HIV Neuropathogenesis: a Tight Rope Walk of Innate Immunity

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of these protective immune responses, however, can be a double-edged sword. As protective immune mediators, cytokines have the ability to function in networks and co-operate with other host/viral mediators to tip the balance from a protective to toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the key immune cell types of the CNS with their respective soluble immune mediators: (1) cooperative interaction of IFN-γ with the host/virus factor (platelet-derived host factor (PDGF)/viral Tat) in the induction of neurotoxic chemokine CXCL10 by macrophages, (2) response of astrocytes to viral infection, and (3) protective role of PDGF and MCP-1 in neuronal survival against HIV Tat toxicity. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. The ultimate outcome of HIV infection in the CNS will thus be dependent on the regulation of the net balance of cell-specific protective versus detrimental responses.     

Short Toxin-like Proteins Attack the Defense Line of Innate Immunity

ClanTox (classifier of animal toxins) was developed for identifying toxin-like candidates from complete proteomes. Searching mammalian proteomes for short toxin-like proteins (coined TOLIPs) revealed a number of overlooked secreted short proteins with an abundance of cysteines throughout their sequences. We applied bioinformatics and data-mining methods to infer the function of several top predicted candidates. We focused on cysteine-rich peptides that adopt the fold of the three-finger proteins (TFPs). We identified a cluster of duplicated genes that share a structural similarity with elapid neurotoxins, such as α-bungarotoxin. In the murine proteome, there are about 60 such proteins that belong to the Ly6/uPAR family. These proteins are secreted or anchored to the cell membrane. Ly6/uPAR proteins are associated with a rich repertoire of functions, including binding to receptors and adhesion. Ly6/uPAR proteins modulate cell signaling in the context of brain functions and cells of the innate immune system. We postulate that TOLIPs, as modulators of cell signaling, may be associated with pathologies and cellular imbalance. We show that proteins of the Ly6/uPAR family are associated with cancer diagnosis and malfunction of the immune system.     

Adrenergic and Dopaminergic Modulation of Immunity in Multiple Sclerosis: Teaching Old Drugs New Tricks?

Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS.     

丙酸氟替卡松对鼻黏膜上皮细胞表达的天然免疫分子的免疫调节作用

目的 检测丙酸氟替卡松对人鼻黏膜上皮细胞表达天然免疫分子的影响.方法 采用丙酸氟替卡松和/或聚肌胞苷酸( Polyinosinic:polycytidylic acid,Poly I∶C)、细菌脂多糖(Lipopolysaccharides,LPS)等刺激离体培养的鼻黏膜上皮细胞后,通过实时定量PCR检测Toll样受体...     

A Current Review of Cypermethrin-Induced Neurotoxicity and Nigrostriatal Dopaminergic Neurodegeneration

Cypermethrin, a class II pyrethroid pesticide, is used to control insects in the household and agricultural fields. Despite beneficial roles, its uncontrolled and repetitive applications lead to unintended effects in non-target organisms. Cypermethrin crosses the blood-brain barrier and induces neurotoxicity and motor deficits. Cypermethrin prolongs the opening of sodium channel, a major site of its action, leading to hyper-excitation of the central nervous system. In addition to sodium channel, cypermethrin modulates chloride, voltage-gated calcium and potassium channels, alters the activity of glutamate and acetylcholine receptors and adenosine triphosphatases and induces DNA damage and oxidative stress in the neuronal cells. Cypermethrin also modulates the level of neurotransmitters, including gamma-aminobutyric acid and dopamine. It is one of the most commonly used pesticides in neurotoxicology research not only because of its variable responses depending upon the doses, time and routes of exposure and strain, age, gender and species of animals used across multiple studies but also owing to its ability to induce the nigrostriatal dopaminergic neurodegeneration. This article describes the effect of acute, chronic, developmental and adulthood exposures to cypermethrin in experimental animals. The article sheds light on cypermethrin-induced changes in the central nervous system, including its contribution in the onset of specific features, which are associated with the nigrostriatal dopaminergic neurodegeneration. Resemblances and dissimilarities of cypermethrin-induced nigrostriatal dopaminergic neurodegeneration with sporadic and chemicals-induced disease models along with its advantages and pitfalls are also discussed.     

丙酸氟替卡松对鼻黏膜上皮细胞表达的天然免疫分子的免疫调节作用

目的检测丙酸氟替卡松对人鼻黏膜上皮细胞表达天然免疫分子的影响。方法 采用丙酸氟替卡松和/或聚肌胞苷酸(Polyinosinic:polycytidylic acid,Poly I:C)、细菌脂多糖(Lipopolysaccharides,LPS)等刺激离体培养的鼻黏膜上皮细胞后,通过实时定量PCR检测Toll样受体(Toll like receptor,TLR)的表达,采用酶联免疫吸附试验检测细胞培养上清中血清淀粉样蛋白A(Serum amyloidA,SAA)、骨桥蛋白(Osteopontin,OPN)等的表达水平。结果丙酸氟替卡松单独刺激能够增加鼻黏膜上皮细胞表达TLR-3 mRNA(7.5倍)和TLR-4 mRNA(4.5倍),Poly I:C单独刺激能够增加鼻黏膜上皮细胞表达TLR-3 mRNA 28.5倍,LPS单独刺激能够增加鼻黏膜上皮细胞表达TLR-4 mRNA 18.4倍,丙酸氟替卡松刺激后细胞培养上清中SAA和OPN水平也出现显著增加。丙酸氟替卡松和Poly I:C以及LPS对增加细胞培养上清中SAA和OPN水平具有协调效应。结论丙酸氟替卡松能够增强鼻黏膜上皮细胞的天然免疫反应。     

Role of the Mannose Receptor (CD206) in Innate Immunity to Ricin Toxin

The entry of ricin toxin into macrophages and certain other cell types in the spleen and liver results in toxin-induced inflammation, tissue damage and organ failure. It has been proposed that uptake of ricin into macrophages is facilitated by the mannose receptor (MR; CD206), a C-type lectin known to recognize the oligosaccharide side chains on ricin's A (RTA) and B (RTB) subunits. In this study, we confirmed that the MR does indeed promote ricin binding, uptake and killing of monocytes in vitro. To assess the role of MR in the pathogenesis of ricin in vivo, MR knockout (MR(-/-)) mice were challenged with the equivalent of 2.5× or 5× LD(50) of ricin by intraperitoneal injection. We found that MR(-/-) mice were significantly more susceptible to toxin-induced death than their age-matched, wild-type control counterparts. These data are consistent with a role for the MR in scavenging and degradation of ricin, not facilitating its uptake and toxicity in vivo.     

棘白菌素类药物对宿主固有免疫系统的调节机制

目的 对棘白菌素类抗真菌药物与机体固有免疫系统的协同作用机制进行探讨和综述。方法 通过查阅文献,综述了近年来国内外讨论棘白菌素类药物对宿主机体免疫系统影响的研究,并按照机制进行分类阐述。结果 棘白菌素类药物通过干扰β-1,3-葡聚糖的合成起到抗真菌的作用,同时通过对Dectin-1受体、Toll样受体及甘露糖结合凝集素等位点进行调控,激活宿主的固有免疫反应,从而达到直接或间接杀灭真菌的效果。结论 棘白菌素类药物与宿主的固有免疫系统的协同作用机制使其可以有效的治疗真菌侵袭性疾病,这种药-菌协同作用机制为寻找其他更加有效的药物提供了思路。     

Dopaminergic effects of lergotrile: Possible involvement of a metabolite

Intraperitoneal administration of lergotrile in rats with unilateral 6-hydroxy-dopamine lesions of substantia nigra (SNX) produced long lasting contralateral rotation whereas intrastriatal administration of lergotrile failed to cause a rotation response. In intact rats, lergotrile produced intense stereotyped behavior. Both the rotation and stereotypy produced by lergotrile were significantly antagonized by haloperidol or α-methyl-p-tyrosine (α-mpt). The production of stereotypy by lergotrile was also antagonized by SK&F 525-A, a microsomal enzyme inhibitor. These studies suggest that a metabolite(s) may be responsible for the dopaminergic effects observed after systemic administration of lergotrile.     

Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity,Attenuates Cognitive Deficits in APP/PS1 Mice

Journal of Neuroimmune Pharmacology - Neuroinflammation plays an early and prominent role in the pathology of Alzheimer’s disease (AD). Tumor necrosis factor-α-induced protein 8-like 2...     

Dopaminergic mediation of a behavioral effect of l-cathinone

Ten male rats were trained to discriminate between the stimulus properties of 0.6 mg/kg l-cathinone and saline in a two-lever food-motivated operant task. Once trained, rats showed a dose-dependent increase in discrimination over a dosage range of 0.15-1.2 mg/kg l-cathinone. Analysis of this dose-response relationship indicated an ED50 of 0.27 mg/kg. Pretreatment with 0.2 mg/kg of the specific dopamine blocking drug haloperidol increased this ED50 to 0.47 mg/kg and significantly decreased discriminative performance when co-administered with either 0.15, 0.3, or 0.6 mg/kg l-cathinone. Since the dose-effect curves for cathinone with and without haloperidol pre-treatment were parallel, it is suggested that l-cathinone, the active constituent in khat, produces its discriminative properties, in part, by mediation of dopaminergic neuronal systems.     

Dopaminergic system genes in ADHD: toward a biological hypothesis.

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.     

Dopaminergic activity of quipazine

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Administration of 1.0 mg/kg quipazine, a putative serotonin agonist, produced apomorphine-appropriate responding with a maximal effect occurring at 45 min post-injection. Pretreatment with either 2.0 mg/kg methysergide or 0.4 mg/kg haloperidol reduced quipazine-induced responding upon the apomorphine-appropriate lever to levels observed with methysergide or haloperidol administered alone. These results evidence a dopaminergic action for quipazine and suggest that central serotonergic and dopaminergic pathways may interact cooperatively to control behavior.     

Dopaminergic effects of buspirone,a novel anxiolytic agent

The novel anxiolytic drug buspirone raised striatal levels of the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) 1 hr after oral administration. This effect was dose-dependent with a peak at 60 min. No changes were observed in the levels of 3-methyxytyramine (3MT), the extraneuronal metabolite of dopamine. Noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were not affected. Buspirone displaced [³H]spiroperidol from striatal binding sites, with an ic₅₀ (1.8 × 10^?7 M), comparable to that of clozapine ($\text{ic}{}_{50}\text{= 1.4 × 10}{}^{\mathrm{?7}}\text{M}$) but considerably lower than that of haloperidol (4.7 × 10^?9 M). Buspirone was only a weak inhibitor of dopamine-stimulated adenyl cyclase. Buspirone was not active on the binding of trifluoperazine to calmodulin and did not modify calmodulin-induced activation of phosphodiesterase (PDE). Repeated administration of buspirone did not increase the number of DA receptors. These data show that, although buspirone has antidopaminergic activity, it can hardly be classified as a classic neuroleptic agent.     

Keeping a Critical Eye on the Science and the Regulation of Oral Drug Absorption: A Review

This review starts with an introduction on the theoretical aspects of biopharmaceutics and developments in this field from mid-1950s to late 1970s. It critically addresses issues related to fundamental processes in oral drug absorption such as the complex interplay between drugs and the gastrointestinal system. Special emphasis is placed on drug dissolution and permeability phenomena as well as on the mathematical modeling of oral drug absorption. The review ends with regulatory aspects of oral drug absorption focusing on bioequivalence studies and the US Food and Drug Administration and European Medicines Agency guidelines dealing with Biopharmaceutics Classification System and Biopharmaceutic Drug Disposition Classification System.     

Dopaminergic properties of nomifensine

Nomifensine and a proposed dihydroxy metabolite produced stimulation of motor behavior in mice with nomifensine being more potent. Weak cage-climbing behavior (stereotypy) was also produced. The stimulatory effects were greater in mice in which dopamine receptor sensitivity was increased by long-term haloperidol. Both of the analogs were potent inhibitors of dopamine and norepinephrine uptake in vitro with nomifensine approximately 3 times more potent than the metabolite. In contrast, the two analogs had weak affinity for the post-synaptic dopamine receptor (as measured by displacement of ligand binding in vitro) with dihydroxynomifensine approximately 6 times more potent than nomifensine. These results suggest that the behavioral effects of nomifensine are largely dependent on presynaptic catecholamine mechanisms but that weak direct dopamine agonist properties do exist, particularly in vivo where the drug may be metabolized to a more active form.