Breaking Down Barriers: Easter Island's First Telestroke Thrombolysis Experience and Case Report.

Easter Island (Rapa Nui), Chile, is remote, located in the Polynesian Triangle in Oceania. The closest continental point is Chile, 3,512 km east. It has a population of 7,750 inhabitants, who are Chilean citizens, and receives more than 60,000 tourists a year. For this entire population, there is a medium complexity hospital without a neurology specialist. In 2019, local professionals were trained in a Telestroke program with remote clinical support conducted by neurologists located on mainland Chile. We present a 50-year-old native male, with unknown medical history, who suddenly presented right-half-body weakness and aphasia. He was evaluated via Telestroke consultation, and thrombolysis with tenecteplase was indicated. The patient improved rapidly and 45 min later the NIHSS score was 0 points. To our knowledge, this is the first reported case of Telestroke treatment in such a remote area, highlighting the importance of telemedicine to overcome geographical and technological stroke care barriers and to improve patients' outcome, no matter where they live.

Cervical Artery Dissections with and without stroke, risk factors and prognosis: a Chilean prospective cohort.

We aimed to characterize spontaneous cervical artery dissection (CeAD) patients with and without stroke and describe risk factors for cerebrovascular complications in a Chilean prospective cohort. METHODS: Consecutive CeAD patients admitted to a Chilean center confirmed by neuroimaging. Logistic regression was used. RESULTS: 168 patients were included, median follow-up time was 157 days. Stroke occurred in 49 (29.2%) cases, 4 (2%) patients died, all of whom had a stroke, and 10 (6%) presented CeAD recurrence. In univariate analyses, men (odds ratio [OR] 3.97, 95% confidence interval [CI] 1.97-8.00, P < 0.001), internal carotid artery CeAD (OR 2.82, 95% CI 1.38-5.78, P = 0.005) and vessel occlusion (OR 4.45, 95% CI 1.38-14.38, P = 0.035) increased stroke risk. Conversely, vertebral artery dissection (OR 0.35, 95% CI 0.16-0.74, P = 0.006) and longer symptom onset to admission (O-A) time (OR 0.79, 95% CI 0.70-0.90, P < 0.001) were associated to decreased stroke risk. After multivariate analysis, men (OR 2.88, 95% CI 1.32-6.27, P = 0.008) and O-A time (OR 0.80, 95% CI 0.69-0.92, P = 0.002) remained independently associated with stroke. CONCLUSION: CeAD presented commonly as a non-stroke entity, with favorable prognosis. Albeit to a higher frequency of CeAD in women, stroke occurred predominantly in men, who were admitted earlier.

Mesenchymal stem cells and IL-37: a powerful combination.

Mesenchymal stem cells (MSCs) are able to exert immunomodulatory and anti-inflammatory actions. Thanks to these properties, MSCs may be a promising alternative approach for the treatment of inflammatory disease. Important cytokines involved in inflammation are those included in the IL-1 family. Interleukin-37 (IL-37) is one of the member able to suppress both innate and adaptive immunity. Recently, it was found that MSCs and their derivatives can modulate IL-37, and MSCs expressing IL-37 seem to have an enhanced therapeutic efficacy.

Pyroelectric Effect Enables Simple and Rapid Evaluation of Biofilm Formation.

Biofilms are detrimental to human life and industrial processes due to potential infections, contaminations, and deterioration. Therefore, the evaluation of microbial capability to form biofilms is of fundamental importance for assessing how different environmental factors may affect their vitality. Nowadays, the approaches used for biofilm evaluation are still poor in reliability and rapidity and often provide contradictory results. Here, we present what we call biofilm electrostatic test (BET) as a simple, rapid, and highly reproducible tool for evaluating in vitro the ability of bacteria to form biofilms through electrostatic interaction with a pyroelectrified carrier. The results show how the BET is able to produce viable biofilms with a density 6-fold higher than that on the control, after just 2 h incubation. The BET could pave the way to a rapid standardization of the evaluation of bacterial resistance among biofilm-producing microorganisms. In fact, due to its simplicity and cost-effectiveness, it is well suited for a rapid and easy implementation in a microbiology laboratory.

Mesenchymal stem cell therapy in Parkinson's disease animal models.

Parkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, and as a consequence, by decreased dopamine levels in the striatum. Currently available therapies are not able to stop or reverse the progression of the disease. A novel therapeutic approach is based on cell therapy with stem cells, in order to replace degenerated neurons. Among stem cells, mesenchymal stem cells seemed the most promising thanks to their capacities to differentiate toward dopaminergic neurons and to release neurotrophic factors. Indeed, mesenchymal stem cells are able to produce different molecules with immunomodulatory, neuroprotective, angiogenic, chemotactic effects and that stimulate differentiation of resident stem cells. Mesenchymal stem cells were isolated for the first time from bone marrow, but can be collected also from adipose tissue, umbilical cord and other tissues. In this review, we focused our attention on mesenchymal stem cells derived from different sources and their application in Parkinson's disease animal models.

miR-2861 is involved in osteogenic commitment of human periodontal ligament stem cells grown onto 3D scaffold.

miR-2861 endorsing osteoblast differentiation through the overexpression of Runt-related transcription factor 2 (RUNX2) protein has been recently described. In this study we evaluated: the performance of living construct, composed by human Periodontal Ligament Stem Cells (hPDLSCs) and 3D scaffold (EXg), and the behaviour of miR-2861/RUNX2 expression pathway on the osteogenic commitment. Human PDLSCs were seeded with and without EXg scaffold and cultured under basal and osteogenic conditions. Morphological features, adhesiveness and differentiation abilities were analysed using scanning electron and confocal laser scanning microscopy. Time-course of RUNX2, ALP, OPN and miR-2861 were evaluated through RT-PCR analysis. Our results highlighted that the osteogenic differentiation was mostly obvious in the hPDLSCs, grown onto 3D scaffold in presence of osteoinductive medium. Moreover, the overexpression of miR-2861 and RUNX2 in hPDLSCs cultured in presence of EXg under osteogenic and standard conditions was demonstrated. In synthesis, the increased expression of miR-2861/RUNX2 provides new insights regarding miRNA signaling network in the presence of scaffold providing an additional method to evaluate the performance of biomaterial in bone regeneration.

Is ß-catenin neutralization cross-involved in the mechanisms mediated by natalizumab action?

Aberrant activation of Wnt/ß-catenin signaling pathway is commonly associated to cancer development. However, molecular mechanisms controlling Wnt/ß-catenin signaling pathway have been clarified only in part. Here, we show that ß-catenin is differently modulated in patients with multiple sclerosis (MS), displaying that different pharmacological treatments used for clinical MS management cause different nuclear expression levels of ß-catenin. Proteins extracted by peripheral blood mononuclear cells were assessed to evaluate the western blot expression levels of ß-catenin. Analyzing our results, we realized that ß-catenin is totally inhibited by Natalizumab and could have a role in MS management. This could offer new promising studies focused on the possible therapeutic control of ß-catenin translocation.

4(α-L-RHAMNOSYLOXY)-BENZYL ISOTHIOCYANATE, A BIOACTIVE PHYTOCHEMICAL THAT DEFENDS CEREBRAL TISSUE AND PREVENTS SEVERE DAMAGE INDUCED BY FOCAL ISCHEMIA/REPERFUSION.

Natural compounds are a promising source to treat several pathologies. The present study shows the in vivo pharmacological beneficial effect of 4(α-L-rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) obtained from glucomoringin (GMG; 4(α;-L-rhamnosyloxy)- benzyl glucosinolate), purified from Moringa oleifera seeds and hydrolyzed by myrosinase enzyme (β-thioglucoside glucohydrolase; E.C. 3.2.1.147). Cerebral ischemia/reperfusion (CIR) was induced in rats according to a classic model of carotid artery occlusion for a time period of 1 h and the reperfusion time was prolonged for seven days. GMG-ITC (3.5 mg GMG/ml plus 30 µl enzyme/rat; one ml i.p./rat) was administered 15 min after the beginning of ischemia and daily. The results clearly show that GMG-ITC possesses the capability to counteract the CIR-induced damage reducing TNF-alpha release, IκB-alpha cytosolic degradation/NFκBp65 nuclear translocation, as well as several other direct or indirect markers of inflammation (phospho-ERK p42/44, p-selectin) and oxidative stress (inducible Nitric Oxide Synthase (iNOS), MMP-9). GMG-ITC was shown to exert neuroprotective properties in preventing CIR-induced damage and the related cascade of inflammatory and oxidative mediators that exacerbate the progression of this disease in an experimental rat model. Our results clearly show that the tested phytochemical GMG-ITC possesses the capability to counteract CIR-induced damage.

Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis.

OBJECTIVE: Multiple Sclerosis (MS) is a global concern disease leading to a progressive, chronic and demyelinating condition, affecting the central nervous system (CNS). The pathology has an inflammatory/autoimmune origin; nevertheless, neuronal cell death mechanisms are not to be underestimated. The present study was designed to test the effects of intraperitoneal administration of cannabidiol (CBD), the main non-psychotropic cannabinoid of Cannabis sativa (CS), in an experimental model of MS. The aim is to evaluate the capability of CBD administration to thwart the cascade of mediators involved in MS-induced apoptosis. MATERIALS AND METHODS: Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunization with myelin oligodendroglial glycoprotein (MOG)35-55 peptide in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Disease signs were evaluated using a standardized scoring system. RESULTS: Immunohistochemical and Western blot assessments of key apoptotic markers reveal that CBD treatment is able to avoid Fas pathway activation, phospho-ERK p42/44 and cleaved caspase-3 triggering as well as alterations in mitochondrial permeability due to Bax/Bcl-2 unbalance. Moreover, CBD interferes with p53-p21 axis activation. As results, the absence of tissue apobody formation in spinal cord tissues of EAE-mice treated with CBD was established. Most of therapeutic properties of CS are currently ascribed to the psychotropic effects of phenylterpenoid delta-9 tetrahydrocannabinol. CONCLUSIONS: We have demonstrated that, alone, purified CBD possesses an anti-apoptotic power against the neurodegenerative processes underlying MS development. This represents an interesting new profile of CBD that could lead to its introduction in the clinical management of MS.

The protective effects of bioactive (RS)-glucoraphanin on the permeability of the mice blood-brain barrier following experimental autoimmune encephalomyelitis.

OBJECTIVES: Alterations in blood-brain barrier (BBB) permeability are due to the disruption of the Tight Junctions (TJs), large multiprotein complexes important for the maintenance of structural integrity and for permeability of the barrier. In this experimental study we evaluated the neuroprotective role of (RS)-glucoraphanin, a glucosinolate present in Brassicaceae, notably in Tuscan black kale, and bioactivated with myrosinase enzyme (bioactive RS-GRA) (10 mg/kg/d intraperitoneally), to prevent the dysfunction of BBB, in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). MATERIALS AND METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in mice. By western blot analysis of brain tissues, we evaluated expression and distribution of the TJ-associated proteins, claudin-1, -3, -5 and ZO-1. Additionally, in order to gain a better insight into the mechanisms of action of bioactive RS-GRA, we investigated Foxp3, ERK1/2 and caspase 3 expression associated both to inflammatory response as well as to apoptotic pathway. RESULTS: Our results demonstrated that treatment with bioactive RS-GRA counteracts the alteration of all these parameters and preserves TJ integrity through an antinflammatory and antiapoptotic activity during MS. CONCLUSIONS: Bioactive RS-GRA, could be a therapeutic perspective helpful in preventing dysfunction of the BBB.

Severe septal panniculitis in a multiple sclerosis patient treated with interferon-beta.

We report a memorable case of severe septal panniculitis in an MS patient following the subcutaneous administration of interferon beta-1b, manifesting as a painful, indurated, erythematous lesion of the thigh, which appeared at the injection site.

Foveolar cells phagocytose apoptotic neutrophils in chronic active Helicobacter pylori gastritis.

The recognition and removal of apoptotic inflammatory cells by tissue macrophages and non-professional phagocytes, in a process called efferocytosis, is required for resolution of inflammation and is actively anti-inflammatory. We have previously demonstrated phagocytosis of apoptotic neutrophils by tumor cells in human gastric carcinoma, but to date, there have been no studies investigating this process in chronic active Helicobacter pylori gastritis. Biopsy specimens from 28 subjects with or without H. pylori infection and active inflammation were examined and graded according to the updated Sydney system. Light microscopy, electron microscopy, and Terminal Deoxynucleotidyltransferase-Mediated UTP End Labeling staining were used to identify apoptosis. H. pylori infection was detected by histology and by molecular assay in 16 out of 28 cases. DNA from paraffin-embedded gastric biopsies was amplified using primers specific for cagA, for the cag "empty site" as well as for the s and m alleles of vacA. The more virulent cagA-positive strains were found in five out of nine patients with chronic active gastritis. The vacA s1/m1 and s2/m1 genotypes were more common in nine patients with chronic active gastritis, while the vacA s2/m2 genotype was more frequent in seven patients with chronic inactive gastritis. Apoptotic neutrophils were also detected within the cytoplasmic vacuoles of the foveolar cells of nine cases with chronic active gastritis. Transmission electron micrographs revealed further apoptotic neutrophils within spacious phagosomes of foveolar cells in a similar manner to those described in late-phase efferocytosis both in vivo and in vitro. These new observations expand the morphological spectrum of gastritis in patients infected with more virulent H. pylori strains, compatible with an anti-inflammatory role for the gastric epithelial cells in their removal of apoptotic neutrophils during active chronic gastritis.

The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice.

BACKGROUND AND PURPOSE: Pancreatitis represents a life-threatening inflammatory condition where leucocytes, cytokines and vascular endothelium contribute to the development of the inflammatory disease. The glucocorticoid-induced tumour necrosis factor (TNF) receptor family-related protein (GITR) is a costimulatory molecule for T lymphocytes, modulates innate and adaptive immune system and has been found to participate in a variety of immune responses and inflammatory processes. Our purpose was to verify whether inhibition of GITR triggering results in a better outcome in experimental pancreatitis. EXPERIMENTAL APPROACH: In male GITR knock-out (GITR(-/-)) and GITR(+/+) mice on Sv129 background, acute pancreatitis was induced after i.p. administration of cerulein. Other experimental groups of GITR(+/+) mice were also treated with different doses of Fc-GITR fusion protein (up to 6.25 µg·mouse⁻¹), given by implanted mini-osmotic pump. Clinical score and pro-inflammatory parameters were evaluated. KEY RESULTS: A less acute pancreatitis was found in GITR(-/-) mice than in GITR(+/+) mice, with marked differences in oedema, neutrophil infiltration, pancreatic dysfunction and injury. Co-treatment of GITR(+/+) mice with cerulein and Fc-GITR fusion protein (6.25 µg·mouse⁻¹) decreased the inflammatory response and tissue injury, compared with treatment with cerulein alone. Inhibition of GITR triggering was found to modulate activation of nuclear factor κB as well as the production of TNF-α, interleukin-1ß, inducible nitric oxide synthase, nitrotyrosine, poly-ADP-ribose, intercellular adhesion molecule-1 and P-selectin. CONCLUSIONS AND IMPLICATIONS: The GITR-GITR ligand system is crucial to the development of acute pancreatitis in mice. Our results also suggest that the Fc-GITR fusion protein could be useful in the treatment of acute pancreatitis.

Neuroprotective effects of almond skins in experimental spinal cord injury.

BACKGROUND & AIMS: Functional deficits following spinal cord injury (SCI) arise from both mechanical injury and from secondary tissue reactions involving inflammation. Natural almond skins (NS) were tested to evaluate anti-inflammatory effects on an animal model of SCI. METHODS: SCI was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. In the present study, to elucidate whether the protective effects of NS are related to the total phenolic content, we also investigated the effect of a blanched (BS) almond skins (industrially obtained by removing bran from the nut) in SCI. NS and BS (30 mg/kg respectively) were administered per os, 1 h and 6 h, after SCI. RESULTS: SCI in mice resulted in severe injury characterized by edema, tissue damage, production of inflammatory mediators and apoptosis (measured by Bax, Bcl-2 and Tunel assay). NS treatment, 1 and 6 h after SCI, reduced all parameters of inflammation as neutrophil infiltration, NF-κB activation, PAR formation, iNOS expression and apoptosis. However, treatment with BS did not exert any protective effect. CONCLUSIONS: Our results suggest that NS treatment, reducing the development of inflammation and tissue injury, may be useful in the treatment of SCI.

Selective adenosine A(2a) receptor agonists reduce the apoptosis in an experimental model of spinal cord trauma.

Adenosine is an important regulator of inflammatory mechanisms. Functional studies indicate a protective effect of adenosine A2A receptor agonists in spinal cord injury (SCI). The basic molecular mechanisms accounting for their protective effects from spinal cord injury have to be fully elucidated. The aim of this study is to evaluate in vivo protection by two selective A2A receptor agonists, 2-[p-(2-carboxyethyl)phenylethylamino]-50-ethylcarboxamidoadenosine (CGS 21680, 100 microg/kg) and (4-[3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydro-furan-2-yl)-9H-purin-2-yl)prop-2-ynyl] piperidine-1-carboxylic acid methyl ester) (ATL 313, 3 microg/kg) on the degree of apoptosis, in the experimental model of spinal cord injury. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord trauma in mice was characterised by edema, neutrophilic infiltration and apoptosis. ATL 313, administered by subcutaneously implanted osmotic minipumps after SCI, clearly reduced motor deficit for up to 19 days after operation. The selective A2A receptor agonists ATL 313 and CGS 21680 administered after SCI, reduced tissue damage, TUNEL staining, cytokine (TNF-alpha) expression, Bax, Fas-L and Caspase-3 expression, Annexin-V staining, while increasing Bcl-2 expression. In conclusion, our results demonstrate that treatment with adenosine A2A receptor agonists prevents the apoptotic process that is an important step of secondary damage after SCI.

Role for endothelial nitric oxide synthase in nitrite-induced protection against renal ischemia-reperfusion injury in mice.

Nitrite is protective against renal ischemia/reperfusion injury (IRI); an effect due to its reduction to nitric oxide (NO). In addition to other reductase pathways, endothelial NO synthase (eNOS) may also facilitate nitrite reduction in ischemic environments. We investigated the role of eNOS in sodium nitrite (60 microM, 10 ml/kg applied topically 1 min before reperfusion)-induced protection against renal IRI in C57/BL6 wild-type (WT) and eNOS knockout (eNOS KO) mice subjected to bilateral renal ischemia (30 min) and reperfusion (24h). Markers of renal dysfunction (plasma [creatinine] and [urea]), damage (tubular histology) and inflammation (cell recruitment) were elevated following IRI in WT mice; effects significantly reduced following nitrite treatment. Chemiluminescence analysis of cortical and medullary sections of the kidney demonstrated rapid (within 1 min) distribution of nitrite following application. Whilst IRI caused a significant (albeit substantially reduced compared to WT mice) elevation of markers of renal dysfunction and damage in eNOS KO mice, the beneficial effects of nitrite were absent or reduced, respectively. Moreover, nitrite treatment enhanced renal dysfunction in the form of increased plasma [creatinine] in eNOS KO mice. Confirmation of nitrite reductase activity of eNOS was provided by demonstration of nitrite (100 microM)-derived NO production by kidney homogenates of WT mice, that was significantly reduced by L-NMMA. L-NMMA was without effect using kidney homogenates of eNOS KO mice. These results support a role for eNOS in the pathways activated during renal IRI and also identify eNOS as a nitrite reductase in ischemic conditions; activity which in part underlies the protective effects of nitrite.

GW0742, a high affinity PPAR-ß/δ agonist reduces lung inflammation induced by bleomycin instillation in mice.

Peroxisome Proliferator-Activated Receptor ß/δ belongs to a family of ligand-activated transcription factors. Recent data have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target. Moreover, although its role in acute inflammation remains unclear, being the nuclear receptor PPAR ß/δ widely expressed in many tissues, including the vascular endothelium, we assume that the infiltration of PMNs into tissues, a prominent feature in inflammation, may also be related to PPAR ß/δ. Mice subjected to intratracheal instillation of bleomycin (BLEO, 1 mg/kg), a glycopeptide produced by the bacterium Streptomyces verticillus, develop lung inflammation and injury characterized by a significant neutrophil infiltration and tissue oedema. Therefore, the aim of this study is to investigate the effects of GW0742, a synthetic high affinity PPAR ß/δ agonist, and its possible role in preventing the advance of inflammatory and apoptotic processes induced by bleomycin, that long-term leads to the appearance of pulmonary fibrosis. Our data showed that GW0742-treatment (0.3 mg/Kg, 10 percent DMSO, i.p.) has therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters detected by measurement of: 1) cytokine production; 2) leukocyte accumulation, indirectly measured as decrease of myeloperoxidase (MPO) activity; 3) IkBα degradation and NF-kB nuclear translocation; 4) ERK phosphorylation; 5) stress oxidative by NO formation due to iNOS expression; 6) nitrotyrosine and PAR localization; 7) the degree of apoptosis, evaluated by Bax and Bcl-2 balance, FAS ligand expression and TUNEL staining. Taken together, our results clearly show that GW0742 reduces the lung injury and inflammation due to the intratracheal BLEO--instillation in mice.

Ethyl pyruvate therapy attenuates experimental severe arthritis caused by type II collagen (CII) in the mouse (CIA).

This study tested the hypothesis that ethyl pyruvate (EP), a simple aliphatic ester with anti-inflammatory effects, can reduce type II collagen-induced mouse arthritis (CIA). DBA/1J mice were used for the study, developing erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund?s adjuvant (CFA). The incidence of CIA was 100 percent by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint margins. EP-treatment (40 mg/kg/day i.p.) starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26-35 and improved histological status in the joint and paw. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS) revealed a positive staining in inflamed joints from mice subjected to CIA, while no staining was observed for HO-1 and Nrf-2 in the same group. The degree of staining for nitrotyrosine, PAR, iNOS, was significantly reduced in CII-challenged mice treated with the EP. Immuno-positive-staining for HO-1 and Nrf-2 was observed instead, in joints obtained from the EP-treated group. Plasma levels of TNF-α, IL-6 and the joint tissue levels of macrophage inflammatory protein (MIP)-1α and MIP-2 were also significantly reduced by EP treatment. Thirty-five days after immunization, EP-treatment significantly increased plasma levels of IL-10. These data demonstrate that EP treatment exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA.

Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice.

The aim of the present study is to evaluate the contribution of mitogen-activated protein kinase 1-3 MAPK3/MAPK1) in a model of acute lung inflammation in mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent adhesion molecule expression (I-CAM and P-selectin), lipid peroxidation, and increased production of tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced lung apoptosis (Bax and Bcl-2 expression) as well as nitrotyrosine formation, NF-kB activation, and pJNK expression, as determined by immunohistochemical analysis of lung tissues and the degree of lung inflammation and tissue injury (histological score). Administration of PD98059, an inhibitor of MAPK3/MAPK1 (10 mg/kg) 1 h after carrageenan caused a reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that inhibitors of the MAPK3/MAPK1 signaling pathways, such as PD98059, may be useful in the treatment of various inflammatory diseases.

Effects of the immunomodulator, VGX-1027, in endotoxin-induced uveitis in Lewis rats.

BACKGROUND AND PURPOSE: VGX-1027 is a novel, low molecular weight, immunomodulatory compound that has shown efficacy against a variety of immuno-inflammatory disease models in animals including autoimmune diabetes in NOD mice, collagen-induced arthritis and chemically induced inflammatory colitis. Here, we have studied the effects of VGX-1027 on the development of endotoxin-induced uveitis (EIU) in male Lewis rats, as a model of inflammatory ocular diseases in humans. EXPERIMENTAL APPROACH: EIU was induced by a single footpad injection of 200 microg lipopolysaccharide (LPS). Groups of rats were treated with either VGX-1027 (25 mg kg(-1)) or its vehicle at different time points (30 min, 6 h or 12 h) after the challenge with LPS or, as positive control, with dexamethasone. The rats were killed within 16 h after LPS challenge, and the eyes and aqueous humor were collected to study serological, immunological and histological signs of EIU. KEY RESULTS: The rats treated with VGX-1027 within 6 h after LPS challenge exhibited milder clinical, histological and laboratory signs of EIU than those treated with vehicle. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that systemic treatment with VGX-1027 counteracts the uveitis-inducing effect of LPS in rats and suggests that this drug may have potential in the treatment of immuno-inflammatory conditions of the eye in humans.