Importance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with impairment of cognition, memory deficits and behavioral abnormalities. Accumulation of amyloid beta (Aβ) is a characteristic hallmark of AD. Microglia express several GPCRs, which, upon activation by modulators, mediate microglial activation and polarization phenotype. This GPCR-mediated microglial activation has both protective and detrimental effects. Microglial GPCRs are involved in amyloid precursor protein (APP) cleavage and Aβ generation. In addition, microglial GPCRs are featured in the regulation of Aβ degradation and clearance through microglial phagocytosis and chemotaxis. Moreover, in response to Aβ binding on microglial Aβ receptors, they can trigger multiple inflammatory pathways. However, there is still a lack of insight into the mechanistic link between GPCR-mediated microglial activation and its pathological consequences in AD. Currently, the available drugs for the treatment of AD are mostly symptomatic and dominated by acetylcholinesterase inhibitors (AchEI). The selection of a specific microglial GPCR that is highly expressed in the AD brain and capable of modulating AD progression through Aβ generation, degradation and clearance will be a potential source of therapeutic intervention. Here, we have highlighted the expression and distribution of various GPCRs connected to microglial activation in the AD brain and their potential to serve as therapeutic targets of AD

Reactive Oxygen Species and Inhibitors of Inflammatory Enzymes, NADPH Oxidase, and iNOS in Experimental Models of Parkinson's Disease

Reactive oxygen species (ROSs) are emerging as important players in the etiology of neurodegenerative disorders including Parkinson's disease (PD). Out of several ROS-generating systems, the inflammatory enzymes nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inducible nitric oxide synthase (iNOS) were believed to play major roles. Mounting evidence suggests that activation of NADPH oxidase and the expression of iNOS are directly linked to the generation of highly reactive ROS which affects various cellular components and preferentially damage midbrain dopaminergic neurons in PD. Therefore, appropriate management or inhibition of ROS generated by these enzymes may represent a therapeutic target to reduce neuronal degeneration seen in PD. Here, we have summarized recently developed agents and patents claimed as inhibitors of NADPH oxidase and iNOS enzymes in experimental models of PD

Regulation of Toll-Like Receptor (TLR) Signaling Pathway by Polyphenols in the Treatment of Age-Linked Neurodegenerative Diseases: Focus on TLR4 Signaling

Neuronal dysfunction initiates several intracellular signaling cascades to release different proinflammatory cytokines and chemokines, as well as various reactive oxygen species. In addition to neurons, microglia, and astrocytes are also affected by this signaling cascade. This release can either be helpful, neutral or detrimental for cell survival. Toll-like receptors (TLRs) activate and signal their downstream pathway to activate NF-κB and pro-IL-1β, both of which are responsible for neuroinflammation and linked to the pathogenesis of different age-related neurological conditions. However, herein, recent aspects of polyphenols in the treatment of neurodegenerative diseases are assessed, with a focus on TLR regulation by polyphenols. Different polyphenol classes, including flavonoids, phenolic acids, phenolic alcohols, stilbenes, and lignans can potentially target TLR signaling in a distinct pathway. Further, some polyphenols can suppress overexpression of inflammatory mediators through TLR4/NF-κB/STAT signaling intervention, while others can reduce neuronal apoptosis via modulating the TLR4/MyD88/NF-κB-pathway in microglia/macrophages. Indeed, neurodegeneration etiology is complex and yet to be completely understood, it may be that targeting TLRs could reveal a number of molecular and pharmacological aspects related to neurodegenerative diseases. Thus, activating TLR signaling modulation via natural resources could provide new therapeutic potentiality in the treatment of neurodegeneration

Advances in Neuroprotective Ingredients of Medicinal Herbs by Using Cellular and Animal Models of Parkinson’s Disease

Parkinson’s disease (PD) is a multifactorial disorder, which is neuropathologically identified by age-dependent neurodegeneration of dopaminergic neurons in the substantia nigra. Development of symptomatic treatments has been partly successful for PD research, but there remain a number of inadequacies in therapeutic strategies for the disease. The pathogenesis of PD remains intricate, and the present anti-PD treatments appears to be clinically insufficient. Comprehensive research on discovery of novel drug candidates has demonstrated that natural products, such as medicinal herbs, plant extracts, and their secondary metabolites, have great potential as therapeutics with neuroprotective activity in PD. Recent preclinical studies suggest that a number of herbal medicines and their bioactive ingredients can be developed into optimum pharmaceuticals for treating PD. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. Here we focus on recent advances of the evidence-linked neuroprotective activity of bioactive ingredients of herbal origin in cellular and animal models of PD research

Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.The research was supported by the Republic of Korea (Government-wide R&D Fund project for infectious disease research (GFID), HG18C0084)

Whole-genome, transcriptome, and methylome analyses provide insights into the evolution of platycoside biosynthesis in Platycodon grandiflorus, a medicinal plant

Triterpenoid saponins (TSs) are common plant defense phytochemicals with potential pharmaceutical properties. Platycodon grandiflorus (Campanulaceae) has been traditionally used to treat bronchitis and asthma in East Asia. The oleanane-type TSs, platycosides, are a major component of the P. grandiflorus root extract. Recent studies show that platycosides exhibit anti-inflammatory, antiobesity, anticancer, antiviral, and antiallergy properties. However, the evolutionary history of platycoside biosynthesis genes remains unknown. In this study, we sequenced the genome of P. grandiflorus and investigated the genes involved in platycoside biosynthesis. The draft genome of P. grandiflorus is 680.1Mb long and contains 40,017 protein-coding genes. Genomic analysis revealed that the CYP716 family genes play a major role in platycoside oxidation. The CYP716 gene family of P. grandiflorus was much larger than that of other Asterid species. Orthologous gene annotation also revealed the expansion of beta -amyrin synthases (bASs) in P. grandiflorus, which was confirmed by tissue-specific gene expression. In these expanded gene families, we identified key genes showing preferential expression in roots and association with platycoside biosynthesis. In addition, whole-genome bisulfite sequencing showed that CYP716 and bAS genes are hypomethylated in P. grandiflorus, suggesting that epigenetic modification of these two gene families affects platycoside biosynthesis. Thus whole-genome, transcriptome, and methylome data of P. grandiflorus provide novel insights into the regulation of platycoside biosynthesis by CYP716 and bAS gene families

Role of C-Reactive Protein in the Development of Atherosclerosis in Diet-induced Lipidemia in Albino Rats

Purpose: Anethum graveolens Linn. (Umbelliferae, A. graveolens) is a widely used spice with a long history of traditional medicinal use for the treatment of various ailments. The present study examines the anti-stress and cognition-improving effects of A. graveolens extract in a rat model. Methods: Urinary vanillylmandelic acid (VMA) and ascorbic acid were estimated as biomarkers for evaluating antistress activity in rats. Conditioned avoidance response using Cook’s pole climbing apparatus in normal and scopolamine-induced amnestic rats was used to assess cognitive-improving activities. Thiobarbituric acid reactive substances (TBARS) assay was used to evaluate antioxidant activity. Results: Daily administration of A. graveolens at doses of 100, 200 and 300 mg/kg body weight 1 h prior to induction of stress inhibited stress-induced urinary biochemical changes in a dose-dependent manner without altering the levels in normal control groups. Changes in cognition (as determined by the acquisition), retention and recovery in rats were dose-dependent. The extract also produced significant lipid peroxidation inhibition in both rat liver and brain, compared to a reference standard antioxidant, ascorbic acid. Conclusion: The aqueous extract of A. graveolens exhibited significant anti-stress, antioxidant and memory enhancing activities. The study provides a scientific basis for the traditional use of the plant as a culinary spice in food

Anti-Stress and Anti-Amnesic Effects of Coriandrum sativum Linn (Umbelliferae) Extract – an Experimental Study in Rats

Purpose: Coriandrum sativum Linn. (Umbelliferae, C. sativum) is cultivated throughout the world for its use as spice and as a folk medicine. This study deals with the anti-stress and anti-amnestic properties of C. sativum extract in rats. Methods: Urinary levels of vanillylmandelic acid (VMA) and ascorbic acid were used to evaluate antistress activity in rats, while conditioned avoidance response test in normal and scopolamine-induced amnesic rats was used to evaluate anti-amnesic effects. C. sativum extract was also evaluated for its antioxidant activities by inhibition of lipid peroxidation in brain and liver homogenates of the rats. Results: Daily administration of C. sativum extract (100, 200 and 300 mg/kg body weight) 1 h prior to induction of stress significantly decreased the stress-induced urinary levels of VMA from 382.79 ± 10.70 to 350.66 ± 15.15, 291.21 ± 16.53 and 248.86 ± 13.56 μg/kg/24 h and increased the ascorbic acid excretion levels from 66.73 ± 9.25 to 69.99 ± 7.37, 105.28 ± 13.74 and 135.32 ± 12.54 μg/kg/24 h at 100, 200 and 300 mg/kg, respectively, in a dose-dependent fashion without affecting the normal levels in control groups. The amnesic deficits (acquisition, retention and recovery) induced by scopolamine (1mg/kg, i.p.) in rats was reversed by C. sativum dose dependently. The extract also inhibited lipid peroxidation in both rat liver and brain to a greater extent than the standard antioxidant, ascorbic acid. Conclusion: C. sativum may be useful remedy in the management of stress and stress related disorders on account of its multiple actions such as anti-stress, anti-amnestic and antioxidant effects

Neuroprotective Role of Atractylenolide-I in an In Vitro and In Vivo Model of Parkinson’s Disease

Parkinson’s disease (PD) is an age-related neurological disorder characterized by a loss of dopaminergic neurons within the midbrain. Neuroinflammation has been nominated as one of the key pathogenic features of PD. Recently, the inadequate pharmacotherapy and adverse effects of conventional drugs have spurred the development of unconventional medications in the treatment of PD. The purpose of this study is to investigate the anti-neuroinflammatory mechanisms of Atractylenolide-I (ATR-I) in in vivo and in vitro models of PD. Nitrite assay was measured via Griess reaction in lipopolysaccharide (LPS) stimulated BV-2 cells. mRNA and protein levels were determined by a reverse transcription-polymerase chain reaction (RT-PCR) and immunoblot analysis, respectively. Further, flow cytometry, immunocytochemistry, and immunohistochemistry were employed in BV-2 cells and MPTP-intoxicated C57BL6/J mice. Pre-treatment with ATR-I attenuated the inflammatory response in BV-2 cells by abating the nuclear translocation of nuclear factor-κB (NF-κB) and by inducing heme oxygenase-1 (HO-1). The intraperitoneal administration of ATR-I reversed MPTP-induced behavioral deficits, decreased microglial activation, and conferred protection to dopaminergic neurons in the mouse model of PD. Our experimental reports establish the involvement of multiple benevolent molecular events by ATR-I in MPTP-induced toxicity, which may aid in the development of ATR-I as a new therapeutic agent for the treatment of PD