Ana B Muñoz-Manchado

Universidad de Sevilla, Hispalis, Andalusia, Spain

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Publications (6)25.78 Total impact

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    ABSTRACT: Despite the different animal models of Parkinson's disease (PD) developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of PD, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2015; DOI:10.1111/jnc.13409 · 4.28 Impact Factor
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    A B Muñoz-Manchado · C Foldi · S Szydlowski · L Sjulson · M Farries · C Wilson · G Silberberg · J Hjerling-Leffler ·
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    ABSTRACT: Histological and morphological studies indicate that approximately 5% of striatal neurons are cholinergic or γ-aminobutyric acidergic (GABAergic) interneurons (gINs). However, the number of striatal neurons expressing known interneuron markers is too small to account for the entire interneuron population. We therefore studied the serotonin (5HT) receptor 3a-enhanced green fluorescent protein (5HT3aEGFP) mouse, in which we found that a large number of striatal gINs are labeled. Roughly 20% of 5HT3aEGFP-positive cells co-express parvalbumin and exhibit fast-spiking (FS) electrophysiological properties. However, the majority of labeled neurons do not overlap with known molecular interneuron markers. Intrinsic electrical properties reveal at least 2 distinct novel subtypes: a late-spiking (LS) neuropeptide-Y (NPY)-negative neurogliaform (NGF) interneuron, and a large heterogeneous population with several features resembling low-threshold-spiking (LTS) interneurons that do not express somatostatin, NPY, or neuronal nitric oxide synthase. Although the 5HT3aEGFP NGF and LTS-like interneurons have electrophysiological properties similar to previously described populations, they are pharmacologically distinct. In direct contrast to previously described NPY+ LTS and NGF cells, LTS-like 5HT3aEGFP cells show robust responses to nicotine administration, while the 5HT3aEGFP NGF cell type shows little or no response. By constructing a molecular map of the overlap between these novel populations and existing interneuron populations, we are able to reconcile the morphological and molecular estimates of striatal interneuron numbers.
    Cerebral Cortex 08/2014; DOI:10.1093/cercor/bhu179 · 8.67 Impact Factor
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    ABSTRACT: The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. Moreover, glomus cells exhibited voltage-dependent Na+, Ca2+ and K+ currents that were qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca2+-dependent increase of cytosolic Ca2+ and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advance age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans.
    The Journal of Physiology 10/2013; 591(24). DOI:10.1113/jphysiol.2013.263657 · 5.04 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is characterized by the progressive degeneration of specific neuronal populations, particularly the dopaminergic neurons in the substantia nigra (SN) projecting to the striatum. Loss of these neurons leads to a lack of striatal dopamine, which is responsible for the principal motor symptoms characteristic of the disease (tremor, rigidity, slowness of movement and postural instability). 1–3 Current PD pharmacological therapies are based on the administration of pro-dopaminergic drugs, such as levodopa (a dopamine precursor), agonists of dopamine receptors, or inhibitors of dopamine degradation. However, none of these therapeutic strategies can stop disease progression. Moreover, they become less effective with time and can eventually produce motor complications as dyskinesias. 4
    Emerging Drugs and Targets for Parkinson’s Disease, Edited by Ana Martinez, Carmen Gil, 01/2013: chapter 16: pages 363-375; Royal Society of Chemistry., ISBN: 978-1-84973-735-7
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    ABSTRACT: Intrastriatal transplantation of dopaminergic carotid body (CB) cells ameliorates parkinsonism in animal models and, with less efficacy, in Parkinson's disease patients. CB-based cell therapy was initially proposed because of its high dopamine content. However, later studies suggested that its beneficial effect might be due to a trophic action exerted on nigrostriatal neurons. Compatible with this concept are the high levels of neurotrophic factors encountered in CB cells. To test experimentally this idea, unilateral striatal transplants were performed with a sham graft in the contralateral striatum, as a robust internal control. Thereafter, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6, -tetrahydropyridine was injected during 3 months. CB grafts protected from degeneration ipsilateral nigral dopaminergic neurons projecting to the transplant in a dose-dependent manner regarding size and glial cell line-derived neurotrophic factor expression. Grafts performed at different times after the onset of the neurotoxic treatment demonstrated with histological and behavioral methods protection and repair of the nigrostriatal pathway by CB transplants. This study provides a mechanistic explanation for the action of CB transplants on parkinsonian models. It should also help to improve cell therapy approaches to Parkinson's disease.
    Neurobiology of aging 06/2012; 34(3). DOI:10.1016/j.neurobiolaging.2012.06.001 · 5.01 Impact Factor
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    ABSTRACT: A major limiting factor for cell therapy in Parkinson's disease is that the survival of grafted dopaminergic neurons is very poor, which may be improved by administration of GDNF, for which the carotid body is a good source. Rats with total unilateral dopaminergic denervation were grafted with a cell suspension of rat dopaminergic neuroblasts with or without cell aggregates from the rat carotid body. At 1, 2 and 3 months after grafting, the rats were tested in the cylinder and the rotometer and killed 4 months after grafting. We observed that the survival of dopaminergic neurons and graft-derived dopaminergic innervation were higher in rats that received mixed grafts. Both grafted groups showed complete recovery in the amphetamine-induced rotation test. However, rats with cografts performed significantly better in the cylinder test. Cografting of carotid body cells may constitute a useful strategy for cell therapy in Parkinson's disease.
    Regenerative Medicine 05/2012; 7(3):309-22. DOI:10.2217/rme.12.22 · 2.79 Impact Factor

Publication Stats

25 Citations
25.78 Total Impact Points


  • 2013-2015
    • Universidad de Sevilla
      • • Departamento de Fisiología Médica y Biofísica
      • • Instituto de Biomedicina de Sevilla (IBIS)
      Hispalis, Andalusia, Spain
  • 2012
    • Instituto de Biomedicina de Sevilla (IBIS)
      Hispalis, Andalusia, Spain