Pleiotrophin regulates microglia-mediated neuroinflammation.

BACKGROUND: Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved. METHODS: In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 µg/ml) and LPS (1.0 µg/ml) and assessed for the release of nitric oxide (NO). RESULTS: We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS. CONCLUSIONS: Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.

Vascular Dysfunction in Mother and Offspring During Preeclampsia: Contributions from Latin-American Countries.

Pregnancy is a physiologically stressful condition that generates a series of functional adaptations by the cardiovascular system. The impact of pregnancy on this system persists from conception beyond birth. Recent evidence suggests that vascular changes associated with pregnancy complications, such as preeclampsia, affect the function of the maternal and offspring vascular systems, after delivery and into adult life. Since the vascular system contributes to systemic homeostasis, defective development or function of blood vessels predisposes both mother and infant to future risk for chronic disease. These alterations in later life range from fertility problems to alterations in the central nervous system or immune system, among others. It is important to note that rates of morbi-mortality due to pregnancy complications including preeclampsia, as well as cardiovascular diseases, have a higher incidence in Latin-American countries than in more developed countries. Nonetheless, there is a lack both in the amount and impact of research conducted in Latin America. An impact, although smaller, can be seen when research in vascular disorders related to problems during pregnancy is analyzed. Therefore, in this review, information about preeclampsia and endothelial dysfunction generated from research groups based in Latin-American countries will be highlighted. We relate the need, as present in many other countries in the world, for increased effective regional and international collaboration to generate new data specific to our region on this topic.

Midkine Is a Novel Regulator of Amphetamine-Induced Striatal Gliosis and Cognitive Impairment: Evidence for a Stimulus-Dependent Regulation of Neuroinflammation by Midkine.

Midkine (MK) is a cytokine that modulates amphetamine-induced striatal astrogliosis, suggesting a possible role of MK in neuroinflammation induced by amphetamine. To test this hypothesis, we studied astrogliosis and microglial response induced by amphetamine (10 mg/kg i.p. four times, every 2 h) in different brain areas of MK-/- mice and wild type (WT) mice. We found that amphetamine-induced microgliosis and astrocytosis are enhanced in the striatum of MK-/- mice in a region-specific manner. Surprisingly, LPS-induced astrogliosis in the striatum was blocked in MK-/- mice. Since striatal neuroinflammation induced by amphetamine-type stimulants correlates with the cognitive deficits induced by these drugs, we also tested the long-term effects of periadolescent amphetamine treatment (3 mg/kg i.p. daily for 10 days) in a memory task in MK-/- and WT mice. Significant deficits in the Y-maze test were only observed in amphetamine-pretreated MK-/- mice. The data demonstrate for the first time that MK is a novel modulator of neuroinflammation depending on the inflammatory stimulus and the brain area considered. The data indicate that MK limits amphetamine-induced striatal neuroinflammation. In addition, our data demonstrate that periadolescent amphetamine treatment in mice results in transient disruption of learning and memory processes in absence of endogenous MK.

Pleiotrophin differentially regulates the rewarding and sedative effects of ethanol.

Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up-regulation of PTN mRNA and protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN(-/-) ) mice and in mice with cortex- and hippocampus-specific transgenic PTN over-expression (PTN-Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN(-/-) compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN-Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN-Tg mice, suggesting that up-regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.

Endogenous pleiotrophin and midkine regulate LPS-induced glial responses.

Pleiotrophin (PTN) and Midkine (MK) are two growth factors that modulate neuroinflammation. PTN overexpression in the brain prevents LPS-induced astrocytosis in mice but potentiates microglial activation. The modest astrocytic response caused by a low dose of LPS (0.5mg/kg) is blocked in the striatum of MK-/- mice whereas microglial response is unaffected. We have now tested the effects of an intermediate dose of LPS (7.5mg/kg) in glial response in PTN-/- and MK-/- mice. We found that LPS-induced astrocytosis is prevented in prefrontal cortex and striatum of both PTN-/- and MK-/- mice. Some of the morphological changes of microglia induced by LPS tended to increase in both genotypes, particularly in PTN-/- mice. Since we previously showed that PTN potentiates LPS-induced activation of BV2 microglial cells, we tested the activation of FYN kinase, a substrate of the PTN receptor RPTPß/ζ, and the subsequent ERK1/2 phosphorylation on LPS and PTN-treated BV2 cells. LPS effects on BV2 cells were not affected by the addition of PTN, suggesting that PTN does not recruit the FYN-MAP kinase signaling pathway in order to modulate LPS effects on microglial cells. Taking together, evidences demonstrate that regulation of astroglial responses to LPS administration are highly dependent on the levels of expression of PTN and MK. Further studies are needed to clarify the possible roles of endogenous expression of PTN and MK in LPS-induced microglial responses.

Obesity is independently associated with impaired quality of life in patients with rheumatoid arthritis.

Obesity is a modifiable major cause of morbidity and mortality in the general population, but little is known about the association of obesity and quality of life in patients with rheumatoid arthritis (RA). Thus, we set out a study to test the hypothesis that obesity is independently associated with lower quality of life in patients with RA. Three hundred and fifty nine patients with RA underwent an interview, physical exam, and all clinical charts were reviewed. Based on body mass index (BMI), patients were classified as normal (BMI < 25 kg/m(2)), overweight (BMI = 25-29.9 kg/m(2)), and obese (BMI > or = 30 kg/m(2)). Quality of life was quantified with the Medical Outcomes Study Short Form 36 (SF-36). Data obtained included demographic variables, extra-articular disease, comorbidities, presence of X-ray erosions, rheumatoid factor, and depression. The association between obesity and quality of life was examined with the use of multiple lineal regression models. One hundred and seventy-two patients (47.9%) had normal BMI, 126 (35.1%) were overweight, and 61 patients (17%) were obese. Obese patients had lower quality of life (30.8 +/- 18.1) than overweight patients (43.3 +/- 20.1) and patients with normal weight (43.8 +/- 22.2), P < 0.001. The association between obesity and impaired quality of life was confirmed with a linear regression model (Coef = -12.9, P < 0.001) and remained significant after adjustment for age, sex, disease activity, extra-articular disease, comorbidities, X-ray erosions, presence of rheumatoid factor, depression, education, and disease duration (Coef = -5.3, P = 0.039). In conclusion, obesity is independently associated with the impaired quality of life in patients with rheumatoid arthritis.

Short-term vitamin E treatment impairs reactive oxygen species signaling required for adipose tissue expansion, resulting in fatty liver and insulin resistance in obese mice.

OBJECTIVES: The use of antioxidant therapy in the treatment of oxidative stress-related diseases such as cardiovascular disease, diabetes or obesity remains controversial. Our aim is to demonstrate that antioxidant supplementation may promote negative effects if used before the establishment of oxidative stress due to a reduced ROS generation under physiological levels, in a mice model of obesity. METHODS: C57BL/6J mice were fed with a high-fat diet for 14 weeks, with (OE group) or without (O group) vitamin E supplementation. RESULTS: O mice developed a mild degree of obesity, which was not enough to induce metabolic alterations or oxidative stress. These animals exhibited a healthy expansion of retroperitoneal white adipose tissue (rpWAT) and the liver showed no signs of lipotoxicity. Interestingly, despite achieving a similar body weight, OE mice were insulin resistant. In the rpWAT they presented a reduced generation of ROS, even below physiological levels (C: 1651.0 ± 212.0; O: 3113 ± 284.7; OE: 917.6 ±104.4 RFU/mg protein. C vs OE p< 0.01). ROS decay may impair their action as second messengers, which could account for the reduced adipocyte differentiation, lipid transport and adipogenesis compared to the O group. Together, these processes limited the expansion of this fat pad and as a consequence, lipid flux shifted towards the liver, causing steatosis and hepatomegaly, which may contribute to the marked insulin resistance. CONCLUSIONS: This study provides in vivo evidence for the role of ROS as second messengers in adipogenesis, lipid metabolism and insulin signaling. Reducing ROS generation below physiological levels when the oxidative process has not yet been established may be the cause of the controversial results obtained by antioxidant therapy.

Genetic inactivation of midkine modulates behavioural responses to ethanol possibly by enhancing GABA(A) receptor sensitivity to GABA(A) acting drugs.

Midkine (MK) is a cytokine with important functions in dopaminergic neurons that is found upregulated in the prefrontal cortex of alcoholics. We have studied the behavioural effects of ethanol in MK genetically deficient (MK-/-) and wild type (MK+/+) mice. A low dose of ethanol (1.0g/kg), unable to cause conditioned place preference (CPP) in MK+/+ mice, induced a significant CPP in MK-/- mice, suggesting that MK prevents the rewarding effects of low doses of ethanol. However, this difference between genotypes is lost when a higher, rewarding, dose of ethanol (2.0g/kg) is used. Accordingly, the anxiolytic effects of 1.0mg/kg diazepam, other GABA(A) acting drug, were significantly enhanced in MK-/- mice compared to MK+/+ mice; however, 2.0mg/kg diazepam caused increased anxiolytic effects in MK+/+ mice. In addition, MK-/- mice showed a significant delayed recovery from ethanol (2.0g/kg)-induced ataxia whereas the sedative effects induced by ethanol (3.6g/kg), tested in a loss of righting reflex paradigm, were found to be similar in MK-/- and MK+/+ mice. The data indicate that MK differentially regulates the behavioural responses to ethanol. The results suggest that differences in the sensitivity of GABA(A) receptors to GABA(A) acting drugs caused by genetic inactivation of MK could underlie the different behavioural responses to ethanol in MK-/- mice. Overall, these results suggest that MK may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of MK signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.