Centro Investigacion Principe Felipe

Valencia, Spain

Centro Investigacion Principe Felipe

Valencia, Spain
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The invention relates to 3-arms star-shaped polyglutamic derivatives which are able to self-assemble to form bioresponsive nanometric globular structures with controllable size and shape. These multivalent constructs also present the ability of disassemble under specific physiological conditions and of linking covalently to agent(s) such as a drug and/or imaging probes and/or targeting moiety so that they can be used as carries in biomedical applications.


Johansson M.,Umecrine Cognition AB | Agusti A.,INCLIVA | Llansola M.,Centro Investigacion Principe Felipe | Montoliu C.,INCLIVA | And 6 more authors.
American journal of physiology. Gastrointestinal and liver physiology | Year: 2015

Hepatic encephalopathy (HE) is one of the primary complications of liver cirrhosis. Current treatments for HE, mainly directed to reduction of ammonia levels, are not effective enough because they cannot completely eliminate hyperammonemia and inflammation, which induce the neurological alterations. Studies in animal models show that overactivation of GABAA receptors is involved in cognitive and motor impairment in HE and that reducing this activation restores these functions. We have developed a new compound, GR3027, that selectively antagonizes the enhanced activation of GABAA receptors by neurosteroids such as allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (THDOC). This work aimed to assess whether GR3027 improves motor incoordination, spatial learning, and circadian rhythms of activity in rats with HE. GR3027 was administered subcutaneously to two main models of HE: rats with chronic hyperammonemia due to ammonia feeding and rats with portacaval shunts (PCS). Motor coordination was assessed in beam walking and spatial learning and memory in the Morris water maze and the radial maze. Circadian rhythms of ambulatory and vertical activity were also assessed. In both hyperammonemic and PCS rats, GR3027 restores motor coordination, spatial memory in the Morris water maze, and spatial learning in the radial maze. GR3027 also partially restores circadian rhythms of ambulatory and vertical activity in PCS rats. GR3027 is a novel approach to treatment of HE that would normalize neurological functions altered because of enhanced GABAergic tone, affording more complete normalization of cognitive and motor function than current treatments for HE. Copyright © 2015 the American Physiological Society.


Cauli O.,Centro Investigacion Principe Felipe | Cauli O.,University of Valencia | Llansola M.,Centro Investigacion Principe Felipe | Agusti A.,Centro Investigacion Principe Felipe | And 6 more authors.
Liver International | Year: 2014

Background & Aims: Low-grade cytotoxic oedema is considered a main contributor to the neurological (motor and cognitive) alterations in patients with hepatic encephalopathy (HE). This assumption is mainly based on studies with cultured astrocytes treated with very large ammonia concentrations or with animal models of acute liver failure with strong HE. However, the possible contribution of cerebral oedema (vasogenic or cytotoxic) to cognitive or motor alterations in chronic mild HE has not been demonstrated. The aim of this work was to assess whether cerebral oedema contributes to cognitive and/or motor alterations in rats with chronic mild HE. Methods: Motor activity and coordination and different types of learning and memory were assessed in rats with porta-caval shunts (PCS). Brain oedema was assessed by gravimetry in cerebellum and cortex and apparent diffusion coefficient (ADC) by magnetic resonance in 16 areas. Results: Four weeks after surgery, PCS rats show reduced motor activity and coordination, impaired ability to learn a conditional discrimination task in the Y maze and reduced spatial memory in the Morris water maze. PCS rats did not show increased brain water content at 4 or 10 weeks or changes in ADC at 4 weeks. At 10 weeks, increased ADC in some areas is compatible with vasogenic but not cytotoxic oedema. Conclusion: Cerebral oedema is not involved in motor and cognitive alterations in rats (and likely in humans) with mild HE. Proper understanding of the mechanisms responsible for the neurological alterations in HE is necessary to design efficient treatments. © 2013 John Wiley & Sons A/S.


Felipo V.,Centro Investigacion Principe Felipe | Ordono J.F.,Hospital Arnau Of Vilanova | Ordono J.F.,Psychopatology and Neurophysiology Unit | Urios A.,Fundacion Investigacion Hospital Clinico Universitario | And 10 more authors.
Hepatology | Year: 2012

Attention deficit is an early event in the cognitive impairment of patients with minimal hepatic encephalopathy (MHE). The underlying mechanisms remain unclear. Mismatch negativity (MMN) is an auditory event-related potential that reflects an attentional trigger. Patients with schizophrenia show impaired attention and cognitive function, which are reflected in altered MMN. We hypothesized that patients with MHE, similarly to those with schizophrenia, should show MMN alterations related with attention deficits. The aims of this work were to assess whether (1) MMN is altered in cirrhotic patients with MHE, compared to those without MHE, (2) MMN changes in parallel with performance in attention tests and/or MHE in a longitudinal study, and (3) MMN predicts performance in attention tests and/or in the Psychometric Hepatic Encephalopathy Score (PHES). We performed MMN analysis as well as attention and coordination tests in 34 control subjects and in 37 patients with liver cirrhosis without MHE and 23 with MHE. Patients with MHE show reduced performance in selective and sustained attention tests and in visuomotor and bimanual coordination tests. The MMN wave area was reduced in patients with MHE, but not in those without MHE. In the longitudinal study, MMN area improved in parallel with performance in attention tests and PHES in 4 patients and worsened in parallel in another 4. Logistic regression analyses showed that MMN area predicts performance in attention tests and in PHES, but not in other tests or critical flicker frequency. Receiver operating characteristic curve analyses showed that MMN area predicts attention deficits in the number connection tests A and B, Stroop tasks, and MHE, with sensitivities of 75%-90% and specificities of 76%-83%. Conclusion: MMN area is useful to diagnose attention deficits and MHE in patients with liver cirrhosis. © 2011 American Association for the Study of Liver Diseases.


PubMed | Fundacion Investigacion Clinico Of Valencia Institute Investigacion Sanitaria, Hospital Clinico Universitario Of Valencia and Centro Investigacion Principe Felipe
Type: Journal Article | Journal: Heart and vessels | Year: 2015

Acute kidney injury (AKI) is a common complication after coronary angiography. Early biomarkers of this disease are needed since increase in serum creatinine levels is a late marker. To assess the usefulness of urinary kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL) and liver-type fatty acid-binding protein (uL-FABP) for early detection of AKI in these patients, comparing their performance with another group of cardiac surgery patients. Biomarkers were measured in 193 patients, 12 h after intervention. In the ROC analysis, AUC for KIM-1, NGAL and L-FABP was 0.713, 0.958 and 0.642, respectively, in the coronary angiography group, and 0.716, 0.916 and 0.743 in the cardiac surgery group. Urinary KIM-1 12 h after intervention is predictive of AKI in adult patients undergoing coronary angiography, but NGAL shows higher sensitivity and specificity. L-FABP provides inferior discrimination for AKI than KIM-1 or NGAL in contrast to its performance after cardiac surgery. This is the first study showing the predictive capacity of KIM-1 for AKI after coronary angiography. Further studies are still needed to answer relevant questions about the clinical utility of biomarkers for AKI in different clinical settings.


Agusti A.,Centro Investigacion Principe Felipe | Dziedzic J.L.,Columbia University | Hernandez-Rabaza V.,Centro Investigacion Principe Felipe | Guilarte T.R.,Columbia University | Felipo V.,Centro Investigacion Principe Felipe
Metabolic Brain Disease | Year: 2014

Neuroinflammation plays a main role in neurological deficits in rats with minimal hepatic encephalopathy (MHE) due to portacaval shunt (PCS). Treating PCS rats with SB239063, an inhibitor of MAP-kinase-p38, reduces microglial activation and brain inflammatory markers and restores cognitive and motor function. The translocator protein-(18-kDa) (TSPO) is considered a biomarker of neuroinflammation. TSPO is increased in brain of PCS rats and of cirrhotic patients that died in hepatic coma. Rats with MHE show strong microglial activation in cerebellum and milder in other areas when assessed by MHC-II immunohistochemistry. This work aims were assessing: 1) whether binding of TSPO ligands is selectively increased in cerebellum in PCS rats; 2) whether treatment with SB239063 reduces binding of TSPO ligands in PCS rats; 3) which cell type (microglia, astrocytes) increases TSPO expression. Quantitative autoradiography was used to assess TSPO-selective 3H-(R)-PK11195 binding to different brain areas. TSPO expression increased differentially in PCS rats, reaching mild expression in striatum or thalamus and very high levels in cerebellum. TSPO was expressed in astrocytes and microglia. Treatment with SB239063 did not reduces 3[H]-PK11195 binding in PCS rats. SB239063 reduces microglial activation and levels of inflammatory markers, but not binding of TSPO ligands. This indicates that SB239063-induced neuroinflammation reduction in PCS rats is not mediated by effects on TSPO. Also, enhanced TSPO expression is not always associated with cognitive or motor deficits. If enhanced TSPO expression plays a role in mechanisms leading to neurological alterations in MHE, SB239063 would interfere these mechanisms at a later step. © 2013, Springer Science+Business Media New York.

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