important soluble immune cascade; and (4) the role of chemokines and cytokines which help to conduct and cross-link the interplay between the different immune elements. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. A dual role of these components with both harmful and protective effects further enhances the complexity of the mutual interactions.

Adhesion proteins on human microglial cells and modulation of their expression by IL1α and TNFα

Expression of adhesion proteins on human microglial cells was studied by immunocytochemistry. Both microglial cells and peripheral blood monocytes expressed beta 2 integrins and molecules of the immunoglobulin superfamily at similar levels whereas the expression of the beta 1 integrins (alpha 2-VLA (very late antigen), alpha 4-VLA, alpha 5-VLA, alpha 6-VLA) was higher on microglial cells than on monocytes. Stimulation of microglial cells with interleukin-1 alpha and tumour necrosis factor-alpha, the main cytokines detected in HIV1-infected central nervous system (CNS), increased the microglial expression of alpha 1-VLA, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and beta 2-LFA-1 (leukocyte-function-associated molecule-1) but not of alpha L-LFA-1. Such an induction of adhesion molecules could facilitate penetration of HIV1-infected monocytes into brain parenchyma and their adhesion to CNS cells, and could maintain a chronic inflammation during human immunodeficiency virus-1 (HIV1) encephalopathy.