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Suardiaz M.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Galan-Arriero I.,Hospital Nacional Of Paraplejicos | Avila-Martin G.,Hospital Nacional Of Paraplejicos | Estivill-Torrus G.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | And 6 more authors.
European Journal of Pain (United Kingdom) | Year: 2016

Background Although activation of the lysophosphatidic acid receptor 1 (LPA1) is known to mediate pronociceptive effects in peripheral pain models, the role of this receptor in the modulation of spinal nociception following spinal cord injury (SCI) is unknown. Aim In this study, LPA1 regulation of spinal excitability mediated by supraspinal descending antinociceptive control systems was assessed following SCI in both wild-type (WT) and maLPA1-null receptor mice. Methods The effect of a T8 spinal compression in WT and maLPA1-null mice was assessed up to 1 month after SCI using histological, immunohistochemical and behavioural techniques analysis including electrophysiological recording of noxious toes-Tibialis Anterior (TA) stimulus-response reflex activity. The effect of a T3 paraspinal transcutaneous electrical conditioning stimulus on TA noxious reflex temporal summation was also assessed. Results Histological analysis demonstrated greater dorsolateral funiculus damage after SCI in maLPA1-null mice, without a change in the stimulus-response function of the TA noxious reflex when compared to WT mice. While T3 conditioning stimulation in the WT group inhibited noxious TA reflex temporal summation after SCI, this stimulus strongly excited TA reflex temporal summation in maLPA1-null mice. The functional switch from descending inhibition to maladaptive facilitation of central excitability of spinal nociception demonstrated in maLPA1-null mice after SCI was unrelated to a general change in reflex activity. Conclusions These data suggest that the LPA1 receptor is necessary for inhibition of temporal summation of noxious reflex activity, partly mediated via long-tract descending modulatory systems acting at the spinal level. © 2015 European Pain Federation.


PubMed | University of Castilla - La Mancha, Scripps Research Institute, Hospital Nacional Of Paraplejicos, Instituto Cajal and Hospitales Universitarios Regional Of Malaga rgen Of La Victoria
Type: Journal Article | Journal: European journal of pain (London, England) | Year: 2016

Although activation of the lysophosphatidic acid receptor 1 (LPA1) is known to mediate pronociceptive effects in peripheral pain models, the role of this receptor in the modulation of spinal nociception following spinal cord injury (SCI) is unknown.In this study, LPA1 regulation of spinal excitability mediated by supraspinal descending antinociceptive control systems was assessed following SCI in both wild-type (WT) and maLPA1-null receptor mice.The effect of a T8 spinal compression in WT and maLPA1-null mice was assessed up to 1 month after SCI using histological, immunohistochemical and behavioural techniques analysis including electrophysiological recording of noxious toes-Tibialis Anterior (TA) stimulus-response reflex activity. The effect of a T3 paraspinal transcutaneous electrical conditioning stimulus on TA noxious reflex temporal summation was also assessed.Histological analysis demonstrated greater dorsolateral funiculus damage after SCI in maLPA1-null mice, without a change in the stimulus-response function of the TA noxious reflex when compared to WT mice. While T3 conditioning stimulation in the WT group inhibited noxious TA reflex temporal summation after SCI, this stimulus strongly excited TA reflex temporal summation in maLPA1-null mice. The functional switch from descending inhibition to maladaptive facilitation of central excitability of spinal nociception demonstrated in maLPA1-null mice after SCI was unrelated to a general change in reflex activity.These data suggest that the LPA1 receptor is necessary for inhibition of temporal summation of noxious reflex activity, partly mediated via long-tract descending modulatory systems acting at the spinal level.


Garcia-Diaz B.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Garcia-Diaz B.,Columbia University | Riquelme R.,Autonomous University of Madrid | Varela-Nieto I.,Autonomous University of Madrid | And 12 more authors.
Brain Structure and Function | Year: 2015

Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA1–6). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases. © 2014, Springer-Verlag Berlin Heidelberg.


Tur A.G.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Casares N.G.,University of Malaga | De La Cruz Cosme C.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Parras M.J.,Hospital Regional Universitario rgen Of La Victoria | And 4 more authors.
Emergencias | Year: 2015

Objective. To analyze the variables associated with better functional outcome 3 months after ischemic stroke treated with fibrinolytic agents. Material and methods. The cases of 63 patients with characteristics leading to activation of a stroke code were analyzed retrospectively. The patients received fibrinolytic therapy in a referral hospital for the western district of Malaga, Spain. We recorded the time until start of fibrinolytic therapy, severity according to the National Institute of Health Stroke Scale (NIHSS) at baseline and at 24 hours, and functional outcome at 3 months according to the modified Rankin Scale. Results. Data for 63 patients with a mean (SD) age of 65 (11) years were included. The mean time until start of fibrinolytic therapy was 151 (42) minutes. The mean NIHSS scores were 15.5 (4.8) points at baseline and 9.1 (7.13) at 24 hours. The mean change in score at 24 hours was 6.3 (5.8) points. The findings of correlation analysis between scores on the modified Rankin scale and other variables were as follows: NIHSS score at 24 hours, ρ = 0.73; P <.01; NIHSS at baseline, ρ = 0.34; P =.01); age, ρ = 0.41; P =.001); time until start of fibrinolysis, ρ = 0.21; P =.09); change in NIHSS score at 24 hours, ρ = –0.61; P =.001). Conclusions. The prognosis for the functional recovery of patients given intravenous fibrinolytic therapy after stroke depends on such factors as age, time treatment is started, severity, and the patient’s status at 24 hours. The last factor is the one that is most strongly related to prognosis. © 2015, Emergencias. All rights reserved.


Castilla-Ortega E.,Hospital Regional Universitario Of Malaga | Blanco E.,University of Lleida | Serrano A.,Hospital Regional Universitario Of Malaga | Ladron De Guevara-Miranda D.,University of Malaga | And 5 more authors.
Addiction Biology | Year: 2016

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. © 2015 Society for the Study of Addiction.


PubMed | University of Malaga, Hospital Regional Universitario Of Malaga and Hospitales Universitarios Regional Of Malaga rgen Of La Victoria
Type: Journal Article | Journal: Behavioural brain research | Year: 2015

The identification of behavioral traits that could predict an individuals susceptibility to engage in cocaine addiction is relevant for understanding and preventing this disorder, but investigations of cocaine addicts rarely allow us to determinate whether their behavioral attributes are a cause or a consequence of drug use. To study the behaviors that predict cocaine vulnerability, male C57BL/6J mice were examined in a battery of tests (the elevated plus maze, hole-board, novelty preference in the Y-Maze, episodic-like object recognition and forced swimming) prior to training in a cocaine-conditioned place preference (CPP) paradigm to assess the reinforcing value of the drug. In a second study, the anatomical basis of high and low CPP in the mouse brain was investigated by studying the number of neurons (neuronal nuclei-positive) in two addiction-related limbic regions (the medial prefrontal cortex and the basolateral amygdala) and the number of dopaminergic neurons (tyrosine hydroxylase-positive) in the ventral tegmental area by immunohistochemistry and stereology. Correlational analyses revealed that CPP behavior was successfully predicted by anxiety-like measures in the elevated plus maze (i.e., the more anxious mice showed more preference for the cocaine-paired compartment) but not by the other behaviors analyzed. In addition, increased numbers of neurons were found in the basolateral amygdala of the high CPP mice, a key brain center for anxiety and fear responses. The results support the theory that anxiety is a relevant factor for cocaine vulnerability, and the basolateral amygdala is a potential neurobiological substrate where both anxiety and cocaine vulnerability could overlap.


PubMed | University of Lleida, Hospital Regional Universitario Of Malaga, University of Malaga and Hospitales Universitarios Regional Of Malaga rgen Of La Victoria
Type: Journal Article | Journal: Addiction biology | Year: 2016

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.


Marin-Banasco C.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Garcia M.S.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Guerrero I.H.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | Sanchez R.M.,Hospitales Universitarios Regional Of Malaga rgen Of La Victoria | And 3 more authors.
Stem Cell Research and Therapy | Year: 2014

Introduction: Mesenchymal stem cells (MSCs) are a multipotent population of adult stem cells, which may represent a promising therapeutic approach for neurological autoimmune diseases such as multiple sclerosis. The mouse is the most used species for obtaining and studying the characteristics of MSC and their potential as autologous transplants in pre-clinical models. However, conflicting data have been published disclosing intraspecies variations. The choice of the mouse strain and the tissue source appear, among others, as important factors in the experimental application of MSCs. Methods: Adipose tissue-derived MSCs obtained from the SJL/JCrl mouse strain (SJL-AdMSC) have been cultured for a long time (from passage 0 up to 15) under controlled experimental conditions, and their growth rate, morphology, stromal and haematopoietic marker expression profiles and differentiation capacity towards adipocytes, osteocytes and chondrocytes have been determined. Moreover, their preclinical efficacy has been assessed by autologous transplant in relapsing-remitting experimental autoimmune encephalomielitis (RR-EAE)-induced SJL mice (a well established mice model for the study of RR-multiple sclerosis). Results: We demonstrate that SJL-AdMSCs show the same fibroblastic shape, growth rate, profile of markers expression and multipotency described for MSCs in every passage evaluated (up to passage 15). Additionally, SJL-AdMSCs ameliorate the RR-EAE course, suggesting that they could modulate disease progression. Moreover, their features studied are fully comparable with the standardized Ad-MSCs obtained from the C57BL/6 mouse strain, which strengthens their use in cell therapy. Conclusion: SJL-AdMSCs might be a suitable source of Ad-MSCs for studies related to the properties of MSCs and their application as promising therapeutic tools in autologous transplants in experimental medicine. © 2014 Marin-Bañasco et al.; licensee BioMed Central.

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