Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease

The aim of this review is to summarize and critically discuss the complex role played by adenosine A_2A receptors (A_2ARs) in Huntington's disease (HD). Since A_2ARs are mainly localized on the neurons, which degenerate early in HD, and given their ability to stimulate glutamate outflow and inflammatory gliosis, it was hypothesized that they could be involved in the pathogenesis of HD, and that A_2AR antagonists could be neuroprotective. This was further sustained by the demonstration that A_2ARs and underlying signaling systems undergo profound changes in cellular and animal models of HD. More recently, however, the equation A_2A receptor blockade = neuroprotection has appeared too simplistic. First, it is now definitely clear that, besides mediating ‘bad’ responses (for example, stimulation of glutamate outflow and excessive glial activation), A_2ARs also promote ‘good’ responses (such as trophic and antinflammatory effects). This implies that A_2AR blockade results either in pro-toxic or neuroprotective effects according to the mechanisms involved in a given experimental model. Second, since HD is a chronically progressive disease, the multiple mechanisms involving A_2ARs may play different relative roles along the degenerative process. Such different mechanisms can be influenced by A_2AR activation or blockade in different ways, even leading to opposite outcomes depending on the time of agonist/antagonist administration. The number, and the complexity, of the possible scenarios is further increased by the influence of mutant Huntingtin on both the expression and functions of A_2ARs, and by the strikingly different effects mediated by A_2ARs expressed by different cell populations within the brain.     

Ageing and Toll-like receptor expression by innate immune cells in chronic human schistosomiasis

There has been no systematic study of the immune response of individuals aged over 60 years living in Schistosomiasis mansoni-endemic areas, although senescence is reportedly associated with susceptibility to infection and progressive decline in immune function. We have shown previously, in two endemic areas in Minas Gerais, Brazil, that the frequency of individuals aged over 60 years with chronic schistosomiasis is no longer negligible. Moreover, several elderly individuals who have always lived in these endemic areas stay protected from infection. An important question for studies of ageing and disease control in developing countries is which differences in the immunological profile of these negatively tested (non-infected) individuals can account for their resistance to either infection or reinfection. We show, in the present study, that non-infected (negative) elderly individuals develop innate immune mechanisms of protection that replace the age-associated decline in T cell function. Non-infected elderly individuals from endemic areas of schistosome infection present an increase in the frequency of the natural killer (NK) CD56(low) subset of NK cells expressing Toll-like receptors (TLR)-1, -2, -3 and -4 as determined by flow cytometry analysis. In addition, the proportion of dendritic cells expressing TLR-1 is elevated as well as the frequency of monocytes expressing TLR-1 and -4. These results suggest that TLR expression by cells of the innate immune system may be related to the negative status of infection in some elderly individuals who are constantly exposed to S. mansoni. Developing mechanisms of protection from infection may represent a biomarker for healthy ageing in this population.     

Influence of KIR gene diversity on the course of HSV-1 infection: resistance to the disease is associated with the absence of KIR2DL2 and KIR2DS2

Herpes simplex virus type 1 (HSV-1) causes lifelong latent infections in most humans. Periodical virus reactivations from latency in the neurons of sensitive ganglia lead to transport to mucocutaneous regions and productive replication, which results in recurrent inflammatory herpetic lesions or in asymptomatic virus shedding. The medical consequences of such lesions and the frequency of recurrences vary greatly in different subjects. Furthermore, many infected individuals never suffer manifestations of the disease, even when exposed to stimuli that trigger clinical recurrences in other humans. The origin of the variability in the clinical course of HSV-1 infection remains unexplained. Herpesviruses and other pathogens sabotage the expression of major histocompatibility complex class I molecules by infected cells, thus subverting T-cell-mediated immunity. Subversion of antigen presentation is counteracted by natural killer cells, which survey the human leukocyte antigen (HLA) expression by specific receptors. These include the killer cell immunoglobulin-like receptors (KIRs), which are encoded by a complex of extremely diverse and rapidly evolving genes. Here, we analyze the contribution of KIR gene diversity to the variable clinical course of HSV-1 infection by comparing the distribution of these genes in humans with clinical manifestations of the disease with that in asymptomatically infected donors. This study provides preliminary evidence that the receptors KIR2DL2 and KIR2DS2 predispose to symptomatic HSV-1 infection and favor the frequently recurring forms of the disease. Possible contribution of the 'HLA-C1' ligand to HSV-1 disease was not statistically supported. Because of an absolute genetic linkage between KIR2DL2 and KIR2DS2, we could not determine which receptor was primarily responsible for the observed association, but our results suggest that presence in the genome of KIR2DL2 and KIR2DS2 hinders an effective cellular response to HSV-1.     

Analysis of toll-like receptor-dependent production of proinflammatory cytokines <Emphasis Type="Italic">in vitro</Emphasis> by human peripheral blood mononuclears of donors and patients with primary immunodeficiency

The production of TNF-α and IFN-α cytokines by peripheral blood mononuclears in response to stimulation by TLR2/6, TLR4, TLR5, TLR9 ligands (zymosan, LPS, flagellin, and CpG-oligodeoxynucleotide, respectively) was studied in donors and patients with common variable immunodeficiency. Individual characteristics of TNF-α production by mononuclears were revealed in donors. Reduced stimulated production of TNF-α in response to stimulation with TLR4 and TLR5 ligands in vitro was detected in patients with common variable immunodeficiency. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 68–71, July, 2007     

Activation of k<Subscript>1</Subscript>-opioid receptor as a method for prevention of ischemic and reperfusion arrhythmias: Role of protein kinase C and K<Subscript>ATP</Subscript> channels

Intravenous pretreatment with κ-opioid receptor antagonist (−)-U-50,488 (1 mg/kg) improved heart resistance to the arrhythmogenic effect of coronary occlusion and reperfusion. Selective κ₁-opioid receptor antagonist norbinaltorphimine and nonselective blocker of peripheral opioid receptors methylnaloxone abolished this antiarrhythmic effect. Preliminary blockade of protein kinase C with chelerythrine or inhibition of ATP-dependent K⁺ channels (K_ATP channels) with glybenclamide abolished the antiarrhythmic effect of κ-opioid receptor activation. Selective inhibitor of sarcolemmal K_ATP channels did not modulate the κ-opioid receptor-mediated increase in cardiac electrical stability. Our results suggest that protein kinase C and mitochondrial K_ATP channels play an important role in the antiarrhythmic effect associated with activation of peripheral κ-opioid receptors. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 2, pp. 145–148, February, 2007     

Agonists of PPAR-α, PPAR-γ, and RXR inhibit the formation of foam cells from macrophages in mice with inflammation

We studied the effect of agonists of peroxisome proliferator-activated receptors α and γ and retinoid X receptors on the concentration and synthesis of lipids in macrophages of C57Bl/6 mice with inflammation induced by intraperitoneal injection of zymosan. We revealed a significant increase in [1-¹⁴C]oleate incorporation into cholesterol esters and triglycerides, increase in the content of free cholesterol, cholesterol esters, and triglycerides, and formation of oil red-stained lipid inclusions in peritoneal macrophages 24 h after administration of zymosan in a dose of 50 mg/kg. Treatment with agonists of retinoid X receptors and peroxisome proliferator-activated receptors α and γ 30 min before and 12 h after zymosan injection decreased the synthesis of triglycerides and cholesterol esters, reduced the content of free cholesterol, cholesterol esters, and triglycerides in macrophages, and prevented the formation of cytoplasmic lipid inclusions in macrophage-derived foam cells during inflammation. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 11, pp. 556–559, November, 2007     

Experimental study of the pharmacokinetics of a tryptophan-containing dipeptide GB-115

Pharmacokinetics of an original compound GB-115 (N-phenylhexanoylglycyltryptophan) synthesized on the basis of the structure of endogenous tetrapeptide cholecystokinin-4 was studied by means of high-performance liquid chromatography. Pharmacokinetic parameters were calculated after intravenous and peroral administration of GB-115. Our results indicate that this dipeptide is resistant to peptidases. The absolute bioavailability of GB-115 is 4.65%. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 9, pp. 285–287, September, 2007     

Control of IsAHP in mouse hippocampus CA1 pyramidal neurons by RyR3-mediated calcium-induced calcium release

In several neuronal preparations, the ryanodine-sensitive calcium store was reported to participate in the generation of slow afterhyperpolarization currents (IsAHP) involved in spike frequency adaptation. We show that calcium release from the ryanodine-sensitive calcium store is a major determinant of the triggering of IsAHP in mouse CA1 pyramidal neurons. Whole-cell patch clamp recordings in hippocampus slices show that the intracellular calcium stores depletion using an inhibitor of the endoplasmic reticulum Ca²⁺-ATPase (5 μM cyclopiazonic acid), as well as the specific blockade of ryanodine receptors (100 μM ryanodine) both reduced the IsAHP by about 70%. Immunohistology, using an anti-RyR3 specific antibody, indicates that RyR3 expression is particularly enriched in the CA1 apical dendrites (considered as the most important site for sAHP generation). We show that our anti-RyR3 antibody acts as a functional RyR3 antagonist and induced a reduction in IsAHP by about 70%. The additional ryanodine application (100 μ M) did not further affect IsAHP, thus excluding RyR2 in IsAHP activation. Our results argue in favor of a specialized function of RyR3 in CA1 pyramidal cells in triggering IsAHP due to their localization in the apical dendrite.     

Angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the increase in TGF-β1 in thyroid hormone-induced cardiac hypertrophy

Increased thyroid hormone (TH) levels are known to induce cardiac hypertrophy. Some studies have provided evidence for a functional link between angiotensin II (ANG II) and transforming growth factor β1 (TGF-β1) in the heart, both being able to also induce cardiac hypertrophy. However, the contribution of this growth factor activated directly by TH or indirectly by ANG II in cardiac hypertrophy development remains unknown. To analyze the possible role of TGF-β1 in cardiac hypertrophy induced by TH and also to evaluate if the TGF-β1 effect is mediated by ANG II receptors, we employed Wistar rats separated into control, hypothyroid (hypo) and hyperthyroid (T4 − 10) groups combined or not with ANG II receptor blockers (losartan or PD123319). Serum levels of T3 and T4, systolic pressure and heart rate confirmed the thyroid state of the groups. The T4 − 10 group presented a significant increase in cardiac TGF-β1 levels; however, TGF-β1 levels in the hypo group did not change in relation to the control. Inhibition of the increase in cardiac TGF-β1 levels was observed in the groups treated with T4 in association with losartan or PD123319 when compared to the T4 − 10 group. These results demonstrate for the first time the TH-modulated induction of cardiac TGF-β1 in cardiac hypertrophy, and that this effect is mediated by ANG II receptors.