[Show abstract][Hide abstract] ABSTRACT: The present study shows the advantages of liposome-based nano-drugs as a novel strategy of delivering active pharmaceutical ingredients for treatment of neurodegenerative diseases that involve neuroinflammation. We used the most common animal model for multiple sclerosis (MS), mice experimental autoimmune encephalomyelitis (EAE). The main challenges to overcome are the drugs' unfavorable pharmacokinetics and biodistribution, which result in inadequate therapeutic efficacy and in drug toxicity (due to high and repeated dosage). We designed two different liposomal nano-drugs, i.e., nano sterically stabilized liposomes (NSSL), remote loaded with: (a) a "water-soluble" amphipathic weak acid glucocorticosteroid prodrug, methylprednisolone hemisuccinate (MPS) or (b) the amphipathic weak base nitroxide, Tempamine (TMN). For the NSSL-MPS we also compared the effect of passive targeting alone and of active targeting based on short peptide fragments of ApoE or of β-amyloid. Our results clearly show that for NSSL-MPS, active targeting is not superior to passive targeting. For the NSSL-MPS and the NSSL-TMN it was demonstrated that these nano-drugs ameliorate the clinical signs and the pathology of EAE. We have further investigated the MPS nano-drug's therapeutic efficacy and its mechanism of action in both the acute and the adoptive transfer EAE models, as well as optimizing the perfomance of the TMN nano-drug. The highly efficacious anti-inflammatory therapeutic feature of these two nano-drugs meets the criteria of disease-modifying drugs and supports further development and evaluation of these nano-drugs as potential therapeutic agents for diseases with an inflammatory component.
PLoS ONE 07/2015; 10(7):e0130442. DOI:10.1371/journal.pone.0130442 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives/HypothesisThe objectives of this study were to examine the presence of β-2 transferrin (β2TRNSF) in cerebrospinal fluid (CSF) contaminated in vitro by various bacteria and explore the mechanism (passive or active) responsible for β2TRNSF elimination. Early diagnosis of CSF leakage may change treatment decisions and minimize the risk of meningitis and encephalitis. β2TRNSF is a protein present exclusively in CSF. Its detection is highly useful in cases of CSF leakage, although it has never been examined in the presence of central nervous system infection.Study DesignProspective patient analysis.Methods
Sterile CSF drawn from patients was contaminated in vitro with several microorganisms chosen for their ability to cause neurosurgical-related infections: Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. β2TRNSF was examined at two time points: following immediate inoculation (t0) and following an overnight incubation (t18) over various bacterial concentrations. Samples of CSF inoculated with S pneumoniae were also examined in the presence of ciprofloxacin. For β2TRNSF analysis we used immunoblotting electrophoresis and enzyme-linked immunosorbent assay (ELISA).ResultsCSF samples collected from nine patients were analyzed. β2TRNSF was not detected following S pneumoniae inoculation at both time points when immunoblotting electrophoresis was used. Quantitative analysis using ELISA demonstrated significant β2TRNSF concentration decrease. The addition of ciprofloxacin led to the same results.ConclusionsCSF leak detection using β2TRNSF may be deceiving in the presence of a S pneumoniae cerebral nervous system infection. A passive process is suggested, as β2TRNSF disappeared either immediately or following incubation with inactive bacteria.Level of EvidenceNA Laryngoscope, 125:556-560, 2015
The Laryngoscope 03/2015; 125(3). DOI:10.1002/lary.24940 · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors, mainly through promoter methylation, correlates with a better therapeutic response and with increased survival. Therefore, it is conceivable to consider MGMT as a potential therapeutic target for the treatment of cancers. Our previous results demonstrated the pivotal role of NF-kappaB in MGMT expression, mediated mainly through p65/NF-kappaB homodimers. Here we show that the non-canonical NF-KappaB motif (MGMT-kappaB1) within MGMT enhancer is probably the major inducer of MGMT expression following NF-kappaB activation. Thus, in an attempt to attenuate the transcription activity of MGMT in tumors we designed locked nucleic acids (LNA) modified decoy oligonucleotides corresponding to the specific sequence of MGMT-kappaB1 (MGMT-kB1-LODN). Following confirmation of the ability of MGMT-kB1-LODN to interfere with the binding of p65/NF-kappaB to the NF-KappaB motif within MGMT enhancer, the efficacy of the decoy was studied in-vitro and in-vivo. The results of these experiments show that the decoy MGMT-kB1-LODN have a substantial antineoplastic effect when used either in combination with temozolomide or as monotherapy. Our results suggest that MGMT-kB1-LODN may provide a novel strategy for cancer therapy.
PLoS ONE 12/2014; 9(12):e113854. DOI:10.1371/journal.pone.0113854 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Screening of putative autoimmune targets in multiple sclerosis (MS) revealed a proportion of patients carrying antibodies (Abs) against KIR4.1, a potassium channel that shares functional properties with AQP4. Both are localized at the perivascular astrocytic processes.
[Show abstract][Hide abstract] ABSTRACT: In this work, we administered to transgenic mice mimicking a genetic prion disease, which develop a late onset fatal disease, a nanoemulsions formulation of pomegranate seed oil, denominated Nano-PSO. We show in the manuscript that this formulation is successful in inhibiting disease onset when given to still asymptomatic mice and disease progression when given to already sick mice. Nano-PSO treatment reduced brain lipid oxidation and other key neurodegeneration features.Figure optionsDownload full-size imageDownload high-quality image (131 K)Download as PowerPoint slide
Nanomedicine: nanotechnology, biology, and medicine 08/2014; 10(6). DOI:10.1016/j.nano.2014.03.015 · 5.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK) resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion infected immune cells infiltrate into the CNS, as is the case for scrapie infected mice induced for Experimental Autoimmune Encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199 K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199 K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199 K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity.
Human Molecular Genetics 03/2014; 23(22). DOI:10.1093/hmg/ddu134 · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the anti-inflammatory effects of Resolvin-D1 (RV-D1) and its mechanism of action in human corneal epithelial (HCE) cells.
HCE cells were incubated with different concentrations of RV-D1 for different time periods. Oleic acid (OA) and Dexamethasone (DM) served as negative and positive controls, respectively. Cells were stimulated with polyriboinosinic:polyribocytidylic acids (poly I:C). The protein contents and mRNA expression levels of Tumor necrosis factor-alpha (TNF-alpha), Interleukin (IL)-6, IL-1beta and IL-8 were evaluated with multiplex fluorescent bead immunoassay (FBI) and real time-PCR, respectively. In addition, the expression of inhibitory factor-kappaBalpha (I-kappaBalpha) was evaluated with real time-PCR.
The protein level of pro-inflammatory cytokines TNF-alpha, IL-6, IL-1beta and IL-8 significantly increased after stimulation with Poly I:C. RV-D1 treatment at concentration of 1 muM decreased the protein level of TNF-alpha to 20.76 +/- 9.3% (P < 0.05), IL-6 to 43.54 +/- 14.16% (P < 0.001), IL-1beta to 46.73 +/- 15.93% (P > 0.05) and IL-8 to 51.15 +/- 13.01% (P < 0.05) compared with cells stimulated with poly I:C alone. Similarly, the mRNA levels of TNF-alpha, IL-6, IL-1beta and IL-8 were significantly reduced after treatment with RV-D1. A highly significant dose response curve was demonstrated for RV-D1 treated HCE cells for TNF-alpha and IL-1beta.DM treatment decreased the protein content for all of the pro-inflammatory cytokines, similar results were demonstrated at the mRNA level. The anti-inflammatory effects of RV-D1 were similar to those of DM for TNF-alpha, IL-6 and IL-8.
RV-D1 may serve as a potent anti-inflammatory agent in ocular surface inflammation, as evaluated in cultured HCE cells. The anti-inflammatory effects of RV-D1 were comparable to those of DM, and were mediated through nuclear factor kappa B (NF-kappaB) signal transduction.
Journal of Inflammation 03/2014; 11(1):6. DOI:10.1186/1476-9255-11-6 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptors (TLRs) are recognized as important contributors to the initiation and modulation of the inflammatory response in the eye. This study investigated the precise expression patterns and functionality of TLRs in human corneal epithelial cells (HCE) and in conjunctival fibroblasts (HCF).
The cell surface expression of TLRs 2-4, TLR7 and TLR9 in HCE and HCF was examined by flow cytometry with or without stimulation with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). The mRNA expression of the TLRs was determined by real-time PCR. The protein content levels of interleukin (IL)-6, IL-8, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) were measured in HCE and HCF using multiplex fluorescent bead immunoassay (FBI).
The surface expression of TLR3 and TLR4 was detected on both HCE and HCF. Following incubation with LPS, the percentage of HCE cells staining for TLR4 decreased from 10.18% to 0.62% (P < 0.001). Incubation with poly I:C lowered the percentage of HCE cells positive for TLR3 from 10.44% to 2.84% (P < 0.001). The mRNA expression of TLRs2, 4, 7 and 9 was detected in HCE only. Activation of HCE with LPS complex elicited protein secretion up to 4.51 +/- 0.85-fold higher levels of IL-6 (P < 0.05), 2.5 +/- 0.36-fold IL-8 (P > 0.05), 4.35 +/- 1.12-fold IL-1beta (P > 0.05) and 29.35 +/- 2.3-fold TNFalpha (P < 0.05) compared to cells incubated in medium.
HCF and HCE both express TLRs that are respond to specific ligands by increased cytokines expression. Following activation, the surface expression of TLR3 and TLR4 on HCE is decreased, thus creating a negative feedback loop, mitigating the effect of TLR activation.
Journal of Inflammation 02/2014; 11(1):3. DOI:10.1186/1476-9255-11-3 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebral malaria is the most severe complication of Plasmodium falciparum infection, and a leading cause of death in children under the age of five in malaria-endemic areas. We report high therapeutic efficacy of a novel formulation of liposome-encapsulated water-soluble glucocorticoid prodrugs, and in particular β-methasone hemisuccinate (BMS), for treatment of experimental cerebral malaria (ECM), using the murine P. berghei ANKA model. BMS is a novel derivative of the potent steroid β-methasone, and was specially synthesized to enable remote loading into nano-sterically stabilized liposomes (nSSL), to form nSSL-BMS. The novel nano-drug, composed of nSSL remote loaded with BMS, dramatically improves drug efficacy and abolishes the high toxicity seen upon administration of free BMS. nSSL-BMS reduces ECM rates in a dose-dependent manner and creates a survival time-window, enabling administration of an antiplasmodial drug, such as artemisone. Administration of artemisone after treatment with the nSSL-BMS results in complete cure. Treatment with BMS leads to lower levels of cerebral inflammation, demonstrated by changes in cytokines, chemokines, and cell markers, as well as diminished hemorrhage and edema, correlating with reduced clinical score. Administration of the liposomal formulation results in accumulation of BMS in the brains of sick mice but not of healthy mice. This steroidal nano-drug effectively eliminates the adverse effects of the cerebral syndrome even when the treatment is started at late stages of disease, in which disruption of the blood-brain barrier has occurred and mice show clear signs of neurological impairment. Overall, sequential treatment with nSSL-BMS and artemisone may be an efficacious and well-tolerated therapy for prevention of CM, elimination of parasites, and prevention of long-term cognitive damage.
PLoS ONE 08/2013; 8(8):e72722. DOI:10.1371/journal.pone.0072722 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the efficiency of nasal drug administration as a new non-invasive treatment strategy for MS. Glatiramer Acetate (GA) and GA-Cannabidiol (CBD) combination administered in nasal delivery system (NDS) resulted in a statistically significant decrease of clinical scores and inflammatory cytokine expression in experimental autoimmune encephalomyelitis (EAE) mice. Even a suboptimal dose of Prednisolone in NDS was effective in preventing the clinical signs of the disease. Neuron regeneration was observed in the hippocampus of EAE mice treated with GA-CBD in NDS. This work shows that nasal administration improved drug efficiency and stimulates further research for a non-invasive strategy for MS.
Journal of neuroimmunology 03/2013; 258(1-2). DOI:10.1016/j.jneuroim.2013.02.013 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: comMultipurpose solutions (MPSs) are the leading method for cleaning and disinfecting soft contact lenses (CLs). During recent years, numerous clinical studies have evaluated the MPS damage to the ocular surface. This study examined the cytotoxic and the inflammatory effects of MPSs and hydrogen peroxide disinfection system (H202) compared to appropriate controls on human corneal epithelial (HCE) cells. Primary cultured HCE cells were exposed to eight different commercially available MPS products (MPS A, ReNu MultiPlus®; MPS B, Opti Free® EverMoist; MPS C, Solo-care Aqua®; MPS-D, Complete®; MPS-E, Unica Sensitive®; MPS-F, Options Multi®; MPS-G, Biotrue®; MPS-H, COMPLETE® RevitaLens). Morphological changes and cytotoxic effects were examined with FITC-Annexin V/ PI and MTT assays. The protein contents of the inflammatory cytokines interleukin (IL)-1β, TNF-α, IL-6 and IL-8 were examined by multiplex fluorescent bead immunoassay (FBI), and the mRNA expression was examined by real time PCR. Lipopolysaccharide (LPS) with 500 ng/ml CD14 and 500 ng/ml LBP (LPS complex), polyinosinic: polycytidylic acid (Poly I:C) and un-neutralized H202 served as positive controls, respectively. Phosphate-buffered saline (PBS) was added as a negative control. The study demonstrated that most of the MPSs induced varying degrees of cytotoxicity to HCE cells, and increased production of pro-inflammatory cytokines compared to the negative control. In addition, several MPS increased the mRNA level of inhibitory factor-κBα (I-κBα). Among the various MPSs, MPS-H induced the highest protein contents of the pro-inflammatory cytokines (14.37±2.2-fold for TNF-α, 41.39±2.5-fold for IL-1β and 5.24±0.6-fold for IL-6) compared to the negative control (p<0.05). In contrast, no significant differences were noted between the neutralized H202 and the negative control. We conclude that most of the currently used MPSs induce significant damage and inflammatory response in corneal epithelial cells. MPS-induced inflammation was mediated through NF-κB signal transduction. This study demonstrates for the first time inflammatory responses at the molecular level in primary HCE cells following exposure to a large series of commercially available and commonly used MPSs. These findings strongly suggest that certain MPSs may be partially involved in the pathogenesis of contact lens intolerance. Therefore, we recommended that practitioners advise patients as to the preferable disinfecting contact lens solutions, and to consider using the hydrogen peroxide disinfection systems instead.
European Journal of Inflammation 02/2013; 1(1):145-160. · 0.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammatory demyelinative diseases of the central nervous system are mostly idiopathic and represent the major cause of neurological disability in young adults. These diseases differ in terms of clinical symptoms, severity, pathological characteristics and epidemiology. However, there are also significant similarities between these diseases, which sometimes bring to a misleading diagnosis. Neuromyelitis optica (NMO) is a demyelinative disease in which the optic nerve and the spinal cord are predominantly affected. The detection of specific antibodies to aquaporin-4 (NMO-IgG) led to a modification of the diagnostic criteria for NMO.
We performed a retrospective study on NMO-IgG positive patients referred to the Department of Neurology MS Center (2006-2011) with suspected NMO. Based on the presenting symptomatology of the patients, we identified the cases with optic neuritis and various parameters that may differentiate between NMO and MS. NMO-IgG were evaluated by ELISA.
A total of 50% of the 107 patients with NMO-IgG fulfilled the revised criteria of NMO; 38 patients had a single attack of optic neuritis or long lesion in the spinal cord and 15 patients presented with an opticospinal type of MS. The visual acuity following a single attack of optic neuritis remained significantly lower in NMO patients as compared to MS patients. Most of the NMO patients with NMO-IgG had additional attacks of optic neuritis within a short time from the initial event.
The finding of NMO-IgG in patients with optic neuritis foreshadows a bad prognosis and relapses. These patients are at high risk of experiencing a second event in the central nervous system and fulfilling the clinical criteria for NMO. Due to the difference in the severity of inflammation of the optic nerve between NMO and MS, it is highly recommended to seek a laboratory check-up for NMO-IgG in serum, immediately after the first event, in order to determine the necessity and the kind of treatment for the patient.
[Show abstract][Hide abstract] ABSTRACT: Background: Central nervous system (CNS) irradiation has detrimental effects which become evident within hours to few days and after a long latency of months and years. However, the delayed effect of irradiation on neuroimmune diseases has not been thoroughly examined. Objectives: We evaluated the delayed effects of irradiation on the course of experimental autoimmune encephalomyelitis (EAE), which is used as a model for neuroimmune inflammation and multiple sclerosis. Methods: Adult male rats were exposed to a dose of 15 Gy given to the thoracolumbar spinal cord. Six months later, EAE was induced by inoculation of rat spinal cord homogenate in complete Freund's adjuvant (CFA). The disease was evaluated by clinical, histopathological and immunological parameters. Results: Irradiated rats developed clinical signs of EAE earlier than the control group and their disease was much more severe. Unlike the control group, all rats in the EAE-irradiated group died within 5 days after the onset of clinical signs. Sections taken from irradiated rats showed diffuse and large hemorrhagic infiltrates of lymphocytes and granulocytes. In contrast, control rats displayed fewer infiltrates, which were less prominent and not hemorrhagic. Conclusions: CNS irradiation has a delayed effect that caused a marked aggravation of the clinical and pathological signs of EAE. The severity of the disease may be a consequence of the effect of irradiation on the CNS vascular bed and impaired blood-brain barrier.
[Show abstract][Hide abstract] ABSTRACT: Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI.
[Show abstract][Hide abstract] ABSTRACT: Neuromyelitis optica (NMO) is an idiopathic demyelinating disease of the CNS that can be clearly distinguished from multiple sclerosis (MS) by clinical, neuroradiogic, and pathologic criteria and the presence of the highly specific serum autoantibodies against the water channel aquaporin-4 (AQP4).(1) Although studies support a central role of the anti-AQP4 antibodies in the pathogenesis of NMO, their exact involvement in the immunopathogenetic cascade of the disease is still not clear, and T cells seem to be equally crucial for the full development of clinical and histopathologic NMO.
[Show abstract][Hide abstract] ABSTRACT: Systemic polyunsaturated fatty acids (PUFAs) were shown to improve the symptoms of dry eye syndrome due to their anti-inflammatory effects. This study evaluated the in vitro anti-inflammatory effects of PUFAs on human corneal epithelial (HCE) cells.
HCE cells were incubated for 2 hours with different concentrations of PUFAs: alpha-linolenic acid (ALA), gamma-linolenic acid (GLA), and linoleic acid (LA). Oleic acid (OA) and dexamethasone (DM) served as negative and positive controls, respectively. Cells were stimulated with either polyinosinic:polycytidylic acid (poly I:C) or lipopolysaccharide (LPS) complex. The protein contents and mRNA expression levels of IL-6, IL-8, IL-1β, and TNF-α were evaluated with multiplex fluorescent bead immunoassay and real-time PCR, respectively. The expression of inhibitory factor-κBα (I-κBα) was evaluated with real-time PCR.
The protein and mRNA levels of IL-6, IL-8, IL-1β, and TNF-α were significantly increased after stimulation with LPS or poly I:C. Following treatment with ALA, a significant decrease was demonstrated in the protein content of TNF-α to 23.81% (P < 0.001), IL-6 to 46.71% (P < 0.001), IL-1β to 20.86% (P < 0.05), and IL-8 to 52.21% (P < 0.001). Similar results were demonstrated at the mRNA level. The anti-inflammatory effects of ALA were similar to those of DM for all of the pro-inflammatory cytokines. The ALA inhibition of the pro-inflammatory cytokines was associated with a significant reduction of I-κBα.
ALA may serve as a potent anti-inflammatory agent in ocular surface inflammation. The anti-inflammatory effects of ALA are comparable to those of corticosteroids, and are mediated through NF-κB signal transduction.
[Show abstract][Hide abstract] ABSTRACT: Prions, composed of a misfolded protein designated PrP(Sc), are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrP(Sc) aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system.
C57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG(35-55) in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co-induced animals were reactivated and subsequently injected into naïve mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrP(Sc) deposition were next evaluated.
We first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrP(Sc). Next, we present evidence that mice infected with activated prion-experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrP(Sc) aggregates in white matter areas in brains and spinal cords.
Our results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrP(Sc) in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products.
Journal of Neuroinflammation 03/2012; 9(1):58. DOI:10.1186/1742-2094-9-58 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We characterized the effect of acute ischemic stroke on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and evaluated the role of glucocorticoids (GC) in the clinical outcome following ischemic stroke. Male spontaneous hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and developed a cortical infarct. At 4h post-PMCAO or sham operation, serum levels of ACTH and corticosterone (CS) were elevated 5 and 4 fold respectively as compared to controls and then returned to basal levels at 24h post surgery. In these experimental groups we found also a significant depletion of median eminence (ME)-CRH(41). In adrenalectomized (Adx) rats that underwent PMCAO the degree of motor disability and infarct volume was similar to that of intact rats. Administration of dexamethasone (Dex) to Adx-PMCAO rats significantly improved the motor disability and decreased the infarct volume. However, in sham-Adx with PMCAO, Dex had no effect on these two parameters. In rats with PMCAO or sham-PMCAO, brain production of PGE(2) was significantly increased. This effect was further enhanced in Adx-PMCAO rats and significantly inhibited by Dex. In conclusion, activation of the HPA axis following PMCAO is due to stress induced by surgery. This activation is mediated by hypothalamic CRH(41). Absence of endogenous GC or administration of Dex in naïve rats does not alter motor and pathological parameters in the acute stage following PMCAO. In contrast, administration of Dex significantly improved the outcome following cerebral ischemia in Adx rats which may be due to increased glucocorticoid receptors. Brain production of PGE(2) does not play an important role in the pathophysiology of the acute phase of cerebral ischemia.
Brain research 08/2011; 1407:90-6. DOI:10.1016/j.brainres.2011.06.035 · 2.83 Impact Factor