Treatment with albumin-hydroxyoleic acid complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation.

Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.) administration of the albumin-oleic acid (A-OA) complex in rats with SCI produced partial improvement of these symptoms and that oral 2-hydroxyoleic acid (HOA, a non-hydrolyzable OA analogue), was efficacious in the modulation and treatment of nociception and pain-related anxiety, respectively. Here we observed that intrathecal treatment with the complex albumin-HOA (A-HOA) every 3 days following T9 spinal contusion injury improved locomotor function assessed with the Rotarod and inhibited TA noxious reflex activity in Wistar rats. To investigate the mechanism of action of A-HOA, microarray analysis was carried out in the spinal cord lesion area. Representative genes involved in pain and neuroregeneration were selected to validate the changes observed in the microarray analysis by quantitative real-time RT-PCR. Comparison of the expression between healthy rats, SCI rats, and SCI treated with A-HOA rats revealed relevant changes in the expression of genes associated with neuronal morphogenesis and growth, neuronal survival, pain and inflammation. Thus, treatment with A-HOA not only induced a significant overexpression of growth and differentiation factor 10 (GDF10), tenascin C (TNC), aspirin (ASPN) and sushi-repeat-containing X-linked 2 (SRPX2), but also a significant reduction in the expression of prostaglandin E synthase (PTGES) and phospholipases A1 and A2 (PLA1/2). Currently, SCI has very important unmet clinical needs. A-HOA downregulated genes involved with inflammation and upregulated genes involved in neuronal growth, and may serve to promote recovery of function after experimental SCI.

Spinal cord injury induced changes of nuclear receptors PPARα and LXRß and modulation with oleic acid/albumin treatment.

In previous studies with animal models of spinal cord injury (SCI) pharmacological activation of peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) were used to reduce tissue damage and promote behavioral recovery in animal models. We have studied the endogenous expression of the transcription factors PPARα and LXRß in the chronic stage after SCI in rats. The immunohistochemical investigation revealed a long lasting increase in the level of PPARα in white matter in the vicinity of the lesion site. The source of this signal was identified in a subpopulation of astrocytes outside of the glial scar area. Intrathecal injections of oleic acid/albumin reduced the lesion-induced PPARα immunoreactivity. In addition, ependymal cells displayed a prominent PPARα signal in the non-injured spinal cord, and continued to express the receptor as they proliferated and migrated within the damaged tissue. The nuclear receptor LXRß was detected at similar levels after SCI as in sham operated animals. We found high levels of immunoreactivity in the gray matter, while in the white matter it was present in subpopulations of astrocytes and oligodendrocytes. Macrophages that had accumulated within the center of the lesion contained LXRß in their cell nuclei. Possible endogenous functions of PPARα and LXRß after SCI are discussed, specifically the control of fatty acid and cholesterol metabolism and the regulation of inflammatory reactions.

Neural differentiation of transplanted neural stem cells in a rat model of striatal lacunar infarction: light and electron microscopic observations.

The increased risk and prevalence of lacunar stroke and Parkinson's disease (PD) makes the search for better experimental models an important requirement for translational research. In this study we assess ischemic damage of the nigrostriatal pathway in a model of lacunar stroke evoked by damaging the perforating arteries in the territory of the substantia nigra (SN) of the rat after stereotaxic administration of endothelin-1 (ET-1), a potent vasoconstrictor peptide. We hypothesized that transplantation of neural stem cells (NSCs) with the capacity of differentiating into diverse cell types such as neurons and glia, but with limited proliferation potential, would constitute an alternative and/or adjuvant therapy for lacunar stroke. These cells showed neuritogenic activity in vitro and a high potential for neural differentiation. Light and electron microscopy immunocytochemistry was used to characterize GFP-positive neurons derived from the transplants. 48 h after ET-1 injection, we characterized an area of selective degeneration of dopaminergic neurons within the nigrostriatal pathway characterized with tissue necrosis and glial scar formation, with subsequent behavioral signs of Parkinsonism. Light microscopy showed that grafted cells within the striatal infarction zone differentiated with a high yield into mature glial cells (GFAP-positive) and neuron types present in the normal striatum. Electron microscopy revealed that NSCs-derived neurons integrated into the host circuitry establishing synaptic contacts, mostly of the asymmetric type. Astrocytes were closely associated with normal small-sized blood vessels in the area of infarct, suggesting a possible role in the regulation of the blood brain barrier and angiogenesis. Our results encourage the use of NSCs as a cell-replacement therapy for the treatment of human vascular Parkinsonism.

Valoración y cuantificación de la espasticidad: revisión de los métodos clínicos, biomecánicos y neurofisiológicos / Evaluation and quantification of spasticity: a review of the clinical, biomechanical and neurophysiological methods

Introducción. La espasticidad es un trastorno sensitivomotor que afecta a cerca del 85% de los pacientes con esclerosis múltiple y entre el 65-78% con lesión medular, entre otras patologías neurológicas. Aunque generalmente la hipertoníasuele ser fácil de reconocer clínicamente, su cuantificación resulta bastante compleja. La gran cantidad de escalas clínicasexistentes y su subjetividad, la discrepancia entre la espasticidad percibida por el paciente y la medición clínica, así como la falta de correlación general entre las medidas neurofisiológicas y la hipertonía, otorgan una especial dificultad metodológica a la hora de realizar una medición válida y fiable del grado de espasticidad presente. Objetivo. Revisar los principales métodos de valoración de la espasticidad aparecidos en la literatura científica, realizando unadescripción y análisis crítico de sus ventajas, limitaciones y propiedades métricas en pacientes con patología neurológica.Desarrollo. Se revisan los diversos métodos descritos para la evaluación de la espasticidad, agrupándolos en tres grandesgrupos, las escalas clínicas específicamente diseñadas a tal efecto, las pruebas biomecánicas, así como los métodos neurofisiológicos. Conclusiones. Existe falta de consenso en la definición de la espasticidad, así como en la necesidad de formación y experiencia por parte de los evaluadores a la hora de evaluarla. Se recomienda utilizar una combinación entre los diferentesinstrumentos de valoración, como son las escalas, métodos biomecánicos y medidas neurofisiológicas descritos en elpresente trabajo, para realizar un diagnóstico general del grado de espasticidad presente en el paciente (AU)

Introduction. Spasticity is a sensory-motor disorder that affects about 85% of the patients with multiple sclerosis and between 65-78% of those with spinal cord injury, among other neurological conditions. Although hypertonia is generally easy to recognise clinically, quantifying it is quite a complex matter. The large number of clinical scales that exist and theirsubjectivity, the discrepancy between the spasticity perceived by the patient and the clinical measurement, as well as thelack of a general correlation between the neurophysiological measures and hypertonia, all make it especially difficult, inmethodological terms, to perform a valid, reliable measurement of the degree of spasticity presented by the patient. Aims. To review the main methods of evaluating spasticity published in the scientific literature and to carry out a description and critical analysis of their advantages, shortcomings and metric properties in patients with a neurological pathology. Development. The different methods described for evaluating spasticity are reviewed and classified in three broad groups,namely, clinical scales specifically designed for such a purpose, biomechanical tests and neurophysiological methods.Conclusions. There is little agreement on the definition of spasticity and the need for the evaluators’ training andexperience when it comes to evaluating it. We recommend using a combination of the different evaluation instruments, such as the scales, biomechanical methods and neurophysiological measures reported in this study, to carry out a general diagnosis of the degree of spasticity present in the patient (AU)

[Evaluation and quantification of spasticity: a review of the clinical, biomechanical and neurophysiological methods]. / Valoracion y cuantificacion de la espasticidad: revision de los metodos clinicos, biomecanicos y neurofisiologicos.

INTRODUCTION: Spasticity is a sensory-motor disorder that affects about 85% of the patients with multiple sclerosis and between 65-78% of those with spinal cord injury, among other neurological conditions. Although hypertonia is generally easy to recognise clinically, quantifying it is quite a complex matter. The large number of clinical scales that exist and their subjectivity, the discrepancy between the spasticity perceived by the patient and the clinical measurement, as well as the lack of a general correlation between the neurophysiological measures and hypertonia, all make it especially difficult, in methodological terms, to perform a valid, reliable measurement of the degree of spasticity presented by the patient. AIMS: To review the main methods of evaluating spasticity published in the scientific literature and to carry out a description and critical analysis of their advantages, shortcomings and metric properties in patients with a neurological pathology. DEVELOPMENT: The different methods described for evaluating spasticity are reviewed and classified in three broad groups, namely, clinical scales specifically designed for such a purpose, biomechanical tests and neurophysiological methods. CONCLUSIONS: There is little agreement on the definition of spasticity and the need for the evaluators' training and experience when it comes to evaluating it. We recommend using a combination of the different evaluation instruments, such as the scales, biomechanical methods and neurophysiological measures reported in this study, to carry out a general diagnosis of the degree of spasticity present in the patient.

Effects of ketamine on electroencephalographic and autonomic arousal and segmental reflex responses in the cat.

OBJECTIVE: To provide evidence concerning doses of ketamine that affect electroencephalographic (EEG) and autonomic signs of arousal during nociceptive stimulation. STUDY DESIGN: Prospective psychophysical test in people. Single injection or progressively increasing infusions of ketamine in cats. ANIMALS AND PEOPLE: Seven people (20-60 years old) and three cats (3-5 kg) for EEG recording and six cats for EMG recordings. METHODS: In order to define innocuous and nociceptive stimulus intensities which could be applied to cats to evaluate arousal, psychophysical evaluations of sensations elicited by compression of the skin overlying phalangeal bones of the hand were obtained from human subjects. Then, following administration of ketamine, recordings of EEG frequency and of autonomic responses (heart rate, respiratory rate and arterial blood pressure) were obtained before and during stimulation of the tails of cats at pressures identified by human observers as either innocuous or nociceptive. Observations of withdrawal reflexes of the hindlimbs following interdigital skin stimulation were interposed between recording periods. In separate sessions, stretch reflex activity was assessed during awake and anesthetic conditions by recording electromyographic activity from soleus muscles and resistive force to dorsiflexion of the tibiotarsal joint. RESULTS: There were no changes in either total EEG (0.5-30.0 Hz), low-frequency (0.6-7.5 Hz) or high-frequency (7.5-30.0 Hz) power produced by nociceptive stimulation for a period of 18-24 minutes following an intramuscular bolus dose of ketamine (33.0 mg kg-1), although withdrawal reflexes were present. Thereafter, nociceptive stimulation produced EEG arousal responses in the low-frequency and total power range and increased systolic blood pressure and respiration rate. In tests after intravenous infusion of ketamine (10.0-22.2 mg kg-1 hour-1), total and low-frequency EEG power and autonomic responses to nociceptive stimulation were eliminated. Organized motor responses were never elicited during IV infusion, but withdrawal reflexes were observed at each dosage. Also, stretch reflexes were shown by quantitative analysis to be retained at all doses of ketamine infusion. CONCLUSIONS AND CLINICAL RELEVANCE: These results show that testing of withdrawal reflexes does not reveal the adequacy of ketamine anesthesia. Segmental stretch and withdrawal reflexes are preserved and can be investigated during infusion of ketamine at doses that eliminate arousal from brief periods of nociceptive stimulation.

Mecanismos involucrados en la promoción de crecimiento axonal por la glia envolvente del bulbo olfatorio / Mechanism involved in axonal growth promotion by olfactory bulb ensheathing cells

La actividad que promueve el crecimiento de axones por la glia envolvente (GE) del bulbo olfatorio depemde de la expresión de diversas moléculas durante el desarrollo, la vida adulta y la reparación de lesiones nerviosas. Diversas moléculas tales como las neurotrofinas y sus receptores, los factores de crecimiento, las moléculas de adhesión celular, las moléculas de matriz extracelular y las moleculas asociadas con la mielinización son producidas por la glia del sistema olfatorio durante el desarrollo. Su expresion sostenida durante la vida adulta parece estar asociada con el reemplazo celular y la alta plasticidad de este sistema. A su vez, su expresión se involucra en procesos de reparación de lesiones mediados por trasplantes de glia. La migración de la GE, que acompaña axones en crecimiento, se observa durante el desarrollo y en procesos de regeneración luego de una lesión. Los trasplantes de GE permiten la navegación de brotes regenerantes a través del tejido gliótico inhbidor formado luego de una lesión del sistema nervioso central. El propósito de esta revisión es profundizar en los mecanismos de actividad promotora de crecimiento axonal