losartan-potassium and Multiple-System-Atrophy

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease-modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)-α-synuclein transgenic mice exposed to 3-nitropropionic acid featuring multiple system atrophy-like pathology including oligodendroglial α-synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3-nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate-regulated phosphoprotein (DARPP-32) was analyzed stereologically. Animals receiving erythropoietin before and after 3-nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3-nitropropionic acid-treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3-nitropropionic acid-induced loss of tyrosine hydroxylase and DARPP-32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin-treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)-α-synuclein 3-nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy.

Topics: alpha-Synuclein; Animals; Cell Death; Convulsants; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Drug Administration Schedule; Erythropoietin; Exploratory Behavior; Humans; Mice; Mice, Transgenic; Motor Activity; Multiple System Atrophy; Myelin Proteolipid Protein; Nitro Compounds; Propionates; Substantia Nigra; Tyrosine 3-Monooxygenase

Symptomatic autonomic neuropathy and in particular sympathetic failure mediated postural hypotension often accompanies Multiple System Atrophy (MSA). Release of erythropietin is under sympathetic control and we and others have previously reported that severe autonomic failure may be associated with a normocytic normochromic anaemia and erythopietin (EPO) deficiency. In this paper we describe the haematological, cardiovascular and clinical observations on a patient with MSA and severe symptomatic autonomic neuropathy who had haematological and clinical improvement (substantial increase in standing blood pressure) following subcutaneous EPO treatment.

Topics: Aged; Autonomic Nervous System Diseases; Blood; Blood Pressure; Cardiovascular System; Erythropoietin; Female; Humans; Multiple System Atrophy; Treatment Outcome

Serum erythropoietin (EPO) levels are partially controlled by the sympathetic outflow to the kidney. We have studied whether patients with multiple system atrophy (MSA), known to be associated with dysautonomia, are EPO-deficient. Eighteen MSA patients were studied along with 32 idiopathic Parkinson's disease (PD) patients, 23 controls with iron-deficiency anaemia, and 18 healthy individuals. Serum creatinine was normal in all groups. Mean haemoglobin (Hb) concentration in MSA patients was 13.7 +/- 1.7 g/dL. Four MSA patients had unexplained anaemia (minimum Hb: 10.5 g/dL) and abnormal autonomic function tests including significant postural hypotension, whereas none of the PD patients was anaemic. Serum EPO levels were suppressed in relation to anaemia in MSA patients compared to elevated EPO levels in iron-deficiency anaemia patients (difference of regression lines P < 0.001), indicating EPO deficiency in the anaemic MSA patients. Serum EPO levels in PD patients were within normal range. A subset of MSA patients has anaemia and postural hypotension, which may be associated with EPO deficiency. This may have therapeutic implications.

Topics: Anemia; Autonomic Nervous System Diseases; Cardiovascular System; Creatinine; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Heart Rate; Hemoglobins; Humans; Hypotension, Orthostatic; Male; Middle Aged; Multiple System Atrophy; Severity of Illness Index