Alfa-sinukleina biomarkatzaile gisa Parkinson gaixotasunaren diagnostikoan

Parkinson disease (PD) is a common neurodegenerative disease, characterized pathologically by the presence of Lewy bodies and the progressive loss of dopaminergic neurons. Currently, the diagnosis of PD is based on clinical criteria; that is, it is diagnosed when motor symptoms appear such as limb tremor, slowness of movement or muscle stiffness. However, by the time motor symptoms appear, more than half of the dopaminergic neurons in the midbrain have been lost. Furthermore, as clinical diagnosis of PD is challenging, misdiagnosis is common. This highlights the need for disease-specific and early-stage biomarkers. Lewy bodies are rich in α-synuclein protein, who plays a fundamental role in the pathogenesis of PD. Therefore, α-synuclein may be useful as a PD biomarker. Therefore, the objective of this review is to summarize the efficacy of body fluid α-synuclein and its proteoforms measurements in the detection of PD. In fact, the identification of specific, sensitive, and non-invasive biomarkers is essential especially in regard to existing and future disease modifying treatments. Although the main candidate has been the measurement of α-synuclein in cerebrospinal fluid (CSF), CSF collection procedure is quite invasive and unsuitable in most clinical settings. Consequently, the presence of this protein and its proteoforms in biofluids such as blood plasma, saliva and tears has been investigated. Based on the results of these studies, phosphorylated and oligomeric α-synuclein are the best candidates for PD diagnosis. Until now, the measurement of α-synuclein has had multiple technical limitations, but the repeatability and reliability of immunoassays created in the last years has increased considerably. Therefore, it is expected that the potential of the main candidate biomarkers for PD diagnosis will be verified in the upcoming years.; Parkinson gaixotasuna ohiko gaixotasun neurodegeneratiboa da, patologikoki Lewy gorputzen presentziagatik eta neurona dopaminergikoen galera progresiboagatik bereizten dena. Gaur egun, Parkinson gaixotasunaren diagnostikoa irizpide klinikoetan oinarrituta dago; hau da, gorputz-adarren dardara, mugimenduen moteltasuna edo muskuluen gogortasuna bezalako sintoma motorrak agertzen direnean diagnostikatzen da. Hala ere, sintoma motorrak azaleratzen direnerako, mesentzefaloko neurona dopaminergikoen erdia baino gehiago galdu direla uste da. Gainera, Parkinsonaren diagnostiko klinikoa erronka bat denez, ohikoak dira diagnostiko okerrak. Horrek argi uzten du gaixotasunaren berariazko diagnostikorako biomarkatzaileak behar direla, batez ere fase goiztiarretan. Lewyren gorputzak aberatsak dira alfa-sinukleina (α-sinukleina) proteinatan, eta hauek funtsezko eginkizuna dute Parkinson gaixotasunaren patogenesian. Hori dela eta, α-sinukleina baliagarria izan daiteke Parkinsonaren biomarkatzaile gisa. Berrikuspen honen helburua, beraz, gorputzeko fluido desberdinetan α-sinukleinaren eta haren proteoformen neurketaren erabilgarritasun-diagnostikoari buruzko ebidentzia laburbiltzea da. Izan ere, espezifikoak, sentikorrak eta eskuragarriak diren biomarkatzaileak identifikatzea ezinbestekoa da Parkinson gaixotasuna aldatzeko dauden eta etorkizunean izango diren tratamenduei dagokienez. Nahiz eta hautagai nagusia α-sinukleina likido zefalorrakideoan (LZR) neurtzea izan den, LZR biltzeko prozedura nahiko inbaditzailea da, eta ez da egokia ingurune kliniko gehienetan. Ondorioz, odol-plasma, listua eta malkoa bezalako biofluidoetan ikertu da proteina honen eta haren proteoformen presentzia. Ikerketa hauen emaitzen arabera, α-sinukleina fosforilatua eta oligomerikoa izan daitezke hautagai egokienak Parkinson gaixotasunaren diagnostikorako. Orain arte α-sinukleinaren neurketak muga tekniko anitz izan dituen arren, azken urteetan sortutako tekniken bitartez entseguen errepikakortasuna eta fidagarritasuna nabarmen areagotu da. Beraz, hautagai nagusiek Parkinsonaren diagnostikorako biomarkatzailegisa izan dezaketen potentziala hurrengo urteetan egiaztatzea espero da

Dopaminergic Denervation Impairs Cortical Motor and Associative/Limbic Information Processing Through the Basal Ganglia and its Modulation by the CB1 Receptor

The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients.This study was supported by grants from the Basque Government (PIBA 2019-38), the University of the Basque Country (GIU19/092), and the MINECO fund SAF2016-77758-R (AEI/FEDER, UE). M.A, has a fellowship from the MECD

Cannabinoids and Motor Control of the Basal Ganglia: Therapeutic Potential in Movement Disorders

Cannabinoid receptors in the brain appear to be intimately involved in the motor control. Cannabinoid CB1 receptors are densely located in the basal ganglia (BG), a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are paralleled to changes in the levels of different neurotransmitters in the BG, including GABA, dopamine and glutamate, all of which are important players in movement control

The Noradrenergic System in Parkinson’s Disease

Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacological-based treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.This study was supported by grants from the Basque Government (PIBA 2019-38, IT1345-19), UPV/EHU (PPGA19/15), and Spanish Government (SAF2016‐77758‐R [AEI/FEDER, UE]). EP-R has a fellowship from the Basque Country and SV-S from the UPV/EHU

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.This study was supported by the grants IT747-13, PI12/00613, UPV/EHU UFI11/32

Sexu-desberdintasunak Parkinson gaixotasunean

Increasing evidence indicates that biological sex is an important factor in the development and phe-notypic expression of Parkinson’s disease. The prevalence of Parkinson’s disease affects men twice more often than women. However, women experience a more rapid progression of the disease. In addition, it is increasingly ac-knowledged that the frequency and/or severity of motor and non-motor symptoms are different in female and male patients with Parkinson’s disease. It is also considered that their response to pharmacological and surgical treat-ments differs significantly. Although the precise underlying mechanisms supporting sex differences are still to be elucidated, the pathophysiological underpinnings are presumably different in women and men with Parkinson’s dis-ease. This review aims to gather the current evidence regarding sex differences in clinical features, risk factors, pathophysiological mechanisms and response to treatments (pharmacological and surgical). Clarifying how the dis-ease affects each sex can improve patient care by tailoring the therapeutic management of men and women and by developing innovative programmes to respond to unmet needs.; Gero eta ebidentzia gehiagok adierazten du sexu biologikoa faktore garrantzitsua dela Parkinson gaixotasunaren garapenean eta adierazpen fenotipikoan. Jakina da Parkinson gaixotasunaren prebalentzia ia bi aldiz altuagoa dela gizonezkoetan emakumezkoetan baino. Hala ere, emakumezkoek gaixotasunaren progresio azkarragoa izaten dute. Gainera, azken urteotan egindako ikerketek agerian utzi dute Parkinson gaixotasunaren ondorioz agertzen diren sintoma motorrak eta ez-motorrak maiztasun edota larritasun desberdina dutela sexuaren arabera. Halaber, emakumeek eta gizonezkoek tratamendu farmakologikoen eta kirurgikoen aurrean duten erantzuna ere desberdina dela uste da. Sexu-desberdintasun hauen oinarriak zehatz-mehatz ezagutzen ez badira ere, mekanismo fisiopatologikoak desberdinak direla iradoki da. Berrikuspen honetan Parkinsona duten emakumezkoen eta gizonezkoen artean dauden desberdintasunak laburbiltzen dira, besteak beste, ezaugarri klinikoetan, arrisku-faktoreetan, gaixotasunaren fisiopatologian eta tratamenduen erantzunean. Patologiak sexu bakoitzari nola eragiten dion argitzeak pazienteen arreta hobetzea ahalbidetu dezake gizonen eta emakumeen maneiu terapeutikoa neurrira diseinatuz eta bakoitzaren beharrei erantzuteko programa berritzaileak garatuz

Kannabisaren terapiarako erabilera mugimenduaren asalduretan

Aurkitu ostean egin izan diren ikerkunzek agerian utzi dute endokannabinoideoek funtzio fisiologikoetan duten parte-hartzea. Hain zuzen ere, sistema honen osagaiak (estekatzaile endokannabinoideoak, hartzaileak, biosintesirako eta degradaziorako proteinak) badaude mugimendua kontrolatzen duten garuneko zirkuitu eta nukleoetan (gongoil basaletan) eta ondorioz, parte hartzen dute funtzio motorraren erregulazioan, batez ere dopaminaren maila modulatuz. Bestalde, gongoil basaletan sistema endokannabinoideoan aldaketak deskribatu dira seinale dopaminergikoa gutxitua dagoenean, Parkinsonen gaixotasunean gertatzen den bezala. Horregatik, lanabes berri bezala proposatu da mugimenduaren asaldurak tratatzeko sistema endokannabinoideoaren modulazioa

Sistema serotonergikoaren eta gongoil basalen arteko elkarrekintza: inplikazio funtzionala eta terapiaren alderdia Parkinsonen gaixotasunean

Serotonina neurotransmisoreak funtzio ezberdinak betetzen ditu informazio-prozesaketaren modulazioan hainbat familiatako hartzaileen aktibazioaren bidez. Hauen artean, erreten ionikoa den hartza ile bat (5-HT3) eta G proteinei lotutako (5-HT1, 5-HT2 , 5-HT4. 7) hartzaileak daude. Neurona serotonergiko gehienak mesentzefaloan kokatuta daude, rafe nukleoetan bereziki . Gongoil basaletara (GB) iristen diren proiekzioak , batez ere dorsal raphe nucleusetik (DRN) heltzen dira. GBak oso ondo antolatuta dauden nukleo subkot1ikalez eratutako sarea da, GB-etako nukleoak striatuma, subthalamic nucleusa (STN), globus pallidusa (barrukoa, GPi eta kanpokoa, GPe) eta substantia nigra (pars compacta, SNc, eta pars reticulata , SNr) direlarik. GBek kontrol motorrean , emozioan eta funtzio kognitiboan parte hartzen dute, eta oso garrantzitsuak dira Parkinsonen Gaixotasunean (PO). Berrikuspen honek serotoninak GBen modulazioan duen funtzioa laburbiltzen du. Bestalde , elkan·ekintza honek PGaren tratamenduan eta L-DOPArebn tratamendu kronikoak eragindako asaldu ra motorretan duen garrantzia eztabaidatzen da

Study of Tissue-Specific Reactive Oxygen Species Formation by Cell Membrane Microarrays for the Characterization of Bioactive Compounds

The production of reactive oxygen species (ROS) increases considerably in situations of cellular stress, inducing lipid peroxidation and multiple alterations in proteins and nucleic acids. However, sensitivity to oxidative damage varies between organs and tissues depending on the triggering process. Certain drugs used in the treatment of diverse diseases such as malaria have side effects similar to those produced by oxidative damage, although no specific study has been conducted. For this purpose, cell membrane microarrays were developed and the superoxide production evoked by the mitochondrial activity was assayed in the presence of specific inhibitors: rotenone, antimycin A and azide. Once the protocol was set up on cell membrane isolated from rat brain areas, the effect of six antimalarial drugs (atovaquone, quinidine, doxycycline, mefloquine, artemisinin, and tafenoquine) and two essential oils (Rosmarinus officinalis and Origanum majoricum) were evaluated in multiple human samples. The basal activity was different depending on the type of tissue, the liver, jejunum and adrenal gland being the ones with the highest amount of superoxide. The antimalarial drugs studied showed specific behavior according to the type of human tissue analyzed, with atovaquone and quinidine producing the highest percentage of superoxide formation, and doxycycline the lowest. In conclusion, the analysis of superoxide production evaluated in cell membranes of a collection of human tissues allowed for the characterization of the safety profile of these antimalarial drugs against toxicity mediated by oxidative stressThis work has been partially supported by grant Ministry of Economy and Competitiveness PID2019-106222RB-C31/SRA (State Research Agency, 10.13039/501100011033), the Basque Government Department of Economic Development, Sustainability and Environment (PUE21-03 and Bikaintek program: 48-AF-W2-2019-7 and 007-B2/2020) and University of the Basque Country (price to the best Master Thesis in collaboration with Institutions and Business)