Fernández Villalba, Emiliano

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Fernández Villalba, Emiliano

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Fernández Villalba, Emiliano

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Universidad de Murcia. Departamento de Medicina

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Open Access
Heart matters: cardiac dysfunction and other autonomic changes in Parkinson’s disease
(SAGE Publications, 2021-02-15) Gonçalves, Valeria C. ; Cuenca Bermejo, Lorena; Fernández Villalba, Emiliano; Martin Balbuena, Sebastian; Fernandes, Maria Jose da Silva; Scorza, Carla A.; Herrero Ezquerro, María Trinidad; Medicina; Facultades de la UMU
It has been more than 200 years since James Parkinson made the first descriptions of the disease that bears his name. Since then, knowledge about Parkinson’s disease has been improved, and its pathophysiology, diagnosis, and treatments are well described in the scientific and medical literature. However, there is no way to prevent the disease from its progressive nature yet and only its symptoms can be minimized. It is known that the process of neurodegeneration begins before the onset of motor signs and symptoms of the disease, when diagnosis is usually made. Therefore, recognizing manifested non-motor symptoms can make an early diagnosis possible and lead to a better understanding of the disease. Autonomic dysfunctions are important non-motor manifestations of Parkinson’s disease and affect the majority of patients. Importantly, heart failure is the third leading cause of death in people suffering from Parkinson’s disease. Several evidences have shown the correlation between Parkinson’s disease and the preexistence of cardiovascular diseases. Therefore, cardiovascular monitoring and identification of its dysfunctions can have a prodromal role for Parkinson’s disease. This review presents studies of the literature that can lead to a better understanding of Parkinson’s disease with special attention to its relation to heart and cardiovascular parameters.
Open Access
Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis
(Nature research, ) Cuenca, L.; González Cuello, A.; Sánchez Rodrigo, C.; Parrado, A.; Vyas, S.; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Fernández Villalba, Emiliano; Enfermería
Open Access
7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate
(The Royal Society Publishing, 2023-03) Herrero Ezquerro, María Trinidad; Yuste Lucas, Juan Luis; Cuenca Bermejo, Lorena; Almela Rojo, Pilar; Arenas-Betancur, L.; De Pablos, V.; González Cuello, Ana María; Del Bel, E.; Navarro Zaragoza, Javier; Fernández Villalba, Emiliano; Anatomía
Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3–4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment ( p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PDpatients.
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Combined 1-Deoxynojirimycin and Ibuprofen treatment decreases microglial activation, phagocytosis and dopaminergic degeneration in MPTP-treated mice
(Springer , 2020-06-21) Costa, T. C. S.; Fernández Villalba, Emiliano; Izura, V.; Lucas Ochoa, a. M.; Menezes Filho, N. J.; Santana, R.; Olivera, M. de; Araújo, F.; Estrada Esteban, C.; Silva, V.; Costa, S. L.; Herrero Ezquerro, María Trinidad; Medicina Interna; Facultades de la UMU::Facultad de Medicina
Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions. Graphical Abstract MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.
Open Access
Cardiac Noradrenaline Turnover and Heat Shock Protein 27 Phosphorylation in Dyskinetic Monkeys.
(Wiley Online Library, 2019-11) Almela, Pilar; Cuenca Bermejo, Lorena; Yuste, José E.; Estrada, Cristina; Pablos, Vicente de; Bautista Hernández, Víctor; Herrero Ezquerro, María Trinidad; Fernández Villalba, Emiliano; Laorden Carrasco, María Luisa; Anatomía Humana y Psicobiología; Medicina Interna
ABSTRACT: Background: Autonomic dysfunction is a well-known dominant symptom in the advanced stages of Parkinson’s disease. However, the role of cardiac sympathetic nerves still needs to be elucidated. Objectives: To evaluate cardiac sympathetic response in Parkinsonian and dyskinetic monkeys. Methods: Adult male monkeys were divided into 1 of the following 3 groups: controls, 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine–treated monkeys, and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine+levodopa–treated animals. Noradrenaline, its metabolite normetanephrine, and phospho-Heat shock proten 27 (p-Hsp27) at erine 82 levels were analyzed in the left and right ventricles of the heart. Tyrosine hydroxylase immunohistochemistry was performed in the ventral mesencephalon. Results: The results were the following: (1) 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine intoxication significantly increased normetanephrine levels and decreased noradrenaline turnover in the right ventricle without changes in the left ventricle; however, (2) levodopa treatment decreased noradrenaline levels and enhanced the normetanephrine/noradrenaline ratio in parallel with a very significant increase of Hsp27 activity in both ventricles. Conclusions: Levodopa treatment could induce protective cardiac effects through the increased Hsp27 activity. © 2019 International Parkinson and Movement Disorder Society
Open Access
Cardiac Changes in Parkinson’s Disease: Lessons from Clinical and Experimental Evidence
(MDPI, 2021-12) Herrero Ezquerro, María Trinidad; Laorden Carrasco, María Luisa; Cuenca Bermejo, Lorena; Almela Rojo, Pilar; Navarro Zaragoza, Javier; González Cuello, Ana María; Fernández Villalba, Emiliano; Enfermería
Dysautonomia is a common non-motor symptom in Parkinson’s disease (PD). Most dysautonomic symptoms appear due to alterations in the peripheral nerves of the autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. The degeneration of sympathetic nerve fibers and neurons leads to cardiovascular dysfunction, which is highly prevalent in PD patients. Cardiac alterations such as orthostatic hypotension, heart rate variability, modifications in cardiogram parameters and baroreflex dysfunction can appear in both the early and late stages of PD, worsening as the disease progresses. In PD patients it is generally found that parasympathetic activity is decreased, while sympathetic activity is increased. This situation gives rise to an imbalance of both tonicities which might, in turn, promote a higher risk of cardiac damage through tachycardia and vasoconstriction. Cardiovascular abnormalities can also appear as a side effect of PD treatment: L-DOPA can decrease blood pressure and aggravate orthostatic hypotension as a result of a negative inotropic effect on the heart. This unwanted side effect limits the therapeutic use of L-DOPA in geriatric patients with PD and can contribute to the number of hospital admissions. Therefore, it is essential to define the cardiac features related to PD for the monitorization of the heart condition in parkinsonian individuals. This information can allow the application of intervention strategies to improve the course of the disease and the proposition of new alternatives for its treatment to eliminate or reverse the motor and non-motor symptoms, especially in geriatric patients.
Open Access
Urolithins: potential biomarkers of gut dysbiosis and disease stage in Parkinson's patients
(The Royal Society of Chemistry, 2022-04-28) Romo Vaquero, María; Cuenca Bermejo, Lorena; Espín de Gea, Juan Carlos; Selma García, María Victoria; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Fernández Villalba, Emiliano; Anatomía Humana y Psicobiología
Gut microbiota alteration (gut dysbiosis) occurs during the onset and progression of Parkinson's disease. Gut dysbiosis biomarkers could be relevant to prodromal disease. Urolithins, anti-inflammatory metabolites produced from some dietary polyphenols by specific gut microbial ecologies (urolithin metabotypes), have been proposed as biomarkers of gut microbiota composition and functionality. However, this has not been explored in Parkinson's disease patients. The current study aimed to assess associations between urolithin metabotypes, gut dysbiosis and disease severity in Parkinson's disease patients. Participants (52 patients and 117 healthy controls) provided stool samples for microbiota sequencing and urine samples for urolithin profiling before and after consuming 30 g of walnuts for three days. Data on demographics, medication, disease duration and Hoehn and Yahr disease stage were collected. We observed a significant gradual increase of urolithin non-producers (metabotype-0) as the disease severity increased. The gut microbiome of metabotype-0 patients and patients with the greatest severity was characterized by a more altered bacterial composition, i.e., increased pro-inflammatory Enterobacteriaceae and reduced protective bacteria against autoimmune and inflammatory processes, including butyrate and urolithin-producing bacteria (Lachnospiraceae members and Gordonibacter). Besides, their microbiome was characterized by predictive functions of lipopolysaccharide biosynthesis and metabolism of glutathione, cysteine and methionine that could indirectly reflect the gut pro-inflammatory status. Urolithin detection in urine is a feasible, non-invasive and fast approach that can reflect gut microbiome dysbiosis and intestinal inflammation in Parkinson's disease patients. Our current study could provide novel strategies for improving diagnostics, and for preventing and treating disease progression in microbiota-based interventions.
Open Access
Unexpected exacerbation of neuroinflammatory response after a combined therapy in old parkinsonian mice
(Frontiers Media, 2018-11-30) Gil Martínez, Ana Luisa; Cuenca Bermejo, Lorena; Estrada, Cristina; Sánchez Rodrigo, Consuelo; Fernández Villalba, Emiliano; Herrero Ezquerro, María Trinidad; Anatomía Humana y Psicobiología; Ingeniería de la Información y las Comunicaciones; Facultades de la UMU::Facultad de Medicina
The design of therapeutic strategies that focus on the repositioning of anti-inflammatory and antioxidant drugs are a great bet to slow down the progression of neurodegenerative disorders. Despite the fact that Parkinson’s disease (PD) is an age-related pathology, almost all experimental studies are carried out in young animals. Here, we evaluated the possible neuroprotective effect of the combination of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory HA-1077 in aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (C57BL/6 mice, 20 months old), whose individual treatment has been shown to have neuroprotective effects in this Parkinsonism model. Interestingly, NAC+HA-1077-based treatment produced a significant increase in dopaminergic neuronal death accompanied by an increase in microglial and astroglial activation in the Substantia Nigra pars compacta (SNpc) and striatum of old-Parkinsonian mice compared to their control group. The astroglial response was also explored by co-immunostaining for GFAP and S100b together with p-JNK and it was found to be particularly exacerbated in the MPTP+NAC+HA-1077 group. The unexpected toxic effects found in the combined use of NAC and HA-1077 in old-Parkinsonian mice highlight the importance of taking into account that in elderly Parkinsonian patients the combination of some drugs (most of them used for other different age-related alterations) can have side effects that may result in the exacerbation of the neurodegenerative process.
Open Access
Identification of predictors of sarcopenia in older adults using machine learning: English Longitudinal Study of Ageing
(MDPI, 2024-11-12) Pavón Pulido, Nieves; Domínguez, Ligia; Blasco García, Jesús Damián; Veronese, Nicola; Lucas Ochoa, Ana María; Fernández Villalba, Emiliano; González Cuello, Ana María; Barbagallo, Mario; Herrero Ezquerro, María Trinidad; GOING FWD Investigators; Medicina Interna; Facultades de la UMU::Facultad de Medicina
Background: After its introduction in the ICD-10-CM in 2016, sarcopenia is a condition widely considered to be a medical disease with important consequences for the elderly. Considering its high prevalence in older adults and its detrimental effects on health, it is essential to identify its risk factors to inform targeted interventions. Methods: Taking data from wave 2 of the ELSA, using ML-based methods, this study investigates which factors are significantly associated with sarcopenia. The Minimum Redundancy Maximum Relevance algorithm has been used to allow for an optimal set of features that could predict the dependent variable. Such a feature is the input of a ML-based prediction model, trained and validated to predict the risk of developing or not developing a disease. Results: The presented methods are suitable to identify the risk of acquired sarcopenia. Age and other relevant features related with dementia and musculoskeletal conditions agree with previous knowledge about sarcopenia. The present classifier has an excellent performance since the “true positive rate” is 0.81 and the low “false positive rate” is 0.26. Conclusions: There is a high prevalence of sarcopenia in elderly people, with age and the presence of dementia and musculoskeletal conditions being strong predictors. The new proposed approach paves the path to test the prediction of the incidence of sarcopenia in older adults.202
Open Access
Study of the link between neuronal death, glial response, and MAPK pathway in old parkinsonian mice
(Frontiers Media, 2020-07-29) Cuenca-Bermejo L,; Gallo-Soljancic P,; Sanchez-Rodrigo C,; Izura V,; Steinbusch HWM,; Fernandez-Villalba E,; Herrero MT; Cuenca Bermejo, Lorena; Gallo-Soljancic, Pablo; Sanchez-Rodrigo, Consuelo; Izura, Virginia; Steinbusch, Harry W. M.; Fernández Villalba, Emiliano; Herrero Ezquerro, María Trinidad; Gil Martínez, Ana Luisa; Medicina Interna; Facultad de Medicina
Parkinson's disease (PD) is described as an age-related neurodegenerative disorder. However, the vast majority of research is carried out using experimental models of young animals lacking the implications of the decline processes associated with aging. It has been suggested that several molecular pathways are involved in the perpetuation of the degeneration and the neuroinflammation in PD. Among others, mitogen-activated protein kinases (MAPKs) have been highly implicated in the development of PD, and regulating components of their activity are indicated as promising therapeutic targets. Methods: To further define how MAPKs expression is related to the glial response and neuronal cell death, Parkinsonism was induced under an acute regimen in old mice. Moreover, the sacrifice was carried out at different time points (4, 8, 24, and 48 h) after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) injections to describe the early dynamic changes over time produced by the intoxication. Results: The results revealed that neuronal death increases as glial response increases in the nigrostriatal pathway. It was observed that both processes increase from 4 h in the ventral mesencephalon (VM), and neuronal death becomes significant at 48 h. In the striatum, they were significantly increased from 48 h after the MPTP administration compared with that in the control mice. Moreover, the p-ERK levels decrease, while phospho-p38 expression increases specifically in the striatum at 48 h after MPTP intoxication. Conclusions: The importance of these data lies in the possibility of elucidating the underlying mechanisms of neurodegenerative processes under aging conditions to provide knowledge for the search of solutions that slow down the progression of PD.