Publications by authors named "Cristina Rosell-Valle"

12 Publications

  • Page 1 of 1

Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol.

Nutrients 2021 Jun 30;13(7). Epub 2021 Jun 30.

Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain.

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.
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http://dx.doi.org/10.3390/nu13072268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308282PMC
June 2021

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse.

Int J Mol Sci 2021 May 20;22(10). Epub 2021 May 20.

Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain.

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg), heterozygous (Tg), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg and Tg mice and increased expression of IL-1β in Tg mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg and Tg mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
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http://dx.doi.org/10.3390/ijms22105365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161294PMC
May 2021

GABAergic deficits in absence of LPA receptor, associated anxiety-like and coping behaviors, and amelioration by interneuron precursor transplants into the dorsal hippocampus.

Brain Struct Funct 2021 Jun 1;226(5):1479-1495. Epub 2021 Apr 1.

Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.

Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA-null mice, lacking the LPA receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA-null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA-null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA receptor. Transplant studies in maLPA-null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA receptor represents a potential target for interneuron-related neuropsychiatric disorders.
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http://dx.doi.org/10.1007/s00429-021-02261-4DOI Listing
June 2021

Evaluation of the effectiveness of a new cryopreservation system based on a two-compartment vial for the cryopreservation of cell therapy products.

Cytotherapy 2021 Aug 11;23(8):740-753. Epub 2021 Mar 11.

Unidad de Producción y Reprogramación Celular, Red Andaluza Para el Diseño y Traslación de Terapias Avanzadas, Sevilla, Spain. Electronic address:

Background Aims: Successful cell cryopreservation and banking remain a major challenge for the manufacture of cell therapy products, particularly in relation to providing a hermetic, sterile cryovial that ensures optimal viability and stability post-thaw while minimizing exposure to toxic cryoprotective agents, typically dimethyl sulfoxide (MeSO).

Methods: In the present study, the authors evaluated the effectiveness and functionality of Limbo technology (Cellulis S.L., Santoña, Spain). This system provides a hermetic vial with two compartments (one for adding cells with the cryoprotective agent solution and the other for the diluent solution) and an automated defrosting device. Limbo technology (Cellulis S.L.) allows reduction of the final amount of MeSO, sidestepping washing and dilution steps and favoring standardization. The study was performed in several Good Manufacturing Practice laboratories manufacturing diverse cell therapy products (human mesenchymal stromal cells, hematopoietic progenitor cells, leukapheresis products, fibroblasts and induced pluripotent stem cells). Laboratories compared Limbo technology (Cellulis S.L.) with their standard cryopreservation procedure, analyzing cell recovery, viability, phenotype and functionality.

Results: Limbo technology (Cellulis S.L.) maintained the viability and functionality of most of the cell products and preserved sterility while reducing the final concentration of MeSO.

Conclusions: Results showed that use of Limbo technology (Cellulis S.L.) offers an overall safe alternative for cell banking and direct infusion of cryopreserved cell products into patients.
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http://dx.doi.org/10.1016/j.jcyt.2020.12.004DOI Listing
August 2021

Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer's Disease in a Preclinical Model: A Therapeutic Opportunity.

Biology (Basel) 2020 Nov 5;9(11). Epub 2020 Nov 5.

Instituto de Investigación Biomédica de Málaga-IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.

Alzheimer's disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer's disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and β-amyloid (Aβ) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aβ's accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aβ deposition.
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http://dx.doi.org/10.3390/biology9110377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694492PMC
November 2020

Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jun 2;108:110156. Epub 2020 Nov 2.

Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain; Unidad de Gestión Clínica de Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain. Electronic address:

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110156DOI Listing
June 2021

Retrieval of germinal zone neural stem cells from the cerebrospinal fluid of premature infants with intraventricular hemorrhage.

Stem Cells Transl Med 2020 09 30;9(9):1085-1101. Epub 2020 May 30.

Departamento de Preclínica, Red Andaluza de Diseño y Traslación de Terapias Avanzadas, Sevilla, Spain.

Intraventricular hemorrhage is a common cause of morbidity and mortality in premature infants. The rupture of the germinal zone into the ventricles entails loss of neural stem cells and disturbs the normal cytoarchitecture of the region, compromising late neurogliogenesis. Here we demonstrate that neural stem cells can be easily and robustly isolated from the hemorrhagic cerebrospinal fluid obtained during therapeutic neuroendoscopic lavage in preterm infants with severe intraventricular hemorrhage. Our analyses demonstrate that these neural stem cells, although similar to human fetal cell lines, display distinctive hallmarks related to their regional and developmental origin in the germinal zone of the ventral forebrain, the ganglionic eminences that give rise to interneurons and oligodendrocytes. These cells can be expanded, cryopreserved, and differentiated in vitro and in vivo in the brain of nude mice and show no sign of tumoral transformation 6 months after transplantation. This novel class of neural stem cells poses no ethical concerns, as the fluid is usually discarded, and could be useful for the development of an autologous therapy for preterm infants, aiming to restore late neurogliogenesis and attenuate neurocognitive deficits. Furthermore, these cells represent a valuable tool for the study of the final stages of human brain development and germinal zone biology.
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http://dx.doi.org/10.1002/sctm.19-0323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445027PMC
September 2020

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

J Med Chem 2020 03 16;63(5):2372-2390. Epub 2019 Dec 16.

Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA agonists among which derivative ()- (UCM-05194) stands out as the most potent and selective LPA receptor agonist described so far ( = 118%, EC = 0.24 μM, = 19.6 nM; inactive at autotaxin and LPA receptors). This compound induces characteristic LPA-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an model of NP.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344333PMC
March 2020

Lysophosphatidic acid-induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine-contextual memory.

Addict Biol 2019 05 26;24(3):458-470. Epub 2018 Feb 26.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Spain.

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA -receptor-deficient mice were acutely infused with LPA, which revealed that LPA -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.
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http://dx.doi.org/10.1111/adb.12612DOI Listing
May 2019

Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

Dis Model Mech 2017 03 30;10(3):323-336. Epub 2017 Jan 30.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, 29010 Málaga, Spain

Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA, parvalbumin (PV) and neuropeptide Y (NPY) interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV and NPY neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.
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http://dx.doi.org/10.1242/dmm.026682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374316PMC
March 2017

Voluntary exercise followed by chronic stress strikingly increases mature adult-born hippocampal neurons and prevents stress-induced deficits in 'what-when-where' memory.

Neurobiol Learn Mem 2014 Mar 11;109:62-73. Epub 2013 Dec 11.

Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, and Instituto de Investigación Biomédica de Málaga (IBIMA), E-29071 Málaga, Spain. Electronic address:

We investigated whether voluntary exercise prevents the deleterious effects of chronic stress on episodic-like memory and adult hippocampal neurogenesis. After bromodeoxyuridine (BrdU) administration, mice were assigned to receive standard housing, chronic intermittent restraint stress, voluntary exercise or a combination of both (stress starting on the seventh day of exercise). Twenty-four days later, mice were tested in a 'what-when-where' object recognition memory task. Adult hippocampal neurogenesis (proliferation, differentiation, survival and apoptosis) and c-Fos expression in the hippocampus and extra-hippocampal areas (medial prefrontal cortex, amygdala, paraventricular hypothalamic nucleus, accumbens and perirhinal cortex) were assessed after behavior. Chronic intermittent restraint stress impaired neurogenesis and the 'when' memory, while exercise promoted neurogenesis and improved the 'where' memory. The 'when' and 'where' memories correlated with c-Fos expression in CA1 and the dentate gyrus, respectively. Furthermore, analysis suggested that each treatment induced a distinct pattern of functional connectivity among the areas analyzed for c-Fos. In the animals in which stress and exercise were combined, stress notably reduced the amount of voluntary exercise performed. Nevertheless, exercise still improved memory and counteracted the stress induced-deficits in neurogenesis and behavior. Interestingly, compared with the other three treatments, the stressed exercising animals showed a larger increase in cell survival, the maturation of new neurons and apoptosis in the dentate gyrus, with a considerable increase in the number of 24-day-old BrdU+cells that differentiated into mature neurons. The interaction between exercise and stress in enhancing the number of adult-born hippocampal neurons supports a role of exercise-induced neurogenesis in stressful conditions.
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http://dx.doi.org/10.1016/j.nlm.2013.12.001DOI Listing
March 2014

Reduced wheel running and blunted effects of voluntary exercise in LPA1-null mice: the importance of assessing the amount of running in transgenic mice studies.

Neurosci Res 2013 Nov 19;77(3):170-9. Epub 2013 Sep 19.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya de Málaga, E-29010 Málaga, Spain. Electronic address:

This work was aimed to assess whether voluntary exercise rescued behavioral and hippocampal alterations in mice lacking the lysophosphatidic acid LPA1 receptor (LPA1-null mice), studying the potential relationship between the amount of exercise performed and its effects. Normal and LPA1-null mice underwent 23 days of free wheel running and were tested for open-field behavior and adult hippocampal neurogenesis (cell proliferation, immature neurons, cell survival). Running decreased anxiety-like behavior in both genotypes but increased exploration only in the normal mice. While running affected all neurogenesis-related measures in normal mice (especially in the suprapyramidal blade of the dentate gyrus), only a moderate increase in cell survival was found in the mutants. Importantly, the LPA1-nulls showed notably reduced running. Analysis suggested that defective running in the LPA1-null mice could contribute to explain the scarce benefit of the voluntary exercise treatment. On the other hand, a literature review revealed that voluntary exercise is frequently used to modulate behavior and the hippocampus in transgenic mice, but half of the studies did not assess the quantity of running, overlooking any potential running impairments. This study adds evidence to the relevance of the quantity of exercise performed, emphasizing the importance of its assessment in transgenic mice research.
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http://dx.doi.org/10.1016/j.neures.2013.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006933PMC
November 2013
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