Serum S100ß Levels Are Linked with Cognitive Decline and Peripheral Inflammation in Spinocerebellar Ataxia Type 2.

Experimental and clinical studies have indicated a potential role of the protein S100ß in the pathogenesis and phenotype of neurodegenerative diseases. However, its impact on spinocerebellar ataxia type 2 (SCA2) remains to be elucidated. The objective of the study is to determine the serum levels of S100ß in SCA2 and its relationship with molecular, clinical, cognitive, and peripheral inflammatory markers of the disease. Serum concentrations of S100ß were measured by enzyme-linked immunosorbent assay in 39 SCA2 subjects and 36 age- and gender-matched controls. Clinical scores of ataxia, non-ataxia symptoms, cognitive dysfunction, and some blood cell count-derived inflammatory indices were assessed. The SCA2 individuals manifested S100ß levels similar to the control group, at low nanomolar concentrations. However, the S100ß levels were directly associated with a better performance of cognitive evaluation within the SCA2 cohort. Moreover, the S100ß levels were inversely correlated with most peripheral inflammatory indices. Indeed, the neutrophil-to-lymphocyte ratio significantly mediated the effect of serum S100ß on cognitive performance, even after controlling for the ataxia severity in the causal mediation analysis. Our findings suggested that, within physiologic concentrations, the protein S100ß exerts a neuroprotective role against cognitive dysfunction in SCA2, likely via the suppression of pro-inflammatory mechanisms.

The effects of Phycocyanobilin on experimental arthritis involve the reduction in nociception and synovial neutrophil infiltration, inhibition of cytokine production, and modulation of the neuronal proteome.

Introduction: The antinociceptive and pharmacological activities of C-Phycocyanin (C-PC) and Phycocyanobilin (PCB) in the context of inflammatory arthritis remain unexplored so far. In the present study, we aimed to assess the protective actions of these compounds in an experimental mice model that replicates key aspects of human rheumatoid arthritis. Methods: Antigen-induced arthritis (AIA) was established by intradermal injection of methylated bovine serum albumin in C57BL/6 mice, and one hour before the antigen challenge, either C-PC (2, 4, or 8 mg/kg) or PCB (0.1 or 1 mg/kg) were administered intraperitoneally. Proteome profiling was also conducted on glutamate-exposed SH-SY5Y neuronal cells to evaluate the PCB impact on this key signaling pathway associated with nociceptive neuronal sensitization. Results and discussion: C-PC and PCB notably ameliorated hypernociception, synovial neutrophil infiltration, myeloperoxidase activity, and the periarticular cytokine concentration of IFN-γ, TNF-α, IL-17A, and IL-4 dose-dependently in AIA mice. In addition, 1 mg/kg PCB downregulated the gene expression for T-bet, RORγ, and IFN-γ in the popliteal lymph nodes, accompanied by a significant reduction in the pathological arthritic index of AIA mice. Noteworthy, neuronal proteome analysis revealed that PCB modulated biological processes such as pain, inflammation, and glutamatergic transmission, all of which are involved in arthritic pathology. Conclusions: These findings demonstrate the remarkable efficacy of PCB in alleviating the nociception and inflammation in the AIA mice model and shed new light on mechanisms underlying the PCB modulation of the neuronal proteome. This research work opens a new avenue to explore the translational potential of PCB in developing a therapeutic strategy for inflammation and pain in rheumatoid arthritis.

Conectividad funcional a partir de la perfusión cerebral en pacientes epilépticos y con enfermedad de Parkinson / Functional connectivity from cerebral perfusion in patients with epilepsy and Parkinson's disease

Introducción: La epilepsia y la enfermedad de Parkinson han sido descritos como trastornos de redes neurales. El estudio de la conectividad por modalidades moleculares puede ser más relevante fisiológicamente que los basados en señales hemodinámicas. Objetivo: Proponer una metodología para la descripción de patrones de conectividad funcional a partir de la perfusión cerebral por tomografía por emisión de fotón único. Métodos: La metodología incluye cuatro pasos principales: preprocesamiento espacial, corrección del volumen parcial, cálculo del índice de perfusión y obtención de la matriz de conectividad funcional mediante el coeficiente de correlación de Pearson. Se implementó en 25 pacientes con distintos trastornos neurológicos: 15 con epilepsia farmacorresistente y 10 con enfermedad de Parkinson. Resultados: Se encontraron diferencias significativas entre los índice de perfusión de varias regiones de los hemisferios ipsilateral y contralateral tanto en pacientes con epilepsia del lóbulo frontal como en pacientes con epilepsia del lóbulo temporal. Igual resultado se obtuvo en los pacientes con enfermedad de Parkinson con distintos estadios de la enfermedad. Para cada grupo se identificaron patrones de conectividad funcional que involucran a regiones relacionadas con la patología en estudio. Conclusiones: Con el desarrollo de esta metodología se ha demostrado que la tomografía por emisión de fotón único aporta información valiosa para estudiar la organización de las redes funcionales del cerebro. Futuras investigaciones con mayor número de pacientes contribuirían a hacer inferencias sobre los correlatos neurales de los distintos trastornos cerebrales(AU)

Introduction: Epilepsy and Parkinson's disease have been described as disorders of neural networks. The study of connectivity by molecular modalities may be more physiologically relevant than those based on hemodynamic signals. Aim: The aim of the present work is to propose a methodology for the description of functional connectivity patterns from brain perfusion by single photon emission tomography. Methods: The methodology includes four main steps: spatial preprocessing, partial volume correction, calculation of the perfusion index and obtaining the functional connectivity matrix using Pearson's correlation coefficient. It was implemented in 25 patients with different neurological disorders: 15 with drug-resistant epilepsy and 10 suffering Parkinson's disease. Results: Significant differences were found between the perfusion indexes of various regions of the ipsilateral and contralateral hemispheres in both patients with frontal lobe epilepsy and patients with temporal lobe epilepsy. The same result was obtained in Parkinson's disease patients with different stages of the disease. For each group, functional connectivity patterns involving regions related to the pathology under study were identified. Conclusions: With the development of this methodology, it has been demonstrated that single photon emission tomography provides valuable information to study the organization of functional brain networks. Future research with a larger number of patients would contribute to make inferences about the neural correlates of the different brain disorders(AU)

Anti-inflammatory mechanisms and pharmacological actions of phycocyanobilin in a mouse model of experimental autoimmune encephalomyelitis: A therapeutic promise for multiple sclerosis.

Cytokines, demyelination and neuroaxonal degeneration in the central nervous system are pivotal elements implicated in the pathogenesis of multiple sclerosis (MS) and its nonclinical model of experimental autoimmune encephalomyelitis (EAE). Phycocyanobilin (PCB), a chromophore of the biliprotein C-Phycocyanin (C-PC) from Spirulina platensis, has antioxidant, immunoregulatory and anti-inflammatory effects in this disease, and it could complement the effect of other Disease Modifying Treatments (DMT), such as Interferon-ß (IFN-ß). Here, our main goal was to evaluate the potential PCB benefits and its mechanisms of action to counteract the chronic EAE in mice. MOG35-55-induced EAE was implemented in C57BL/6 female mice. Clinical signs, pro-inflammatory cytokines levels by ELISA, qPCR in the brain and immunohistochemistry using precursor/mature oligodendrocytes cells antibodies in the spinal cord, were assessed. PCB enhanced the neurological condition, and waned the brain concentrations of IL-17A and IL-6, pro-inflammatory cytokines, in a dose-dependent manner. A down- or up-regulating activity of PCB at 1 mg/kg was identified in the brain on three (LINGO1, NOTCH1, and TNF-α), and five genes (MAL, CXCL12, MOG, OLIG1, and NKX2-2), respectively. Interestingly, a reduction of demyelination, active microglia/macrophages density, and axonal damage was detected along with an increase in oligodendrocyte precursor cells and mature oligodendrocytes, when assessed the spinal cords of EAE mice that took up PCB. The studies in vitro in rodent encephalitogenic T cells and in vivo in the EAE mouse model with the PCB/IFN-ß combination, showed an enhanced positive effect of this combined therapy. Overall, these results demonstrate the anti-inflammatory activity and the protective properties of PCB on the myelin and support its use with IFN-ß as an improved DMT combination for MS.

Positive effects of Phycocyanobilin on gene expression in glutamate-induced excitotoxicity in SH-SY5Y cells and animal models of multiple sclerosis and cerebral ischemia.

Background: Oxidative stress has a predominant role in the pathogenesis of neurodegenerative diseases and therefore the modulation of genes and the identification of biological pathways associated with antioxidant therapies, have an impact on its treatment. Objective: The objective of this study was the comparison of 2 methods for the analysis of real-time PCR (qPCR) data, through the use of the evaluation of genes that mediate the effect of Phycocyanobilin (PCB) and its validation in animal models. Methods: We evaluated the effect of PCB:" in vitro" on gene modulation through qPCR analyzed by parametric ANOVA and multivariate principal component analysis (PCA) in a model of glutamate-induced excitotoxicity in the SH-SY5Y cell line and" in vivo"; in animal models of multiple sclerosis (MS) and cerebral ischemia (CI). Results: The results showed that PCA is a robust and powerful method that allows the assessment of gene expression profiles. We detected the significant down-regulation of the CYBB (NOX2), and HMOX1 by the action of PCB in SH-5YSH cell line insulted with Glutamate. The decrease in pro-inflammatory cytokines and markers related to apoptosis and innate immune response, mediated the effect of PCB in the animal models of MS and CI, respectively. Conclusion: We concluded that the mechanisms by which PCB protected cells included the reduction of oxidative stress damage, which could contribute to its clinical efficacy for the treatment of neurodegenerative diseases.

Clinical Phenotypes and Mortality Biomarkers: A Study Focused on COVID-19 Patients with Neurological Diseases in Intensive Care Units.

Purpose: To identify clinical phenotypes and biomarkers for best mortality prediction considering age, symptoms and comorbidities in COVID-19 patients with chronic neurological diseases in intensive care units (ICUs). Subjects and Methods: Data included 1252 COVID-19 patients admitted to ICUs in Cuba between January and August 2021. A k-means algorithm based on unsupervised learning was used to identify clinical patterns related to symptoms, comorbidities and age. The Stable Sparse Classifiers procedure (SSC) was employed for predicting mortality. The classification performance was assessed using the area under the receiver operating curve (AUC). Results: Six phenotypes using a modified v-fold cross validation for the k-means algorithm were identified: phenotype class 1, mean age 72.3 years (ys)-hypertension and coronary artery disease, alongside typical COVID-19 symptoms; class 2, mean age 63 ys-asthma, cough and fever; class 3, mean age 74.5 ys-hypertension, diabetes and cough; class 4, mean age 67.8 ys-hypertension and no symptoms; class 5, mean age 53 ys-cough and no comorbidities; class 6, mean age 60 ys-without symptoms or comorbidities. The chronic neurological disease (CND) percentage was distributed in the six phenotypes, predominantly in phenotypes of classes 3 (24.72%) and 4 (35,39%); χ² (5) 11.0129 p = 0.051134. The cerebrovascular disease was concentrated in classes 3 and 4; χ² (5) = 36.63, p = 0.000001. The mortality rate totaled 325 (25.79%), of which 56 (17.23%) had chronic neurological diseases. The highest in-hospital mortality rates were found in phenotypes 1 (37.22%) and 3 (33.98%). The SSC revealed that a neurological symptom (ageusia), together with two neurological diseases (cerebrovascular disease and Parkinson's disease), and in addition to ICU days, age and specific symptoms (fever, cough, dyspnea and chilliness) as well as particular comorbidities (hypertension, diabetes and asthma) indicated the best prediction performance (AUC = 0.67). Conclusions: The identification of clinical phenotypes and mortality biomarkers using practical variables and robust statistical methodologies make several noteworthy contributions to basic and experimental investigations for distinguishing the COVID-19 clinical spectrum and predicting mortality.

Novel Insights into the Molecular Mechanisms Involved in the Neuroprotective Effects of C-Phycocyanin against Brain Ischemia in Rats.

BACKGROUND: Ischemic stroke produces a large health impact worldwide, with scarce therapeutic options. OBJECTIVE: This study aimed to reveal the role of NADPH oxidase and neuroinflammatory genes in the cerebral anti-ischemic effects of C-Phycocyanin (C-PC), the chief biliprotein of Spirulina platensis. METHODS: Rats with either focal cerebral ischemia/reperfusion (I/R) or acute brain hypoperfusion, received C-PC at different doses, or a vehicle, for up to 6 h post-stroke. Neurological, behavioral and histochemical parameters were assessed in I/R rats at 24 h. Cerebral gene expression and hippocampal neuron viability were evaluated in hypoperfused rats at acute (24 h) or chronic phases (30 days), respectively. A molecular docking analysis of NOX2 and C-PC-derived Phycocyanobilin (PCB) was also performed. RESULTS: C-PC, obtained with a purity of 4.342, significantly reduced the infarct volume and neurological deficit in a dose-dependent manner, and improved the exploratory activity of I/R rats. This biliprotein inhibited NOX2 expression, a crucial NADPH oxidase isoform in the brain, and the superoxide increase produced by the ischemic event. Moreover, C-PC-derived PCB showed a high binding affinity in silico with NOX2. C-PC downregulated the expression of pro-inflammatory genes (IFN-γ, IL-6, IL-17A, CD74, CCL12) and upregulated immune suppressive genes (Foxp3, IL-4, TGF-ß) in hypoperfused brain areas. This compound also decreased chronic neuronal death in the hippocampus of hypoperfused rats. CONCLUSION: These results suggest that the inhibition of cerebral NADPH oxidase and the improvement of neuroinflammation are key mechanisms mediating the neuroprotective actions of C-PC against brain ischemia.

Phycocyanobilin reduces brain injury after endothelin-1- induced focal cerebral ischaemia.

Pharmacological therapies for interrupting biochemical events of the ischaemic cascade and protecting against stroke in humans are as yet unavailable. Up to now, the neuroprotective activity in cerebral ischaemia of phycocyanobilin (PCB), a tetrapyrrolic natural antioxidant, has not been fully examined. Here, we evaluated if PCB protects PC12 neuronal cells against oxygen and glucose deprivation plus reperfusion, and its protective effects in a rat model of endothelin-1-induced focal brain ischaemia. PCB was purified from the cyanobacteria Spirulina platensis and characterized by spectrophotometric, liquid and gas chromatography and mass spectrometry techniques. In Wistar rats, PCB at 50, 100 and 200 µg/kg or phosphate-buffered saline (vehicle) was administered intraperitoneally at equal subdoses in a therapeutic schedule (30 minutes, 1, 3 and 6 hours after the surgery). Brain expression of myelin basic protein (MBP) and the enzyme CNPase was determined by immunoelectron microscopy. PCB was obtained with high purity (>95%) and the absence of solvent contaminants and was able to ameliorate PC12 cell ischaemic injury. PCB treatment significantly decreased brain infarct volume, limited the exploratory behaviour impairment and preserved viable cortical neurons in ischaemic rats in a dose-dependent manner, compared to the vehicle group. Furthermore, PCB at high doses restored the MBP and CNPase expression levels in ischaemic rats. An improved PCB purification method from its natural source is reported, obtaining PCB that is suitable for pharmacological trials showing neuroprotective effects against experimental ischaemic stroke. Therefore, PCB could be a therapeutic pharmacological alternative for ischaemic stroke patients.

Trastornos neuropsiquiátricos autoinmunes asociados a infecciónestreptocócica en la edad pediátrica / Autoimmune neuropsychiatric disorders associated with streptococcal infection in the pediatric age

Objetivo: Identificar los aspectos clínicos de pacientes pediátricos con trastornos neuropsiquiátricos autoinmunes, asociados a infección estreptocócica.Métodos: Se realizó un estudio descriptivo. Se tomó la información de las historias clínicas de todos los pacientes cubanos con trastornos neuropsiquiátricos autoinmunesasociados a infección estreptocócica en edad pediátrica, atendidos en el CentroInternacional de Restauración Neurológica de La Habana, entre enero de 2001 y agosto de 2018. Hubo 56 pacientes que cumplieron con los criterios diagnósticos de dicho trastorno, y todos fueron incluidos en el estudio. Entre las variables más relevantesanalizadas estuvieron la edad de inicio de los síntomas, la historia de infecciones recurrentes y los síntomas clínicos. Para el análisis de los datos se utilizaron métodos de la estadística descriptiva, como la media aritmética, la moda, la proporción y los porcentajes.Resultados: La edad promedio de inicio del cuadro fue de 6,7 ± 2,7 años (desviación estándar). Refirieron alguna infección a repetición 36 pacientes (64,29 Por ciento). Los síntomasclínicos más frecuentes fueron tics y trastornos de conducta en 52 casos (92,86 Por ciento), seguido por trastorno de déficit de atención con hiperactividad en 41 (73,21 Por ciento) y deterioro en el rendimiento escolar en 27 (48,21 Por ciento).Conclusiones: Los trastornos neuropsiquiátricos autoinmunes asociados a infección estreptocócica en la edad pediátrica fueron más frecuentes en los pacientes del sexomasculino. Están relacionados con la presencia de infecciones a repetición, sobre todo de las vías respiratorias alta. No está claro su carácter hereditario. Los síntomas pueden ser disímiles y, en algunos casos, difíciles de definir. El motivo de consulta más frecuente de estos pacientes fue las tics(AU)

Objective: To identify the clinical aspects of pediatric patients with autoimmune neuropsychiatric disorders associated with streptococcal infection.Methods: A descriptive study was carried out. Information was taken from the medical records of all Cuban pediatric patients with autoimmune neuropsychiatric disorders associated with streptococcal infection, treated at the International NeurologicalRestoration Center of Havana, from January 2001 to August 2018. Fifty-six (56) patients met the diagnostic criteria for this disorder, and all were included in this study.The most relevant variables analyzed were age of the onset of symptoms, history of recurrent infections and clinical symptoms. Descriptive statistics methods were used for data analysis, such as the arithmetic mean, mode, proportion and percentages.Results: The age average of the onset of symptoms was of 6, 7 ± 2,7 years (standard deviation). Thirty-six patients referred some repeated infection (64,29 Per cent). The clinical most frequent symptoms were tics and behavior dysfunctions in 52 cases (92,86 Per cent), followed by dysfunction of deficit of attention with hyperactivity in 41 (73,21 Per cent) and poor school performance in 27 (48,21 Per cent).Conclusions: Autoimmune neuropsychiatric disorders associated with streptococcal infection in the pediatric age were more frequent in male patients. They are related tothe presence of repeated infections, especially of the upper respiratory tract. Its hereditary character is not clear. The symptoms can be dissimilar and, in some cases, difficult to define. The most frequent reason for consultation of these patients was tics(AU)

Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure.

Oxidative stress (OS) has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS) patients compared to a control group (age and sex matched), and the results were related to clinical variables. We examined malondialdehyde (MDA), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), nitric oxide (NO), uric acid, superoxide dismutase (SOD), glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine (3-NT). All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001) while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively). Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005) similarly to SOD activity (p = 0.0001), whereas vitamin C was considerably diminished (p = 0.0001). Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

Follow-Up of Peripheral IL-1ß and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery.

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1ß and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1ß and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

Beneficial effects of oral administration of C-Phycocyanin and Phycocyanobilin in rodent models of experimental autoimmune encephalomyelitis.

The only three oral treatments currently available for multiple sclerosis (MS) target the relapsing forms of the disease and concerns regarding efficacy, safety and tolerability limit their use. Identifying novel oral disease-modifying therapies for MS, targeting both its inflammatory and neurodegenerative components is still a major goal. AIM: The scope of this study was to provide evidence that the oral administration of C-Phycocyanin (C-PC), the main biliprotein of the Spirulina platensis cyanobacteria and its tetrapyrrolic prosthetic group, Phycocyanobilin (PCB), exert ameliorating actions on rodent models of experimental autoimmune encephalomyelitis (EAE). MAIN METHODS: EAE was induced in Lewis rats using the spinal cord encephalitogen from Sprague Dawley rats and in C57BL6 mice with MOG35-55 peptide. Clinical signs, motor function, oxidative stress markers, cytokine levels by ELISA and transmission electron microscopy analysis were assessed. KEY FINDINGS: Either prophylactic or early therapeutic administration of C-PC to Lewis rats with EAE, significantly improved clinical signs and restored the motor function of the animals. Furthermore, C-PC positively modulated oxidative stress markers measured in brain homogenate and serum and protected the integrity of cerebral myelin sheaths as shown by transmission electron microscopy analysis. In C57BL/6 mice with EAE, PCB orally improved clinical status of the animals and reduced the expression levels of brain IL-6 and IFN-γ proinflammatory cytokines. SIGNIFICANCE: These results, for the first time, support the fact that both C-PC and PCB administered orally could potentially improve neuroinflammation, protect from demyelination and axonal loss, which may be translated into an improved quality of life for MS patients.

Transient glutathione depletion in the substantia nigra compacta is associated with neuroinflammation in rats.

Glutathione (GSH) deficiency has been identified as an early event in the progression of Parkinson's disease. However, the role of GSH in the etiology and pathogenesis of this neurodegenerative disorder is not well established. The aim of this study is to assess the effect of transient GSH depletion in the substantia nigra pars compacta (SNpc) on neuroinflammation after the injection of a single dose of l-buthionine sulfoximine (BSO) into the SNpc of male Sprague-Dawley rats. The results showed that BSO treatment stimulates microglia (p<0.01) and astroglial response (p<0.01), c-Jun N-terminal kinase and inducible nitric oxide synthase (iNOS) (p<0.001) in the SNpc, accompanied by dopaminergic dysfunction. In addition, high levels of tumor necrosis factor α (p<0.01), interleukins IL-1ß p<0.01), IL-6 p<0.001) and nitric oxide p<0.01) were found in the treated animals compared to control groups, while no significant differences were found in IL-10 levels. These results suggest that transient GSH depletion can increase the susceptibility of SNpc to degeneration by promoting an inflammatory response and nitrosative stress, reinforcing the possible role of GSH unbalance, oxygen/nitrogen reactive species and neuroinflammation as causal factors on the degeneration of the SNpc.

EPO induces changes in synaptic transmission and plasticity in the dentate gyrus of rats.

Erythropoietin has shown wide physiological effects on the central nervous system in animal models of disease, and in healthy animals. We have recently shown that systemic EPO administration 15 min, but not 5 h, after daily training in a water maze is able to induce the recovery of spatial memory in fimbria-fornix chronic-lesioned animals, suggesting that acute EPO triggers mechanisms which can modulate the active neural plasticity mechanism involved in spatial memory acquisition in lesioned animals. Additionally, this EPO effect is accompanied by the up-regulation of plasticity-related early genes. More remarkably, this time-dependent effects on learning recovery could signify that EPO in nerve system modulate specific living-cellular processes. In the present article, we focus on the question if EPO could modulate the induction of long-term synaptic plasticity like LTP and LTD, which presumably could support our previous published data. Our results show that acute EPO peripheral administration 15 min before the induction of synaptic plasticity is able to increase the magnitude of the LTP (more prominent in PSA than fEPSP-Slope) to facilitate the induction of LTD, and to protect LTP from depotentiation. These findings showing that EPO modulates in vivo synaptic plasticity sustain the assumption that EPO can act not only as a neuroprotective substance, but is also able to modulate transient neural plasticity mechanisms and therefore to promote the recovery of nerve function after an established chronic brain lesion. According to these results, EPO could be use as a molecular tool for neurorestaurative treatments.