losartan-potassium and Multiple-Sclerosis

Cognitive dysfunction is a core feature in a range of neuropsychiatric disorders which reduces patients' workforce capacity - the largest socio-economic cost of these disorders. Nevertheless, there is no clinically available medical treatment with robust and enduring efficacy on cognitive deficits in most neuropsychiatric conditions. Recent research has shown that erythropoietin may have beneficial effects on cognitive dysfunction across neuropsychiatric disorders, including bipolar and unipolar disorders, schizophrenia, Parkinson's disease and multiple sclerosis.

Topics: Bipolar Disorder; Cognition; Cognitive Dysfunction; Erythropoietin; Humans; Mood Disorders; Multiple Sclerosis; Parkinson Disease; Schizophrenia

Erythropoietin (EPO) has neuroprotective effects in many models of damage and disease of the nervous system where neuroinflammation plays a substantial role, including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Since the first pioneering studies, in which EPO was shown to protect rats with acute EAE mainly by inhibiting inflammation, many other studies have pointed out other mechanisms of protection, including oligodendrogenesis and inhibition of axonal damage.Here we review the preclinical studies in which EPO has shown therapeutic efficacy in several models of EAE in mice and rats. Moreover, we report in detail the protocol to administer EPO to mice with myelin oligodendrocyte glycoprotein (MOG)-induced chronic progressive EAE, and a representative result. In this model, EPO inihibits the clinical score of the disease when administered according to a preventive but also to a therapeutic schedule, and therefore at disease onset, suggesting that it might not only inhibit inflammation but also actively stimulate repair.

Topics: Animals; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Mice; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Rats

Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS).. To evaluate a treatment effect of EPO on progressive MS.. This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks.. A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences.. This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

Topics: Adult; Brain; Disability Evaluation; Disease Progression; Double-Blind Method; Erythropoietin; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Treatment Outcome

To investigate the safety, tolerability, and short-term efficacy of treatment with erythropoietin in patients with optic neuritis as a first demyelination event.. We conducted this randomized double-blind pilot study in the Shiraz University of Medical Sciences, Shiraz, Iran, from March 2007 to January 2009. The participants were patients aged 18-45 years with optic neuritis and at least 3 hyperintense lesions on T2-weighted and FLAIR MRI, but no clinically definite multiple sclerosis (MS). They were randomized into 2 groups. The case group (5 patients) received intravenous methyl prednisolone (1000 mg/24 hours) and intravenous erythropoietin (20,000 unit/24 hours) for 5 consecutive days, and the control group (5 patients) received intravenous methyl prednisolone at the same dose as the case group, and a placebo. The groups were followed for one year and compared for adherence to protocol, adverse drug effects, mean duration of conversion to clinically definite MS, and MRI changes.. All patients tolerated the protocol. One patient who received erythropoietin developed cerebral venous sinus thrombosis and anti-cardiolipin antibody positivity. One patient in the control group, but no patients in the case group, fulfilled the McDonald criteria for MS during the follow-up period, but none of the participants in either group developed clinically definite MS according to the Poser criteria.. Erythropoietin may be effective, but should be used with caution.

Topics: Acute Disease; Adolescent; Adult; Demyelinating Diseases; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Glucocorticoids; Humans; Magnetic Resonance Imaging; Middle Aged; Multiple Sclerosis; Optic Neuritis; Pilot Projects; Prednisolone; Severity of Illness Index; Treatment Outcome; Young Adult

Erythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS).. The TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization.. The follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI -6.45 to 8.98,. In line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant.. This study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes.. The trial was preregistered before commencement at clinicaltrials.gov (NCT01962571).

Topics: Erythropoietin; Follow-Up Studies; Humans; Methylprednisolone; Multiple Sclerosis; Optic Neuritis; Quality of Life; Visual Acuity

Topics: Demyelinating Diseases; Erythropoietin; Humans; Multiple Sclerosis

Multiple sclerosis (MS) is a neuro-inflammatory and demyelinating disease. Downregulation of neuronal mitochondrial gene expression and activity have been reported in several studies of MS. We have previously shown that hemoglobin-β (Hbb) signals to the nucleus of neurons and upregulates H3K4me3, a histone mark involved in regulating cellular metabolism and differentiation. The present study was undertaken to evaluate the effect of erythropoietin (EPO) on the upregulation of hemoglobin and mitochondrial-associated neuroprotection. We found that administering EPO (5000 IU/kg intraperitoneally) to mice upregulated brain Hbb expression, levels of H3K4me3, expression of mitochondrial complex III, complex V, and mitochondrial respiration. We also found that the neuronal mitochondrial metabolite N-acetylaspartate (NAA), a marker of neuronal mitochondrial activity, was increased with EPO treatment. Further, we measured the effects of EPO on preventing mitochondrial deficits in the cuprizone toxic demyelinating mouse model of MS. We found that EPO prevented cuprizone-mediated decreases in Hbb, complex III, and NAA. Our data suggest that EPO mediated regulation of Hbb supports neuronal energetics and may provide neuroprotection in MS and other neurodegenerative diseases where a dysfunction of mitochondria contributes to disease.

Topics: Animals; Aspartic Acid; Brain; Cell Respiration; Cuprizone; Disease Models, Animal; Electron Transport Complex III; Erythropoietin; Hemoglobins; Histones; Lysine; Male; Methylation; Mice, Inbred C57BL; Mitochondria; Models, Biological; Multiple Sclerosis; Myelin Basic Protein; Myelin Sheath; Neurons; Up-Regulation

Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs. Other researchers showed that EPO can act as a protectant against severe brain injury and status epilepticus in rats. Therefore, we tried rhLF as a protector against the severe neurologic disorders developed in rats, such as the rotenone-induced model of Parkinson's disease and experimental autoimmune encephalomyelitis as a model of multiple sclerosis, and observed its capacity to mitigate the grave symptoms. Moreover, an intraperitoneal injection of rhLF into mice 1 h after occlusion of the medial cerebral artery significantly diminished the necrosis area measured on the third day in the ischaemic brain. During this period EPO was synthesized in various murine tissues. It was known that EPO induces nuclear translocation of Nrf2, which, like HIF-1-alpha, is a transcription factor. In view that under conditions of hypoxia both factors demonstrate a synergistic protective effect, we suggested that LF activates the Keap1/Nrf2 signaling pathway, an important link in proliferation and differentiation of normal and malignant cells. J774 macrophages were cultured for 3 days without or in the presence of ferric and ferrous ions (RPMI-1640 and DMEM/F12, respectively). Then cells were incubated with rhLF or Deferiprone. Confocal microscopy revealed nuclear translocation of Nrf2 (the key event in Keap1/Nrf2 signaling) induced by apo-rhLF (iron-free, RPMI-1640). The reference compound Deferiprone (iron chelator) had the similar effect. Upon iron binding (in DMEM/F12) rhLF did not activate the Keap1/Nrf2 pathway. Added to J774, apo-rhLF enhanced transcription of Nrf2-dependent genes coding for glutathione S-transferase P and heme oxygenase-1. Western blotting revealed presence of Nrf2 in mice brain after 6 days of oral administration of apo-rhLF, but not Fe-rhLF or equivalent amount of PBS. Hence, apo-LF, but not holo-LF, induces the translocation of Nrf2 from cytoplasm to the nucle

Topics: Animals; Brain Ischemia; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Humans; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; Rats; Rats, Wistar; Recombinant Proteins

To explore the potential decrease of serum erythropoietin (EPO) level in patients with multiple sclerosis (MS) complicated with anemia.. The serum EPO levels were detected in the patients with MS complicated with anemia (MS group, n=31), patients with iron deficiency anemia (IDA group, n=33), and healthy subjects (normal control group, n=80) by enzyme-linked immunosorbent assay (ELISA). Blood routine test, reticulocyte count, hemoglobin, and indexes of liver and kidney function were also detected.. The serum EPO level in MS group was significantly lower than those in IDA group [(101.3±17.6)U/L vs.(166.1±8.7)U/L, P<0.01]. Moreover, the serum EPO level decreased as the severity of anemia in the MS group increased: it was (95.7±9.6), (101.7±8.1), and (123.7±9.3) U/L in patients with mild, moderate, and severe anemia, respectively (P<0.05). Other indicators including blood routine findings, reticulocyte count, hemoglobin, and liver and kidney function parameters showed no significant difference between the MS group and the IDA group (P>0.05).. The serum EPO level decreases in patients with multiple sclerosis complicated with anemia, and the decreasing levels are related with the severity of anemia. Thus EPO therapy may be beneficial for these patients.

Topics: Adolescent; Adult; Aged; Anemia; Case-Control Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Young Adult

Neurodegenerative processes determine the clinical disease course of multiple sclerosis, an inflammatory autoimmune CNS disease that frequently manifests with acute optic neuritis. None of the established multiple sclerosis therapies has been shown to clearly reduce neurodegeneration. In a rat model of experimental autoimmune encephalomyelitis, we recently demonstrated increased neuronal apoptosis under methylprednisolone therapy, although CNS inflammation was effectively controlled. In the present study, we combined steroid treatment with application of erythropoietin to target inflammatory as well as neurodegenerative aspects. After immunization with myelin oligodendrocyte glycoprotein (MOG), animals were randomly assigned to six treatment groups receiving different combinations of erythropoietin and methylprednisolone, or respective monotherapies. After MOG-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of retinal ganglion cells, the neurons that form the axons of the optic nerve, was measured by electroretinograms. Functional and histo pathological data of retinal ganglion cells and optic nerves revealed that neuron and axon protection was most effective when erythropoietin treatment that was started at immunization was combined with high-dose methylprednisolone therapy given from days 1 to 3 of MOG-induced experimental autoimmune encephalomyelitis. In contrast, isolated neuronal or axonal protection without clinical benefit was achieved under monotherapy with erythropoietin or methylprednisolone, respectively.

Topics: Animals; Drug Therapy, Combination; Electroretinography; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Evoked Potentials, Visual; Female; Methylprednisolone; Multiple Sclerosis; Neuroprotective Agents; Optic Nerve; Optic Neuritis; Rats; Rats, Inbred BN; Recombinant Proteins; Retinal Ganglion Cells; Signal Transduction

In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

Topics: Animals; Apoptosis; Caspases; Cell Count; Cell Survival; Disease Models, Animal; Electroretinography; Erythropoietin; Female; In Situ Nick-End Labeling; Multiple Sclerosis; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Optic Nerve; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred BN; Recombinant Proteins; Retinal Ganglion Cells; Signal Transduction

In recent work we reported that systemically administered erythropoietin (EPO) crosses the blood-brain barrier and has protective effects in animal models of cerebral ischemia, brain trauma and in a rat model of experimental autoimmune encephalomyelitis (EAE). Here we characterize the effect of systemic EPO on the inflammatory component of actively induced, acute EAE in Lewis rats. Administration of EPO at doses of 500-5000 U/kg bw i.p., daily from day 3 after immunization with myelin basic protein (MBP), delayed the onset of EAE and decreased its clinical score at peak time (days 12-13). Immunohistochemical analysis of the spinal cord using anti-glial fibrillary acidic protein (GFAP) and anti-CD11b antibodies showed that EPO markedly diminished inflammation and glial activation/proliferation. EAE induced significant levels of TNF and IL-6 in the spinal cord, where IL-6 was maximum at the onset of the disease (day 10) and TNF at its peak (day 12). EPO delayed the increase of TNF levels, without altering their peak levels, and markedly reduced those of IL-6 suggesting that the decreased inflammation and clinical score may be in part upon attenuation of IL-6. On the other hand, EPO was without effect in a model of adjuvant-induced arthritis in Lewis rats, suggesting a specificity towards autoimmune demyelinating diseases. These data suggest that EPO might act as a protective cytokine in inflammatory pathologies of the CNS.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Interleukin-6; Multiple Sclerosis; Rats; Rats, Inbred Lew; Spinal Cord; Tumor Necrosis Factor-alpha