Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof-of-Principle Issues from a Randomized Controlled Study.

BACKGROUND: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. OBJECTIVE: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. METHODS: Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. RESULTS: The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. CONCLUSIONS: This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.

Campo magnético de frecuencia extremadamente baja: Seguridad de su aplicación a nivel del sistema nervioso central / Magnetic field of extremely low frequency: Safety of its application at the level of the central nervous system

Introducción: La enfermedad cerebrovascular constituye un importante problema de salud a nivel mundial. En la actualidad se desarrollan investigaciones científicas dedicadas al estudio de los efectos del campo magnético de frecuencia extremadamente baja para su tratamiento. No es suficientemente clara la información acerca de su inocuidad en las dosis estudiadas. Objetivo: Estudiar la seguridad de la aplicación del campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central a través de un estudio toxicológico a dosis aguda, repetida y ensayo de micronúcleos en médula ósea. Métodos: Se conformaron tres grupos experimentales con ratas Sprague Dawley Cenp:SPRD jóvenes y sanas para los experimentos de toxicidad y ratones CENP: NMRI para la evaluación mutagénica. Se utilizaron controles negativos no tratados. En el ensayo de micronúcleos se incorporó un grupo control positivo al que se administró Ciclofosfamida por vía intraperitoneal. Se aplicó un campo magnético no homogéneo con niveles de inducción magnética de 6,5 y 15 mT, tomando como referencia el valor máximo sobre la superficie de la bobina. Para la aplicación del campo magnético la bobina estimuladora se colocó sobre la cabeza asegurando la exposición completa del encéfalo. Resultados: En ninguno de los ensayos se detectaron signos de toxicidad. Se comprobó así mismo que no se indujeron efectos genotóxicos ni citotóxicos sobre las células somáticas. Conclusiones: El tratamiento con campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central en las condiciones experimentales y dosis estudiadas es seguro(AU)

Introduction: Stroke is a major health problem all over the world. Nowadays are developed scientific researches devoted to the study of extremely low frequency magnetic field effects over this illness. The information about it safety is unclear yet. Objective: To study the safety of extremely low frequency magnetic field applied at central nervous system level wasby means ofa toxicological assay (Acute, repeated doses and micronucleus in bone marrow assay) Methods: Three experimental groups were made with Sprague Dawley Cenp: SPRD young and healthy rats for toxicity experiments and CENP: NMRI mice for mutagen evaluation. Untreated negative controls were used. In the micronucleus assay, an additional positive control group was included. This group received Cyclophosphamide by intraperitoneal administration. Was applied a non-homogenousmagnetic fieldof 6,5 and 15 mT, taken as reference the maximum value over the coil surface. The coil was positioned over the head, ensuring full exposure of brain to magnetic field. Results : In none of trials were detected any sign of toxicity. It was also found no genotoxic or cytotoxic effects induced on somatic cells. Conclusions : These results indicated the safety of treatmentwith extremely low frequency magnetic field at central nervous system level for experimental conditions and doses studied(AU)

Changes in the expression level of MAPK pathway components induced by monosodium glutamate-administration produce neuronal death in the hippocampus from neonatal rats.

Excessive Glutamate (Glu) release may trigger excitotoxic cellular death by the activation of intracellular signaling pathways that transduce extracellular signals to the cell nucleus, which determines the onset of a death program. One such signaling pathway is the mitogen-activated protein kinases (MAPK), which is involved in both survival and cell death. Experimental evidences from the use of specific inhibitors supports the participation of some MAPK pathway components in the excitotoxicity mechanism, but the complete process of this activation, which terminates in cell damage and death, is not clearly understood. The present work, we investigated the changes in the expression level of some MAPK-pathway components in hippocampal excitotoxic cell death in the neonatal rats using an experimental model of subcutaneous monosodium glutamate (MSG) administration on postnatal days (PD) 1, 3, 5 and 7. Data were collected at different ages through PD 14. Cell viability was evaluated using fluorescein diacetate mixed with propidium iodide (FDA-PI), and the Nissl-staining technique was used to evaluate histological damage. Transcriptional changes were also investigated in 98 components of the MAPK pathway that are associated with cell damage. These results are an evidence of that repetitive use of MSG, in neonatal rats, induces cell damage-associated transcriptional changes of MAPK components, that might reflect a differential stage of both biochemical and molecular brain maturation. This work also suggests that some of the proteins evaluated such as phosphorylated retinoblastoma (pRb) protein, which was up-regulated, could regulate the response to excitotoxic through modulation of the process of re-entry into the cell cycle in the hippocampus of rats treated with MSG.

Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study.

BACKGROUND: Delivery of therapeutic agents as erythropoietin (EPO) into Central Nervous System through intranasal route could benefit patients with neurological disorders. A new nasal formulation containing a non-hematopoietic recombinant EPO (NeuroEPO) has shown neuroprotective actions in preclinical models. In the current study, the safety of NeuroEPO was evaluated for the first time in humans. METHODS: A phase I, randomized, parallel, open-label study was carried out in healthy volunteers. They received, intranasally, 1 mg of NeuroEPO every 8 h during 4 days (Group A) or 0.5 mg of NeuroEPO (Group B) with the same schedule. The working hypothesis was that intranasal NeuroEPO produce <10% of severe adverse reactions in the evaluated groups. Therefore, a rigorous assessment of possible adverse events was carried out, which included tolerance of the nasal mucosa and the effect on hematopoietic activity. Clinical safety evaluation was daily during treatment and laboratory tests were done before and on days 5 and 14 after starting treatment. RESULTS: Twenty-five volunteers, 56% women, with a mean age of 27 yrs. were included. Twelve of them received the highest NeuroEPO dose. Twenty types of adverse events occurred, with headache (20%) and increase of hepatic enzymes (20%) as the most reported ones. Nasopharyngeal itching was the most common local event but only observed in four patients (16%), all of them from the lowest dose group. About half of the events were very probably or probably caused by the studied product. Most of the events were mild (95.5%), did not require treatment (88.6%) and were completely resolved (81.8%). No severe adverse events were reported. During the study the hematopoietic variables were kept within reference values. CONCLUSIONS: NeuroEPO was a safe product, well tolerated at the nasal mucosa level and did not stimulate erythropoiesis in healthy volunteers. TRIAL REGISTRATION: Cuban Public Registry of Clinical Trials RPCEC00000157 , June 10, 2013.

Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aß25₋35 non-transgenic mouse model of Alzheimer's disease.

Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aß25₋35 peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aß25₋35 toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aß25₋35-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aß25₋35-induced increase in Bax level, TNFα and IL-1ß production and decrease in Akt activation. A significant prevention of the Aß25₋35-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aß25₋35 AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.

Neuroquímica de la esquizofrenia: bases para una nueva teoría / Neurochemistry of the schizophrenia: bases of the new theory

Desde finales del siglo XX se han obtenido notables progresos en el campo de la ciencia y la tecnología, que han dejado un impacto positivo en la Neurobiología. Muchos de estos estudios van dirigidos a identificar los mecanismos neuronales de los procesos cognitivos normales, así como la comprensión de cómo estos se ven alterados en los trastornos mentales. En este trabajo presentaremos en forma resumida las fundamentales bases neuroquímicas de uno de los fundamentales trastornos mentales: la esquizofrenia, dando aquellos elementos que nos lleva a formular los primeros elementos para una nueva teoría que pudiera explicar los orígenes de la misma, donde los factores neurotróficos, específicamente las neurotrofinas desempeñan un papel protagónico