losartan-potassium and Demyelinating-Diseases

Erythropoietin (EPO) is an endogenous cytokine with antiapoptotic, antiinflammatory, and neurotrophic properties. Apart from being produced by the kidney, liver, and spleen in response to hypoxia, EPO is highly expressed in the brain during development and after neuropathological insults. The observation that receptors for EPO are present on brain capillaries and glial capillary end-feet has suggested that circulating (plasma) EPO may be transferred into the brain. This review summarizes the increasing number of studies indicating that peripherally administered recombinant human (rHu) EPO crosses the blood-brain barrier. Moreover, several of these studies have shown that peripherally administered rHuEPO can protect against the damage caused by a diversity of neuropathological conditions such as (a) stroke, (b) head and spinal cord trauma, (c) inflammatory and demyelinating conditions, (d) toxin-induced epileptic seizures, and (e) retinal ischemia. While all these studies are based on experiments in animal models, the effectiveness of rHuEPO in ischemic stroke in human patients has recently been suggested in a proof-of-concept trial, which is also discussed.

Topics: Animals; Blood-Brain Barrier; Brain Injuries; Controlled Clinical Trials as Topic; Cross-Sectional Studies; Demyelinating Diseases; Disease Models, Animal; Erythropoietin; Evidence-Based Medicine; Female; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Male; Mice; Neuroprotective Agents; Rabbits; Rats; Recombinant Proteins; Sensitivity and Specificity; Spinal Cord Injuries; Stroke; Treatment Outcome

To compare the effect of adding recombinant human erythropoietin (rhEPO) to intravenous methylprednisolone for the treatment of unilateral acute optic neuritis of unknown or demyelinative origin on the logarithm of the minimum angle of resolution (logMAR), perimetric variables [mean deviation (MD) and pattern standard deviation (PSD)], and retinal nerve fiber layer (RNFL) thickness in optical coherence tomography (OCT).. Thirty patients (15 patients in each group) diagnosed with unilateral acute optic neuritis of unknown or demyelinative origin were included. All patients received 1, 000 mg intravenous methylprednisolone per day for 3 days. One intravenous bullous dose of rhEPO with the dose of 33,000 IU was administered at days 1-3 for the patients in group 2. One intravenous bullous dose of 0.9 % normal saline was administered at days 1-3 for group 1 patients. At 6 months post-intervention, in the involved eye, logMAR, MD, PSD, and mean RNFL thickness in each of four quadrants and post-intervention changes in each of the variables were compared between group 1 and group 2.. The amount of MD improvement after the intervention (difference of pre- and post-intervention MDs) was significantly higher in the group 2 patients (p = 0.04). The other post-intervention variables, including post-intervention PSD, amount of PSD improvement, and total and four-quadrant post-intervention RNFL thickness and RNFL loss (difference of pre- and post-intervention RNFL thicknesses), demonstrated no significant differences between group 1 and group 2.. Until more controlled studies are available, the rhEPO is not recommended as an add-on treatment for optic neuritis.

Topics: Acute Disease; Adolescent; Adult; Demyelinating Diseases; Double-Blind Method; Drug Therapy, Combination; Erythropoietin; Female; Glucocorticoids; Humans; Infusions, Intravenous; Male; Methylprednisolone; Nerve Fibers; Optic Neuritis; Recombinant Proteins; Retinal Ganglion Cells; Tomography, Optical Coherence; Visual Acuity; Young Adult

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

Topics: Demyelinating Diseases; Erythropoietin; Humans; Multiple Sclerosis

Here, we sought to delineate the effect of EPO on the remyelination processes using an in vitro model of demyelination. We report that lysolecithin-induced demyelination elevated EPO receptor (EpoR) expression in oligodendrocyte progenitor cells (OPCs), facilitating the beneficial effect of EPO on the formation of oligodendrocytes (oligodendrogenesis). In the absence of EPO, the resultant remyelination was insufficient, possibly due to a limiting number of oligodendrocytes rather than their progenitors, which proliferate in response to lysolecithin-induced injury. By EPO treatment, lysolecithin-induced proliferation of OPCs was accelerated and the number of myelinating oligodendrocytes and myelin recovery was increased. EPO also enhanced the differentiation of neural progenitor cells expressing EpoR at high level toward the oligodendrocyte-lineage cells through activation of cyclin E and Janus kinase 2 pathways. Induction of myelin-forming oligodendrocytes by high dose of EPO implies that EPO might be the key factor influencing the final differentiation of OPCs. Taken together, our data suggest that EPO treatment could be an effective way to enhance remyelination by promoting oligodendrogenesis in association with elevated EpoR expression in spinal cord slice culture after lysolecithin-induced demyelination.

Topics: Animals; Demyelinating Diseases; Erythropoietin; Lysophosphatidylcholines; Myelin Sheath; Neurogenesis; Oligodendroglia; Organ Culture Techniques; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Spinal Cord; Spinal Cord Regeneration

Erythropoietin (EPO) reduces symptoms of experimental autoimmune encephalomyelitis in rodents and shows neuroregenerative effects in chronic progressive multiple sclerosis. The mechanisms of action of EPO in these conditions with shared immunological etiology are still unclear. Therefore, we used a model of toxic demyelination allowing exclusion of T cell-mediated inflammation. In a double-blind (for food/injections), placebo-controlled, longitudinal four-arm design, 8-wk-old C57BL/6 mice (n = 26/group) were assigned to cuprizone-containing (0.2%) or regular food (ground chow) for 6 wks. After 3 wks, mice were injected every other day with placebo or EPO (5,000 IU/kg intraperitoneally) until the end of cuprizone feeding. Half of the mice were exposed to behavioral testing, magnetic resonance imaging (MRI) and histology immediately after treatment cessation, whereas the other half were allowed a 3-wk treatment-free recovery. Immediately after termination of cuprizone feeding, all toxin-exposed mice were compromised regarding vestibulomotor function/coordination, with EPO-treated animals performing better than placebo. Likewise, ventricular enlargement after cuprizone, as documented by MRI, was less pronounced upon EPO. After a 3-wk recovery, remarkable spontaneous improvement was observed in all mice with no measurable further benefit in the EPO group ("ceiling effect"). Histological analysis of the corpus callosum revealed attenuation by EPO of the cuprizone-induced increase in microglial numbers and amyloid precursor protein accumulations as a readout of inflammation and axonal degeneration. To conclude, EPO ameliorates neurological symptoms in the cuprizone model of demyelination, possibly by reduction of inflammation-associated axonal degeneration in white matter tracts. These findings underscore the value of future therapeutic strategies for multiple sclerosis based on EPO or EPO variants.

Topics: Amyloid beta-Protein Precursor; Animals; Axons; Cerebral Ventricles; Corpus Callosum; Cuprizone; Demyelinating Diseases; Erythropoietin; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Postural Balance; Psychomotor Performance

Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.

Topics: Animals; Brain; Brain Damage, Chronic; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Endotoxins; Erythropoietin; Female; Fetal Diseases; Fetal Hypoxia; Injections, Intravenous; Lipopolysaccharides; Nerve Fibers, Myelinated; Neuroprotective Agents; Optic Nerve; Pregnancy; Sheep, Domestic; Treatment Outcome