Correlational Study of Aminopeptidase Activities between Left or Right Frontal Cortex versus the Hypothalamus, Pituitary, Adrenal Axis of Spontaneously Hypertensive Rats Treated with Hypotensive or Hypertensive Agents.

It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin-angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these angiotensinases between the left or right frontal cortex (FC) and the same enzymes in the hypothalamus (HT), pituitary (PT), adrenal (AD) axis (HPA) in control spontaneously hypertensive rats (SHR), in SHR treated with a hypotensive agent in the form of captopril (an angiotensin-converting enzyme inhibitor), and in SHR treated with a hypertensive agent in the form of the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). In the control SHR, there were significant negative correlations between the right FC with HPA and positive correlations between the left FC and HPA. In the captopril group, the predominance of negative correlations between the right FC and HPA and positive correlations between the HPA and left FC was maintained. In the L-NAME group, a radical change in all types of interactions was observed; particularly, there was an inversion in the predominance of negative correlations between the HPA and left FC. These results indicated a better balance of neuro-visceral interactions after captopril treatment and an increase in these interactions in the hypertensive animals, especially in those treated with L-NAME.

Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome.

Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme ß-glucocerebrosidase (ß-GCase), considered the main genetic risk factor for sporadic PD. The loss of ß-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the ß-GCase, ß-galactosidase (ß-gal), ß-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, ß-GAL, ß-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced ß-GCase and ß-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the ß-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.

Aminopeptidase Activities Interact Asymmetrically between Brain, Plasma and Systolic Blood Pressure in Hypertensive Rats Unilaterally Depleted of Dopamine.

Brain dopamine, in relation to the limbic system, is involved in cognition and emotion. These functions are asymmetrically processed. Hypertension not only alters such functions but also their asymmetric brain pattern as well as their bilateral pattern of neurovisceral integration. The central and peripheral renin-angiotensin systems, particularly the aminopeptidases involved in its enzymatic cascade, play an important role in blood pressure control. In the present study, we report how these aminopeptidases from left and right cortico-limbic locations, plasma and systolic blood pressure interact among them in spontaneously hypertensive rats (SHR) unilaterally depleted of dopamine. The study comprises left and right sham and left and right lesioned (dopamine-depleted) rats as research groups. Results revealed important differences in the bilateral behavior comparing sham left versus sham right, lesioned left versus lesioned right, and sham versus lesioned animals. Results also suggest an important role for the asymmetrical functioning of the amygdala in cardiovascular control and an asymmetrical behavior in the interaction between the medial prefrontal cortex, hippocampus and amygdala with plasma, depending on the left or right depletion of dopamine. Compared with previous results of a similar study in Wistar-Kyoto (WKY) normotensive rats, the asymmetrical behaviors differ significantly between both WKY and SHR strains.

Seventy-Two-Hour LRRK2 Kinase Activity Inhibition Increases Lysosomal GBA Expression in H4, a Human Neuroglioma Cell Line.

Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson's disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme ß-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.

Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.

Ultra-slow drilling to obtain autologous bone graft in implantological rehabilitation. A forgotten technique with great advantages

ABSTRACT: Osseointegrated implants are currently the prosthetic treatment by predilection in the oral cavity when dental organs have been lost. Bone deficiency interferes with the placement of these prosthetic attachments; To solve this lack of bone tissue in alveolar ridges, autologous, homologous or heterologous bone grafting techniques are proposed. The ultra-low speed drilling without irrigation, it is possible to collect autologous bone at the time of preparing the surgical site before placing the dental implant, which provides the best properties for bone regeneration without the need for another wound or more morbidity for the patient. We describe our ultra-low speed drilling protocol step by step, obtaining autologous bone from the same surgical site to rehabilitate small bone defects around the implant reducing comorbidities and surgical times.

Asymmetrical response of aminopeptidase A in the medial prefrontal cortex and striatum of 6-OHDA-unilaterally-lesioned Wistar Kyoto and spontaneously hypertensive rats.

Aminopeptidase A is responsible for the hydrolysis of angiotensin II and cholecystokinin. By measuring its activity we obtain a reflection of the functional status of its endogenous substrates. Dopamine coexists with these neuropeptides in striatum and prefrontal cortex. If the content of any of them is altered, the others and the functions they are involved in would also be affected. Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) are rat models with different motor behavior and mood. We hypothesized that aminopeptidase A activity could be modified in WKY or SHR affecting the brain dopamine. The results may provide new insights for the understanding of dopamine-related disorders such as schizophrenia, depression or Parkinson's disease. To analyze the influence of unilateral depletions of dopamine on the intra- and inter-hemispheric behavior of aminopeptidase A in striatum and prefrontal cortex of WKY and SHR, aminopeptidase A activity was measured fluorometrically, using an arylamide derivative as substrate, in the left and right sides of striatum and prefrontal cortex of WKY and SHR treated with saline (control groups) or following left or right intrastriatal injections of 6-hydroxydopamine (lesioned groups). Differential asymmetrical intra- and inter-hemispheric behaviors of aminopeptidase A were observed, depending on the lesioned hemisphere, the region and the strain analyzed. Results also demonstrated differential intra and inter-hemispheric correlations between striatum and prefrontal cortex and between both regions and motor behavior depending on the side of lesion. The changes mostly involved the left hemisphere. The functions in which the aminopeptidase A activity is involved could be modified depending on whether the dopamine depletion occurs on the left or right hemisphere.

Structural genomic variations and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.

Bilateral distribution of enkephalinase activity in the medial prefrontal cortex differs between WKY and SHR rats unilaterally lesioned with 6-hydroxydopamine.

Changes in the basal brain bilateral morphologic, neurochemical and/or functional patterns may be partly responsible for some brain disorders such as those involving mood. WKY and SHR strains as well as 6-hydroxydopamine (6-OHDA)-lesioned animals are validated models for the study of mood disorders. Because dopamine and enkephalins are involved in anxiety-related behaviors, the aim of our study was to analyze enkephalinase activity, assayed as aminopeptidase M activity, in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with saline (sham group) or following left or right intrastriatal injections of the neurotoxic 6-OHDA. Sham left and sham right WKY exhibited a significant left predominance. Left 6-OHDA-lesioned rats inverted the left predominance of sham to right predominance. In right 6-OHDA-lesioned rats, the left predominance in sham right rats disappeared. Sham left as well as sham right SHR did not show any bilateral differences. In contrast, while the left lesion demonstrated a highly significant left predominance, the right lesion showed a slight but significant right predominance. A significant negative correlation between enkephalinase activity of the right mPFC and blood pressure and heart rate was observed only in left-lesioned SHR. Our results demonstrate that unilateral nigrostriatal injections of 6-OHDA influence the bilateral distribution of enkephalinase activity depending on both the side of the lesion and the strain analyzed. These results support the hypothesis that DA pathways may interact asymmetrically with enkephalins in the mPFC and that enkephalinase activity may play a role in the regulatory mechanisms underlying this interaction.

Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio = 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics.

Analysis of the genetic variability in Parkinson's disease from Southern Spain.

To date, a large spectrum of genetic variants has been related to familial and sporadic Parkinson's disease (PD) in diverse populations worldwide. However, very little is known about the genetic landscape of PD in Southern Spain, despite its particular genetic landscape coming from multiple historical migrations. We included 134 PD patients in this study, of which 97 individuals were diagnosed with late-onset sporadic PD (LOPD), 28 with early-onset sporadic PD (EOPD), and 9 with familial PD (FPD). Genetic analysis was performed through a next-generation sequencing panel to screen 8 PD-related genes (LRRK2, SNCA, PARKIN, PINK1, DJ-1, VPS35, GBA, and GCH1) in EOPD and FPD groups and direct Sanger sequencing of GBA exons 8-11 and LRRK2 exons 31 and 41 in the LOPD group. In the EOPD and FPD groups, we identified 11 known pathogenic mutations among 15 patients (40.5%). GBA (E326K, N370S, D409H, L444P) mutations were identified in 7 patients (18.9%); LRRK2 (p.R1441G and p.G2019S) in 3 patients (8.1%); biallelic PARK2 mutations (p.N52fs, p.V56E, p.C212Y) in 4 cases (10.8%) and PINK1 homozygous p.G309D in 1 patient (2.7%). An EOPD patient carried a single PARK2 heterozygous mutation (p.R402C), and another had a novel heterozygous mutation in VPS35 (p.R32S), both of unknown significance. Moreover, pathogenic mutations in GBA (E326K, T369M, N370S, D409H, L444P) and LRRK2 (p.R1441G and p.G2019S) were identified in 13 patients (13.4%) and 4 patients (4.1%), respectively, in the LOPD group. A large number of known pathogenic mutations related to PD have been identified. In particular, GBA and LRRK2 mutations appear to be considerably frequent in our population, suggesting a strong Jewish influence. Further research is needed to study the contribution of the novel found mutation p.R32S in VPS35 to the pathogenesis of PD.

Tissue distribution of CysAP activity and its relationship to blood pressure and water balance.

AIMS: To better understand the functional role of soluble (Sol) and membrane-bound (MB) cystinyl-aminopeptidase (CysAP) activities, we studied differentially their organ distribution in adult male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)with or without treatment with captopril.We searched for a possible tissue-specific association of CysAP with water balance and blood pressure. MAIN METHODS: We used twenty WKY rats distributed in ten controls and ten captopril-treated, and sixteen SHR divided in eight controls and eight captopril-treated. Captopril (100 mg/kg/day) was administered in drinking water for 4 weeks. Systolic blood pressure, water intake and diuresis were measured individually. CysAP was assayed fluorometrically using L-cystine-di-ß-naphthylamide as substrate. KEY FINDINGS: Sol or MB activities were generally higher in SHR compared to WKY notably in hypothalamus and kidney than in the other tissues. Captopril mainly decreased CysAP in SHR whereas it increased in WKY. The distribution of Sol CysAP was more homogeneous among tissues ofWKY than SHR. In contrast, the distribution of MB CysAP was more heterogeneous than Sol CysAP in both WKY and SHR. This suggests that MB CysAP activity acts in a more tissue-specific manner than Sol CysAP. The majority of the significant correlations between tissue activities and the measured physiological parameters were observed mostly in renal medulla and hypothalamus. SIGNIFICANCE: Sol and MB CysAP activities, acting separately or in concert and mainly in renal medulla, regulate the function of their susceptible endogenous substrates, and may participate meaningfully in the control of blood pressure and fluid balance.

Interaction of neuropeptidase activities in cortico-limbic regions after acute restraint stress.

Brain enkephalin, vasopressin and oxytocin are anxiolytic agents involved in the stress response. Acute restraint stress influences certain neuropeptidase activities, such as some enkephalin-degrading peptidases and vasopressinase/oxytocinase, in the medial prefrontal cortex (mPFC), amygdala (AM) or hippocampus (HC), which are involved in this response. Because these regions form a unified circuit and cooperate in their response to stress, it is important to analyze the profile of the regional distribution of these activities as well as their inter-regional model of interaction in this circuit. Regarding the regional study, although most activities showed a marked predominance of the AM over the HC and mPFC, both in control and stressed animals, enkephalin-degrading activity, assayed as membrane-bound alanyl aminopeptidase activity, showed a change after stress, increasing in the HC and decreasing in the AM. The correlational study in controls indicated essentially a positive interaction between the mPFC and AM. In marked contrast, there was a highly significant change in the functional status of this circuit after stress, showing mainly a positive correlation between the mPFC and HC and between the AM and HC. The existence of correlations does not demonstrate a direct relationship between regions. However, reasons for such strong associations after restraint stress should be examined. The present study may indicate a connection between neuropeptidase activities and their corresponding neuropeptidergic substrates due to significant changes in the functional status of the cortico-limbic circuit after restraint stress.

An examination of the mechanisms involved in secondary clinical failure to adalimumab or etanercept in inflammatory arthropathies.

BACKGROUND: Biological therapies against tumor necrosis factor α have revolutionized the treatment of several inflammatory rheumatic diseases. However, 30% of responders will present a clinical failure after having controlled the disease for at least 6 months (secondary clinical failure). Biological therapies may induce an unwanted immune response, which may alter the bioavailability of the drug causing a loss of clinical response. OBJECTIVE: The objective of this study was to assess the correlation between secondary clinical failure (based on Disease Activity Score in 28 Joints or Bath Ankylosing Spondylitis Disease Activity Index) and the type of mechanism involved in failure (based on drug levels) in patients with inflammatory arthropathies treated with anti-tumor necrosis factor α. METHODS: Drug and antidrug antibodies (ADAs) serum levels were determined by enzyme-linked immunosorbent assay immediately before drug administration in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis who presented secondary clinical failure after at least 6 months of treatment with adalimumab (ADL) or etanercept (ETN). RESULTS: Thirty-six patients with secondary clinical failure were recruited: 63.88% had rheumatoid arthritis, 22.22% had psoriatic arthritis, and 13.88% had ankylosing spondylitis; 58.33% did not respond to ADL, whereas 41.66% did not to ETN. None of the patients treated with ETN showed either subtherapeutic drugs levels or ADAs (failure due to a primary mechanism) whereas it was found that 23.80% of the patients treated with ADL had subtherapeutic drug levels for reasons attributable to immunogenicity (failure due to a secondary mechanism; P = 0.000048). CONCLUSIONS: We suggest the utility of measuring drug and ADA levels in patients with secondary clinical failure to ADL for a better optimization and rational use, but not in patients who fail to ETN.

Brain, heart and kidney correlate for the control of blood pressure and water balance: role of angiotensinases.

The renin-angiotensin system (RAS) plays a major role in the control of blood pressure (BP) and water balance by coordinating brain, heart and kidney functions, connected with each other by hormonal and neural mechanisms through the autonomic nervous system (ANS). RAS function may be monitored by the study of the enzymes (angiotensinases) involved in the metabolism of its active peptides. In order to study the relationship between the brain-heart-kidney axis and the control of BP and water balance, we analyzed the correlation of angiotensinase activities, assayed as arylamidase activities, between hypothalamus, left ventricle, renal cortex and renal medulla, collected from Wistar-Kyoto and spontaneously hypertensive rats, treated or not treated with L-NAME [N(G)-nitro-L-arginine methyl ester]. This compound not only inhibits the formation of nitric oxide but also disrupts the normal function of the ANS activating the sympathetic nervous system (SNS) to increase BP. In addition, to assess the influence of the SNS, we studied the effect of its blockade by treatment of both strains with propranolol. The present results support the notion that RAS function of the brain-heart-kidney axis, as reflected by the activities of angiotensinases, is reciprocally connected by afferent and efferent mechanisms between these locations, presumably through the ANS. These results reveal new aspects of neuroendocrine regulation possibly involving the ANS.

[Proteomic biomarkers in Parkinson's disease]. / Biomarcadores proteómicos en la enfermedad de Parkinson.

Parkinson's disease (PD) is a neurodegenerative disorder that affects movement and is caused by the death of the dopaminergic neurons in the compact part of the substantia nigra. Its diagnosis is essentially clinical, but although the signs and symptoms of PD are well known, the rate of diagnostic error is relatively high. It is estimated that 10-30% of patients initially diagnosed with PD are later reclassified. This disease has a high prevalence beyond the age of 60, and one of its biggest problems is that it is diagnosed when the degenerative process is already at a very advanced stage. Therefore, it is necessary to look for other biomarkers that make it possible to carry out an early diagnosis of PD, follow up its development, distinguish it from other related pathologies (parkinsonisms) and help monitor the effect of novel therapies. The fact that there are mutations that lead to PD, as well as polygenetic combinations that can act as risk factors, suggests the possibility of measuring the proteins resulting from the expression of these genes in peripheral tissues. And once their sensitivity and specificity have been proved they could be used as biomarkers for PD, even in the early phases of the disease. The aim of this work is to focus on a detailed review of the main candidate proteomic biomarkers researched to date by discussing the most recent literature.

TITLE: Biomarcadores proteomicos en la enfermedad de Parkinson.La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo que afecta al movimiento, cuya causa es la muerte de las neuronas dopaminergicas de la parte compacta de la sustancia negra. El diagnostico es fundamentalmente clinico, pero, a pesar de que los signos y sintomas de la EP se conocen bien, el error diagnostico es relativamente alto. Se calcula que un 10-30% de los pacientes inicialmente diagnosticados de EP se reclasifican posteriormente. Esta enfermedad tiene una alta prevalencia a partir de los 60 años, y uno de los mayores problemas que tiene es que su diagnostico se hace cuando el proceso degenerativo esta muy avanzado. Por tanto, es necesaria la busqueda de biomarcadores que permitan un diagnostico precoz de la EP, seguir su progresion, diferenciarla de otras patologias relacionadas (parkinsonismos) y que ayuden a monitorizar el efecto de nuevas terapias. El hecho de que existan mutaciones que conducen a la EP, asi como combinaciones poligenicas que pueden actuar como factores de riesgo, sugiere que es posible analizar las proteinas resultantes de la expresion de estos genes en tejidos perifericos, que, una vez demostrada su sensibilidad y especificidad, podrian utilizarse como biomarcadores de la EP, incluso en fases iniciales de la enfermedad. El objetivo del presente trabajo es centrarse en una revision detallada de los principales biomarcadores proteomicos candidatos investigados hasta el momento, discutiendo la literatura mas reciente.

Biomarcadores proteómicos en la enfermedad de Parkinson / Proteomic biomarkers in Parkinson's disease

La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo que afecta al movimiento, cuya causa es la muerte de las neuronas dopaminérgicas de la parte compacta de la sustancia negra. El diagnóstico es fundamentalmente clínico, pero, a pesar de que los signos y síntomas de la EP se conocen bien, el error diagnóstico es relativamente alto. Se calcula que un 10-30% de los pacientes inicialmente diagnosticados de EP se reclasifican posteriormente. Esta enfermedad tiene una alta prevalencia a partir de los 60 años, y uno de los mayores problemas que tiene es que su diagnóstico se hace cuando el proceso degenerativo está muy avanzado. Por tanto, es necesaria la búsqueda de biomarcadores que permitan un diagnóstico precoz de la EP, seguir su progresión, diferenciarla de otras patologías relacionadas (parkinsonismos) y que ayuden a monitorizar el efecto de nuevas terapias. El hecho de que existan mutaciones que conducen a la EP, así como combinaciones poligénicas que pueden actuar como factores de riesgo, sugiere que es posible analizar las proteínas resultantes de la expresión de estos genes en tejidos periféricos, que, una vez demostrada su sensibilidad y especificidad, podrían utilizarse como biomarcadores de la EP, incluso en fases iniciales de la enfermedad. El objetivo del presente trabajo es centrarse en una revisión detallada de los principales biomarcadores proteómicos candidatos investigados hasta el momento, discutiendo la literatura más reciente (AU)

Parkinson’s disease (PD) is a neurodegenerative disorder that affects movement and is caused by the death of the dopaminergic neurons in the compact part of the substantia nigra. Its diagnosis is essentially clinical, but although the signs and symptoms of PD are well known, the rate of diagnostic error is relatively high. It is estimated that 10-30% of patients initially diagnosed with PD are later reclassified. This disease has a high prevalence beyond the age of 60, and one of its biggest problems is that it is diagnosed when the degenerative process is already at a very advanced stage. Therefore, it is necessary to look for other biomarkers that make it possible to carry out an early diagnosis of PD, follow up its development, distinguish it from other related pathologies (parkinsonisms) and help monitor the effect of novel therapies. The fact that there are mutations that lead to PD, as well as polygenetic combinations that can act as risk factors, suggests the possibility of measuring the proteins resulting from the expression of these genes in peripheral tissues. And once their sensitivity and specificity have been proved they could be used as biomarkers for PD, even in the early phases of the disease. The aim of this work is to focus on a detailed review of the main candidate proteomic biomarkers researched to date by discussing the most recent literature (AU)

The brain-heart connection: frontal cortex and left ventricle angiotensinase activities in control and captopril-treated hypertensive rats-a bilateral study.

The model of neurovisceral integration suggests that the frontal cortex (FC) and the cardiovascular function are reciprocally and asymmetrically connected. We analyzed several angiotensinase activities in the heart left ventricle (VT) of control and captopril-treated SHR, and we search for a relationship between these activities and those determined in the left and right FC. Captopril was administered in drinking water for 4 weeks. Samples from the left VT and from the left and right FC were obtained. Soluble and membrane-bound enzymatic activities were measured fluorometrically using arylamides as substrates. The weight of heart significantly decreased after treatment with captopril, mainly, due to the reduction of the left VT weight. In the VT, no differences for soluble activities were observed between control and treated SHR. In contrast, a generalized significant reduction was observed for membrane-bound activities. The most significant correlations between FC and VT were observed in the right FC of the captopril-treated group. The other correlations, right FC versus VT and left FC versus VT in controls and left FC versus VT in the captopril group, were few and low. These results confirm that the connection between FC and cardiovascular system is asymmetrically organized.

Asymmetrical effect of captopril on the angiotensinase activity in frontal cortex and plasma of the spontaneously hypertensive rats: expanding the model of neuroendocrine integration.

There is a reciprocal connection between the frontal cortex (FC) and cardiovascular function, and this connection is functionally lateralized. The possible pathophysiological impact of neuroendocrine asymmetries is largely underestimated. Our aim was to examine the activity of soluble (SOL) and membrane-bound (MB) aminopeptidases (APs) involved in the renin-angiotensin system in the peripheral plasma and in the left and right FC, in both untreated (control) and captopril-treated spontaneously hypertensive rats (SHRs). Enzymatic activities were measured fluorometrically using arylamide derivatives as substrates. Captopril reduced systolic blood pressure, but no differences in plasma AP activity were observed between the control and treated SHRs. In contrast, whereas the bilateral pattern (left vs. right differences) of SOL activities did not substantially change in the FC after captopril treatment, the asymmetries observed for MB activities in the FC markedly increased compared with the control group. Moreover, correlations between the AP activities in the plasma and those in the left or right FC were observed. In the control rats, the plasma AP activities correlated significantly with those in the right FC, whereas they correlated with those in the left FC in the captopril-treated group. In both groups (control and captopril), these correlations were negative for the SOL activity but positive for the MB activity. The present results reveal a pattern of bilateral behavior between the nervous and cardiovascular systems. The inverted bilateral behavior after captopril treatment suggests a systematized, lateralized neuroendocrine response representing a regular bilateral behavior that has yet to be analyzed.

Oxidative stress and aminopeptidases in Parkinson's disease patients with and without treatment.

BACKGROUND/OBJECTIVE: Mitochondrial dysfunction, oxidative stress and protein metabolism impairment are the main molecular events underlying the pathogenesis of Parkinson's disease (PD). However, only few studies have addressed the changes produced by these phenomena in the blood of PD patients. Our purpose was to compare oxidative stress between newly diagnosed PD patients (ntPD) and PD patients under treatment (tPD). We also analyzed changes in plasma activity of several aminopeptidases (AP) involved in the metabolism of various active peptides. METHODS: Plasma lipid peroxide (LPO) and lactate (LAC) concentrations were measured by colorimetric methods, and plasma AP activities were determined by fluorometric assay. RESULTS: LPO and LAC concentrations were significantly elevated in ntPD and tPD patients versus controls, but there were no differences between the PD groups. Alanine-, cystine- and aspartate-AP activities were significantly lower in tPD versus ntPD patients. Nondenaturing electrophoresis and Western blot results confirmed these findings. CONCLUSIONS: The plasma LPO and LAC levels were high in both PD groups, indicating that they are elevated at an early stage of PD and are not affected by anti-PD treatment. The higher AP activities in ntPD versus tPD patients suggest that anti-PD treatment may improve protein metabolism while not altering oxidative stress. A therapy directed to reduce oxidative stress and normalize AP activity may be useful in the treatment of PD.