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Primjenom niza modernih računalnih metoda dobiven je detaljan uvid u interakcije koje antagonist istradefilin ostvaruje s adenozinskim A2A receptorom. Temeljem identifikacije strukturnih elemenata koji najviše doprinose vezanju, dizajnirani su derivati većeg afiniteta. Osim konvencionalnog pristupa koji uključuje uvođenje novih funkcionalnih skupina, primijenjena je i modifikacija deuteriranjem čime je postignuto poboljšano vezanje istradefilina u A2A receptor. U ovom radu izotopna supstitucija predstavlja originalan koncept moduliranja farmakodinamičkih svojstava, a dobiveni rezultati ukazuju na veću učinkovitost istradefilina obogaćenog deuterijem što bi se moglo iskoristiti za poboljšanje njegovog farmakoterapijskog profila u liječenju Parkinsonove bolesti. By utilising a series of modern computational methods, a detailed insight into the interactions of the antagonist istradefylline with the adenosine A2A receptor was obtained. Based on the identification of structural elements that contribute the most to binding, higher affinity derivatives were designed. In addition to the conventional approach that includes the introduction of new functional groups, modification by deuteration was also applied, which achieved improved binding of istradefylline to the A2A receptor. In this work, isotopic substitution represents an original concept of modulating pharmacodynamic properties, and the obtained results indicate a greater efficiency of deuterium-enriched istradefylline, which could be used to improve its pharmacotherapeutic profile in the treatment of Parkinson's disease.

The development of new approaches in the treatment of Parkinson's disease presents a challenge due to the presence of the blood-brain barrier, which hinders effective drug delivery to the brain. Due to their unique physicochemical properties, nanoparticles have the potential to improve conventional therapeutic approaches and enable targeted drug delivery across the blood-brain barrier. The main goal of this doctoral thesis was to synthesize and characterize differently functionalized gold and selenium nanoparticles and to examine their interaction with catechols (levodopa and dopamine) in order to design more effective and safer therapeutic systems for Parkinson's disease. The process of drug binding to the nano-surface was investigated using various spectroscopic, laser and microscopic methods, while the bloodbrain barrier permeability of prepared nano-systems was tested under in vitro settings. The obtained results have provided a better understanding of the processes that occur during the binding of catechol drugs to gold and selenium nanoparticles. This will potentially enable the development of a nano-formulation with targeted drug delivery to the brain with the aim of improving the therapy of Parkinson's disease. Razvoj novih pristupa u liječenju Parkinsonove bolesti predstavlja izazov zbog prisutnosti krvno-moždane barijere koja otežava učinkovitu dostavu lijekova u mozak. Zahvaljujući jedinstvenim fizikalno-kemijskim svojstvima, nanočestice imaju potencijal poboljšati konvencionalne terapijske pristupe i omogućiti ciljanu isporuku lijekova preko krvnomoždane barijere. Glavni cilj ovog doktorskog rada bio je sintetizirati i karakterizirati različito funkcionalizirane nanočestice zlata i selena te ispitati njihovo međudjelovanje s kateholima (levodopa i dopamin) u svrhu dizajniranja učinkovitijih i sigurnijih terapijskih sustava za liječenje Parkinsonove bolesti. Proces vezanja lijekova na nano-površinu ispitivao se pomoću različitih spektroskopskih, laserskih i mikroskopskih metoda, a zatim su se provela istraživanja propusnosti krvno-moždane barijere za novopripravljene nanosustave u in vitro uvjetima. Dobiveni rezultati omogućili su bolje razumijevanje procesa koji se događaju prilikom vezanja lijekova kateholne strukture i novih nanočestica zlata i selena. Na taj način potiče se razvoj nano-formulacija s ciljanom isporukom lijekova u mozak s ciljem poboljšanja terapije za Parkinsonovu bolest.

Upotreba deuterija u farmaceutskoj kemiji doživljava nagli rast u posljednjih nekoliko godina, što je posebno potaknuto odobrenjima FDA agencije za stavljanje na tržište dvaju deuteriranih lijekova, Austeda 2017. i Sotyktua 2022. godine. Pozitivni učinci selektivnog deuteriranja nadilaze osnovnu primjenu u poboljšanju farmakokinetičkih svojstava nedeuteriranih spojeva jer pružaju mogućnost efikasnog rješavanja problema toksičnosti posredovane metabolizmom, interakcije lijekova, niske bioaktivacije, pa čak i šire, deuteriranje može biti učinkovit alat za povećanje afiniteta liganada bez uvođenja značajnih strukturnih promjena.[1] U ovom istraživanju korišten je niz računalnih tehnika kako bi se procijenio efekt selektivnog C–H deuteriranja na afinitet antagonista istradefilina prema adenozinskom A2A receptoru, i to paralelno s kafeinom, dobro poznatim i najčešće korištenim stimulansom koji svoje učinke ostvaruje upravo putem AA2R antagonizma. Dobiveni rezultati ukazuju na veću pozicijsku fleksibilnost manjeg kafeina unutar ortosteričkog mjesta, dok dodatak C8‐stirilnog fragmenta u istradefilinu „zaključava“ ligand u uniforman položaj, što mu omogućava formiranje stabilnijih i jačih interakcija s receptorom te veći afinitet u odnosu na kafein. Nadalje, uočeno je da aromatski supstituent na C8‐položaju pokazuje veću osjetljivost prema deuteriranju od ksantinskog dijela jer izotopna H–D supstitucija dvaju –OCH3 skupina rezultira povećanjem afiniteta za −0, 4 kcal mol−1 u odnosu na nedeuterirani ishodni spoj, što nadilazi povećanje afiniteta od –0, 3 kcal mol−1, postignuto u perdeuteriranom kafeinu. Ipak, puni potencijal ostvaren je deuteriranjem svih alkilnih položaja istradefilina čime je afinitet poboljšan za –0, 6 kcal mol−1, što odgovara povećanju potentnosti lijeka za 2, 8 puta (Slika 1). Ova saznanja podupiru primjenu deuterija u razvoju novih lijekova, a činjenica da se trenutno više od 20 označenih kandidata nalazi u kliničkim ispitivanjima daje naslutiti svijetlu budućnost ove modifikacijske strategije u godinama koje dolaze.[2] [1] (a) L. Hok, J. Mavri, R. Vianello, Molecules 25 (2020) 6017 ; (b) M. Kržan, J. Keuschler, J. Mavri, R. Vianello, Biomolecules 10 (2020) 196. [2] T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 62 (2019) 5276–5297.

Poznata je i kao bolest pokreta ili drhtajuća paraliza. Parkinsonova bolest je podmukla, kronična, napredujuća bolest moždanih stanica. U dubini mozga nalazi se dio koji se naziva crna tvar (substantia nigra). U tom dijelu mozga kod oboljele osobe nakupljaju se u moždanim stanicama neželjene bjelančevine. One razaraju moždane stanice i sprečavaju ih da stvaraju dopamin. Zato se Parkinsonova bolest zove i bolest pokreta ili drhtajuća paraliza. U Hrvatskoj je 2021. bilo oko 15 tisuća takvih bolesnika.

Duboka mozgovna stimulacija (DBS) vodeća je kirurška metoda u liječenju bolesnika s uznapredovanom Parkinsonovom bolešću (PD). Neurorehabilitacijom nakon ugradnje DBS uređaja nastoji se oboljelima omogućiti normalno funkcioniranje u svakodnevnim interakcijama i aktivnostima te na taj način unaprijediti kvalitetu života. U procesu neurorehabilitacije sudjeluje multidisciplinarni tim koji čine neurolog, fizioterapeut i logoped. Uloga neurologa u ovome procesu je prilagođavanje parametara DBS uređaja te prilagodba farmakološke terapije. Uloga fizioterapeuta je održavanje i obnavljanje maksimalne funkcionalne pokretljivosti i sposobnosti, dok je uloga logopeda terapija poremećaja govora na koji DBS ima specifičan utjecaj., Deep brain stimulation (DBS) is the most common surgical treatment for patients with advanced Parkinson’s disease (PD). Following surgery, neurorehabilitation aims to help patients function properly in daily interactions and activities, and thus improve their quality of life. The neurorehabilitation process is overseen by a multidisciplinary team that includes a neurologist, physiotherapist, and speech therapist. The role of neurologist is to change the DBS device’s parameters as well as the pharmacological therapy. The role of the physiotherapist is to maintain and restore maximum functional mobility and ability, while the role of the speech therapist is to assist with speech issues on which DBS can have a significant impact.

Parkinsonova bolest druga je najučestalija neurodegenerativna bolest. Najčešći simptomi pacijenata koji boluju od Parkinsonove bolesti su tremor u mirovanju, rigidnost, bradikinezija i poremećaj hoda. Liječenje Parkinsonove bolesti složeno je. Razlog tome je kompleksnost bolesti te dugogodišnja progresija. Liječenje može biti medikamentozno ili invazivnim metodama liječenja poput duboke mozgovne stimulacije. Kod medikamentoznog liječenja koristimo tri kategorije lijekova. Prva kategorija lijekova povećava razinu dopamina u mozgu, druga kategorija lijekova, kao što su antikolinergički lijekovi, smanjuje simptome Parkinsonove bolesti i treća kategorija djeluje na nemotoričke simptome Parkinsonove bolesti. Ako medikamentozno liječenje nije dostatno, danas se najviše primjenjuje duboka mozgovna stimulacija. Duboka mozgovna stimulacija je neurokirurška intervencija kojom se ugrađuje elektroda u područje subtalamičke jezgre, ventralne intermedijalne jezgre ili u područje globus pallidus, jer se motoričke komplikacije Parkinsonove bolesti ne mogu adekvatno kupirati lijekovima. Prije same neurokirurške intervencije važna je prijeoperacijska priprema i procjena pacijenata koji su potencijalni kandidati za ovakav zahvat. U prijeoperacijskoj pripremi i procjeni pacijenata treba sudjelovati multidisciplinarni tim stručnjaka koji uključuje psihologe, psihijatre, neurokirurge, a posebnu ulogu imaju kliničari, neurolozi, koji svoje pacijente najbolje poznaju te mogu procijeniti daljnju kvalitetu života pacijenta nakon ugradnje DBS-a., Parkinson's disease is the second most common neurodegenrative disease. The most common symptoms of patients with Parkinson's disease are rest tremor, rigidity, bradykinesia and gait disorder. The treatment of Parkinson's disease is very complex. The reason for this is disease's complexity and yearly progression. It can be medicamentous therapy or invasive methods like applying deep brain stimulation (DBS). There are three categories of medicamentous therapy that are used. The first category of drugs increases the level of dopamine in the brain, the second category of drugs reduces the symptoms of Parkinson's disease, such as anticholinergic drugs and the third category of drugs is used for non-motor symptoms of Parkinson's disease. If medicamentous therapy is not sufficient, deep brain stimulation is used today. Deep brain stimulation is the neurosurgical procedure involving the placement an electrode into the area of the subthalamic nucleus, ventral intermediate nucleus (VIM) in thalamus or globus pallidus because the motor complications of Parkinson's disease can not be adequately eliminated with drugs. Before the neurosurgical procedure, the preoperative preparation and evaluation of the patients, who are potential candidates for this procedure, is very important. A complete medical evaluation is necessary for the preoperative preparation of patients. The preoperative preparation and evaluation of patients should involve a multidisciplinary team of experts including psychologists, psychiatrists, neurosurgeons, with a special role for clinicians, neurologists, who know their patients best and can evaluate the patients' further quality of life after DBS is installed.

Parkinson’s disease (PD) is generally considered as a primary movement disorder, but the majority of patients also suffer from non-motor oral, salivary symptoms. The most common salivary symptoms, sialorrhea and xerostomia, have a considerable negative impact on the quality of life. Although these symptoms are completely opposite ones, both significantly impair oral health of patients. Sialorrhea is defined as an increased amount of the retaining saliva. It is related to salivary overproduction, or it may be associated with impaired clearance of saliva. Opposed to sialorrhea, xerostomia is subjectively defined as dryness of mouth and it is related to insufficient salivary secretion. Xerostomia promotes imbalance of oral microflora and oral pathology that often leads to malnutrition in PD patients. It is mostly related to autonomic dysfunction, or it might be considered as a side effect of dopaminergic or anticholinergic medication. In PD, different assessments are used for evaluation of sialorrhea and xerostomia, including validated scales for non-motor symptoms and standardized questionnaires on oral health. Consequently, treatment of salivary symptoms includes pharmacological and nonpharmacological approach, and surgical interventions. A multidisciplinary approach in clinical neurology and dental medicine, which includes accurate evaluation of salivary symptoms and effective treatment, indicates successful management of PD patients., Parkinsonova bolest (PB) općenito se smatra primarnim poremećajem pokreta, ali većina bolesnika pati i od ne-motornih oralnih salivarnih simptoma. Najčešći salivarni simptomi, sijaloreja i kserostomija, imaju značajan negativan utjecaj na kvalitetu života bolesnika. Iako su navedeni simptomi potpuno suprotni, oboje značajno narušavaju oralno zdravlje bolesnika. Sijaloreja se definira kao povećana količina zadržavajuće sline, a povezana je s prekomjernim lučenjem sline ili nedostatnim odstranjivanjem sline. Za razliku od sijaloreje, kserostomija se subjektivno definira kao suhoća usta i povezana je s nedovoljnim lučenjem sline. Kserostomija potiče neravnotežu oralne mikroflore i oralnu patologiju koja često dovodi do pothranjenosti kod bolesnika s PB. Povezana je s autonomnom disfunkcijom ili se može smatrati nuspojavom dopaminergičkih ili antikolinergičkih lijekova. U PB se za procjenu sijaloreje i kserostomije primjenjuju različite metode procjene, uključujući standardizirane ljestvice za procjenu ne-motoričkih simptoma i upitnike oralnog zdravlja. Slijedom toga, liječenje salivarnih simptoma uključuje farmakološki i ne-farmakološki pristup te kirurške intervencije. Multidisciplinarni pristup u kliničkoj neurologiji i dentalnoj medicini, koji obuhvaća preciznu procjenu salivarnih simptoma te učinkovito liječenje, ukazuje na uspješno liječenje bolesnika s PB.

Uvod: Progresijom neizlečivih neuroloških bolesti, poput multiple skleroze (MS), Parkinsonove bolesti (PB) i amiotrofične lateralne skleroze (ALS) dolazi do ispoljavanja složenih fizičkih, psihičkih i kognitivnih oštećenja, koja dovode do funkcionalne onesposobljenosti, gubitka autonomije, poteškoća u socijalnom funkcionisanju i značajnog narušavanja kvaliteta života koje bi se mogle rešiti ili ublažiti palijativnim zbrinjavanjem. Kako bi se adekvatno isplanirale i sprovele usluge palijativnog zbrinjavanja, ključno je identifikovati i definisati potrebe obolelih. Ciljevi ovog istraživanja bili su da se identifikuju fizički simptomi i znakovi bolesti kod obolelih od MS, PB i ALS koji se mogu ublažiti palijativnim zbrinjavanjem, prisustvo bola, kao i da se proceni nivo njihove funkcionalne nezavisnosti u aktivnostima dnevnog života. Materijal i metode: Istraživanje je sprovedeno na Klinici za neurologiju Kliničkog centra Vojvodine u Novom Sadu, kao prospektivna studija sa retrospektivnim delovima. Uzorak je činilo 154 pacijenta. Kao instrumenti istraživanja korišćeni su: Opšti upitnik; Šefildov profil za procenu i upućivanje na negu (SPARC); Numerička skala za procenu intenziteta bola (NPRS); Bartelov indeks (BI); Upitnik o uticaju multiple skleroze (MSIS-29); Upitnik o kvalitetu života za Parkinsonovu bolest (PDQL); Revidirana skala funkcionalnosti pacijenata sa amiotrofičnom lateralnom sklerozom (ALSFRS-R). Rezultati: Utvrđena je značajna razlika u ispoljavanju fizičkih simptoma između tri grupe obolelih (F=14.012, p, Introduction: Progression of incurable neurological diseases, such as multiple sclerosis (MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), leads to the manifestation of complex physical, mental and cognitive impairments, causing functional disability, loss of autonomy, difficulties in social functioning and significant impairment of quality of life that could be solved or mitigated by palliative care. It is crucial to identify and define patients' needs to plan and implement palliative care services adequately. The objectives of this study were to identify physiological symptoms and signs of disease in MS, PB, and ALS patients that can be alleviated by palliative care, determine the presence of pain, and assess the level of their unctional independence in daily activities. Material and methods: The research was carried out at the Neurology Clinic of the Clinical Center of Vojvodina in Novi Sad as a prospective study with retrospective parts. The sample comprised 154 patients. The following were used as research instruments: General questionnaire; Sheffield Profile for Assessment and Referral for Care (SPARC); Numerical Pain Rating Scale (NPRS); Barthel Index (BI); Multiple Sclerosis Impact Scale (MSIS-29); Parkinson's Disease Quality of Life Questionnaire (PDQL); Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Results: A significant difference in the manifestation of physical symptoms was found between the three groups of patients (F = 14.012, p

Parkinsonova bolest predstavlja progresivni poremećaj koji je označen određenim patološkim promjenama i kliničkom slikom. Glavni simptomi ove bolesti su hipokinezija, rigor, tremor koji je prisutan u mirovanju, gubitak posturalnih refleksa, rjeđe je vidljiva hipofonija i dizartija. Uz glavne simptome javlja se cijeli niz nemotoričkih simptoma poput: bolova, osjetnih smetnji, anskioznost, depresija, poremećaj spavanja, prisutna su i kognitivna oštećenja te autoimune disfunkcije (osjećaj nedovoljnog pražnjenja mjehura, prekomjerno znojenje, opstipacija). Dijagnoza PB-a se postavlja isključivo klinički, na temelju kliničkog nalaza jer ne postoje određene metode koje se koriste za dijagnosticiranje bolesti. Zbog toga, potreban je precizan neurološki pregled te obrada koja bi pomogla u dijagnosticiranju bolesti. Kod liječenja PB-a bitno je da se svakom bolesniku pristupi individualno, bez obzira o dobi bolesnika i u kojem stadiju se bolest nalazi. Kod liječenja PB-a vrlo je bitan i potreban multidiscipliniran pristup pošto je riječ o bolesti koja zahvaća brojne sustave. Liječenje se svodi na medikamentno (farmakološko) i neurološko te je od velikog značaja kompleksna neurorehabilitacija s kojom se počinje odmah od početka nakon dijagnosticiranja bolesti. Neurorehabilitacijom se ublažuju i preveniraju komplikacije koje mogu nastati i poticati redukcijske te kompenzacijske mehanizme i neuroplasticitet. Fizioterapija i fizioterapijski procesi imaju veliku ulogu u liječenju PB-a. Nakon točno postavljenje dijagnoze, nakon što se uzme točna anamneza te provede fizikalno ispitivanje počinje se primjenjivati fizikalna medicina i rehabilitacijski postupci. Isključivo taj proces vodi bolesnikovu brzom izlječenju i rehabilitaciji. Glavna svrha rehabilitacije je u najvećoj mogućoj mjeri osposobiti bolesnika od PB-a te ga pripremiti za samostalnost u svakodnevnim aktivnostima, preko edukacije i programe medicinske rehabilitacije, a uz podršku pacijentove obitelji. Od fizioterapijskih procesa u liječenju vrlo bitnu ulogu ima kineziterapija te se primjenjuju vježbe jačanja, koordinacije, ravnoteže, disanja te vježbe istezanja. Od ostalih postupaka mogu se koristiti elektroterapija, medicinska masaža, PNF i Bobath koncept. Parkinson's disease is a progressive disorder that is marked by certain pathological changes and the clinical picture. The main symptoms of this disease are hypokinesia, rigor, tremor that is present at rest, loss of postural reflexes, hypophony and dysarthria are less common. In addition to the main symptoms, there are a number of non-motor symptoms such as: pain, sensory disturbances, anxiety, depression, sleep disorders, cognitive impairment and autoimmune dysfunction (feeling of insufficient bladder emptying, excessive sweating, constipation). The diagnosis of PB is made exclusively clinically, based on the clinical finding because there are no specific methods used to diagnose the disease. Therefore, a precise neurological examination and treatment is needed to help diagnose the disease. In the treatment of PD, it is important that each patient is approached individually, regardless of the patient's age and stage of the disease. A multidisciplinary approach is very important and necessary in the treatment of PD, as it is a disease that affects many systems. Treatment is reduced to medication (pharmacological) and neurological, and complex neurorehabilitation is of great importance, which is started immediately from the beginning after the diagnosis of the disease. Neurorehabilitation alleviates and prevents complications that can occur and encourages reduction and compensation mechanisms and neuroplasticity. Physiotherapy and physiotherapy processes play a major role in the treatment of PB. After the correct diagnosis is made, after the correct anamnesis is taken and a physical examination is performed, physical medicine and rehabilitation procedures are applied. This process alone leads to the patient's rapid healing and rehabilitation. The main purpose of rehabilitation is to train the patient with PB as much as possible and prepare him for independence in daily activities, through education and medical rehabilitation programs, with the support of the patient's family. Of the physiotherapeutic processes, kinesitherapy plays a very important role in treatment, and strengthening, coordination, balance, breathing and stretching exercises are used. Other procedures include electrotherapy, medical massage, PNF and the Bobath concept.

Ljudski mozak je nedokučivi organ i mali, ali najsloženiji sustav u prirodi za koji znamo. Većim dijelom je građen od neurona, čija oštećenja i/ili odumiranja, a samim tim i nefunkcionalnost, uzrokuju neurodegenerativne bolesti, među kojima su najpoznatije i najčešće Alzheimerova i Parkinsonova bolest. Obje bolesti se uglavnom javljaju u starijoj životnoj dobi, imaju raznovrsne čimbenike rizika, progresivne su, iscrpljujće i neizlječive. Dok u Alzheimerovoj nedostatak acetilkolina razara umne sposobnosti, u Parkinsonovoj bolesti nedostatak dopamina uzrokuje tremor, rigiditet mišića i akineziju te cijeli niz nemotoričkih simptoma. Nažalost, simptomi im se dijagnosticiraju tek u poodmaklim fazama, a liječenje je iznimno dugotrajno., The human brain is an unfathomable organ and a small but most complex system in nature that we know of. It is mostly made up of neurons, whose damage and / or death, and thus dysfunction, are caused by neurodegenerative diseases, among which the most well-known and most common are Alzheimer's and Parkinson's disease. Both diseases mostly occur in old age, have a variety of risk factors, are progressive, exhausting, and incurable. While in Alzheimer's the lack of acetylcholine destroys mental abilities, in Parkinson's disease the lack of dopamine causes tremor, muscle rigidity and akinesia and a whole range of non-motor symptoms. Unfortunately, their symptoms are diagnosed only in advanced stages, and the treatment is extremely longlasting.

PB je kronična progresivna neurodegenerativna bolest u kojoj dolazi do odlaganja abnormalnih agregata u područje pars compacte substantie nigre, što dovodi do gubitka dopaminergičnih neurona i strijatalne dopaminske deficijencije. To je najčešći poremećaj kretanja i drugi najučestaliji neurodegenerativni poremećaj koji pogađa čak 2-3% populacije u dobi od ≥65 godina. Bolest se najčešće pojavljuje između 65. i 70. godine života, a početak prije 40. godine uočava se u manje od 5% slučajeva. Nažalost, točan uzrok PB je još uvijek nepoznat, ali se pretpostavlja da bi bolest mogla biti multifaktorijalne, što bi uključivalo genetske i okolišne čimbenike. Patološko obilježje PB je prisutnost abnormalnih intracitoplazmatskih inkluzija, Lewyjevih koja su građena od proteina alfa-sinukleina. Glavni motorički simptomi PB, još se nazivaju i kardinalnim, mogu se nabrojati akronimom TRAP, što bi predstavljalo tremor u mirovanju, rigiditet, akineziju (ili bradikineziju) i posturalnu nestabilnost. Uz motoričke simptome prisutni su i NMS-i, poput senzornih, neuropsihijatrijskih, poremećaja spavanja i budnosti i poremećaja autonomnog živčanog sustava. Levodopa je već 60 godina zlatni standard u liječenju PB. Iako ima dobar učinak na većinu simptoma PB, postoje simptomi koji su rezistentni na njenu primjenu. Također, dugotrajnim korištenjem levodope dolazi do nastupa motoričkih komplikacija. Drugi konvencionalni lijekovi su manje efikasni i teže se podnose, dok starije neurokirurške metode, talamotomija i palidotomija, imaju značajan rizik mortaliteta i morbiditeta. Novija saznanja o patogenezi i genetici PB otvorila su put k razvoju novih terapijskih metoda. Brojne obećavajuće i inovativne metode napredovale su do faza kliničkih ispitivanja te bi se za nekoliko godina mogle široko upotrebljavati u klinici., PB is a chronic progressive neurodegenerative disease in which abnormal aggregates are deposited in the area of the pars compacta substantia nigra, leading to loss of dopaminergic neurons and striatal dopamine deficiency. It is the most common movement disorder and the second most common neurodegenerative disorder affecting as many as 2-3% of the population aged ≥65 years. The disease most often occurs between the ages of 65 and 70, and onset before the age of 40 is observed in less than 5% of cases. Unfortunately, the exact cause of PB is still unknown, but it is hypothesized that the disease could be multifactorial, involving genetic and environmental factors. The pathological feature of PB is the presence of abnormal intracytoplasmic inclusions, Lewy bodies that are constructed from the alpha-synuclein protein. The main motor symptoms of PB, also called cardinal, can be listed by the acronym TRAP, representing tremor at rest, rigidity, akinesia (or bradykinesia), and postural instability. In addition to motor symptoms, NMSs are present, such as sensory, neuropsychiatric, sleep and wakefulness disorders, and autonomic nervous system disorders. Levodopa has been the gold standard in the treatment of PB for 60 years. Although it has a good effect on most symptoms of PB, some symptoms are resistant to its application. Also, long-term use of levodopa leads to motor complications. Other conventional drugs are less effective and more difficult to tolerate, while older neurosurgical methods, thalamotomy and pallidotomy, have a significant risk of mortality and morbidity. Recent findings on the pathogenesis and genetics of PD have paved the way for developing new therapeutic methods. Numerous promising and innovative approaches have advanced to the stages of clinical trials and could be widely used in the clinic in a few years.

Cilj: Sindrom diskinezija-hiperpireksija hitno je stanje u Parkinsonovoj bolesti do kojeg dolazi zbog pretjerane dopaminergične stimulacije. Kolebanje koncentracije dopamina uzrokuje generalizirane atetotske diskinezije s izrazitom hipertermijom, rabdomiolizom te konfuznim stanjem. Cilj ovog rada jest prikazati slučaj bolesnika koji boluje od Parkinsonove bolesti, a prezentirao se diskinezijama i hiperpireksijom. Prikaz slučaja: Prikazujemo slučaj bolesnika u dobi od 55 godina koji je zatražio pomoć zbog visokog febriliteta i pogoršanja diskinezija u trajanju od 15 dana. Bolesnik je, usprkos detaljnom kliničkom pregledu i laboratorijskoj obradi, bio neprepoznat. U daljnjem tijeku liječenja stanje bolesnika se pogoršalo u vidu izrazite hiperpireksije uz razvoj respiratorne insuficijencije i cirkulacijske nestabilnosti. Nakon četiri tjedna liječenja u jedinici intenzivnog liječenja, bolesnik s teškom autonomnom disfunkcijom završio je smrtnim ishodom. Zaključak: Ovaj slučaj upućuje na važnost ranog prepoznavanja diskinezija i hiperpireksije kao hitnog stanja u bolesnika oboljelih od Parkinsonove bolesti s ciljem rane medikamentne potpore te sprječavanja po život opasnih posljedica., Aim: Dyskinesia-hyperpyrexia syndrome is a rare case of medical emergency in Parkinson's disease caused by excessive dopaminergic stimulation. It is characterized with severe continuous dyskinesias associated with rhabdomyolysis, hyperthermia, and subsequent alteration of the mental state. The aim of this paper is to present a clinical case of a patient suffering from Parkinson's disease presenting with dyskinesia and hyperpyrexia. Case report: We present a case of a fifty-five-year-old patient who presented with fifteen-day high body temperature and worsening of dyskinesia. The patient, in spite of a detailed clinical examination and laboratory examination, was unidentified as such. In the further course of the treatment, the condition of the patient deteriorated in the sense of extreme hyperpyrexia with the development of respiratory insufficiency and circulatory instability. After four weeks of treatment in the Intensive Care Unit, a patient with severe autonomic dysfunction, passed away. Conclusion: This case points out the importance of early recognition of dyskinesia and hyperpyrexia as an emergency in Parkinson's disease with the aim of early medical support and the prevention of life-threatening consequences.

Parkinsonova bolest, osim što se smatra poremećajem kretanja, može se manifestirati i pojavom kognitivnih poremećaja. U nastanak kognitivnog deficita u Alzheimerovoj bolesti uključeni su poremećaji glutamatne i inzulinske signalizacije. Jedan od glavnih ciljeva ovog rada je istražiti kogniciju štakorskog modela Parkinsonove bolesti, te povezanost s glutamatnom i inzulinskom signalizacijom u mozgu, induciranoga obostranom intrastrijatalnom primjenom 6-hidroksidopamina. 6-hidroksidopamin je toksin koji se koristi za selektivnu depleciju dopaminergičkih neurona. Tri mjeseca nakon primjene 6-hidroksidopamina provedeni su motorički i kognitivni testovi (test rotirajućeg cilindra, Morrisov test plivanja u labirintu, test pasivnog izbjegavanja), te su životinje bile žrtvovane. U regijama mozga (hipokampus, hipotalamus i strijatum) promatrane su promjene ekspresije proteina uključenih u inzulinsku i glutamatnu signalizaciju, te ekspresija tirozin hidroksilaze imunofluorescencijom, Westernskom metodom otiska i enzimskog testa visoke osjetljivosti (ELISA). Tri mjeseca nakon primjene 6-hidroksidopamina uočen je kognitivni i motorički deficit, dok je ekspresija proteina uključenih u inzulinsku signalizaciju ostala uglavnom nepromijenjena. Uz motorički i kognitivni deficit, uočena je smanjena ekspresija tirozin hidroksilaze, te snižena aktivacija AMPAR-a u hipokampusu i strijatumu, dok su dopaminergičke jezgre u supstanciji nigri ostale očuvane. Rezultati upućuju na moguću povezanost disfunkcije glutamatne signalizacije i kognitivnog deficita u štakorskom modelu Parkinsonove bolesti. Parkinson's disease, in addition to being considered a motoric disorder, can be manifested by the appearance of cognitive deficit. Glutamate and insulin signalling dysfunction is involved in the development of cognitive deficit in Alzheimer's disease. One of the main goals of this thesis is to investigate cognition in rat model of Parkinson’s disease, and its association with brain glutamate and insulin signalling, induced by bilateral intrastriatal injection of 6-hydroxydopamine (toxin used for the selective depletion of dopaminergic neurons). Three months after 6-hydroxydopamine treatment, animals were subjected to motoric and cognitive tests (RotaRod, Passive avoidance, Morris Water Maze) and later sacrificed. Expression of tyrosine hydroxylase and proteins involved in insulin and glutamate signalling were assessed in hippocampus, hypothalamus and striatum by immunofluorescence, Western blot and ELISA methods. Cognitive and motor deficit was observed three months after the administration of 6-hydroxydopamine, while protein expression involved in insulin signalling remained largely unchanged. Motor and cognitive deficit were observed as well as a decrease in tyrosine hydroxylase expression and AMPAR activation the hippocampus and striatum, while dopaminergic nuclei in substantia nigra were preserved, suggesting a possible association between glutamate signalling dysfunction and cognitive deficit in a rat model of Parkinson’s disease.

Parkinsonova bolest je složena neurodegenerativna bolest. Uzrok bolesti, kao i mehanizmi nastanka nisu u potpunosti razjašnjeni. Uglavnom se radi o kombinaciji nasljednih i okolišnih čimbenika, a rjeđe nalazimo specifične genske abnormalnosti. Bolest se manifestira poremećajem pokreta koji nastaje zbog gubitka dopaminergičkih neurona nigrostrijatalnog puta, a zahvaća i velik broj drugih regija mozga. Vodeći sindrom bolesti je parkinsonizam, hipokinetički poremećaj pokreta koji se klinički manifestira bradikinezom, rigorom, tremorom u mirovanju i gubitkom posturalnih refleksa. Dijagnoza Parkinsonove bolesti je predominantno klinička i temelji se na kombinaciji klinički utvrđenog parkinsonizma i suportivnih simptoma uz odsutnost atipičnih znakova. Konačna dijagnoza bolesti se postavlja post-mortem na temelju nalaza Lewyjevih tjelešaca u stanicama bazalnih ganglija i degeneraciji supstancije nigre. Parkinsonizam, međutim, nije isključivo vezan za Parkinsonovu bolest nego se može javiti i u čitavom nizu različitih bolesti i stanja pa govorimo o sekundarnom, atipičnom ili parkinsonizmu u sklopu neurodegenerativnih oboljenja. Iscrpna anamneza i detaljan klinički pregled potpomognuti kako slikovnim tako i laboratorijskim pretragama preduvjet su za postavljanje ispravne dijagnoze što u konačnici vodi ka boljoj kvaliteti života i produljenom životnom vijeku., Parkinson's disease is a complex neurodegenerative disease. The cause of the disease, as well as the mechanism of its occurrence, have not been fully elucidated. It is mainly caused by combination of hereditary and environmental factors, and less often by specific genetic abnormalities. The disease is manifested by a movement disorder caused by the loss of dopaminergic neurons of the nigrostriatal pathway. A large number of other brain regions may be affected. The leading syndrome of the disease is parkinsonism, a hypokinetic movement disorder that is clinically manifested by bradykinesia, rigidity, tremor at rest, and postural instability. The diagnosis of Parkinson's disease is predominantly clinical, based on a combination of clinically established parkinsonism and supportive symptoms in the absence of atypical signs. The final diagnosis of the disease is made postmortem based on the finding of Lewy bodies in the cells of the basal ganglia and the degeneration of the grey matter. Parkinsonism, however, is not exclusively related to Parkinson's disease, but can also occur in a number of different diseases and conditions, so we are talking about secondary, atypical or parkinsonism as part of neurodegenerative diseases. A comprehensive history and detailed clinical examination, supported by both imaging and laboratory tests, are a prerequisite for making a correct diagnosis, ultimately leading to better quality of life and extended lifespan.

Parkinsonova bolest je kronična progresivna neurodegenerativna bolest koja je karakterizirana propadanjem dopaminergičnih neurona u supstanciji nigri. Bolest se očituje pojavom motoričkih i nemotoričkih simptoma te narušava sposobnost kretanja. Razvoj bolesti je polagan, tako da do primjećivanja prvih tegoba može doći tek nakon nekoliko mjeseci ili godina nakon pojave simptoma. Dijagnoza Parkinsonove bolesti uglavnom se postavlja klinički, budući da nema nijedan pouzdan test ili pretraga koja može potvrditi bolest. Osnova liječenja Parkinsonove bolesti je simptomatsko liječenje, stoga su kontrola motoričkih simptoma i poboljšanje kvalitete života osnovni ciljevi liječenja. Kod pacijenata oboljelih od Parkinsonove bolesti pravilna i uravnotežena prehrana je ključan čimbeniku djelotvornosti terapije budući da mnogi antiparkinsonici bolju djelotvornost postižu uz adekvatnu prehranu. Parkinsonova bolest uvelike smanjuje kvalitetu života pacijenta budući da svojim simptomima i komplikacijama sprječavaju čovjeka u njegovom ostvarenju svakodnevnih aktivnosti, stoga je cilj sestrinske skrbi pacijenta smanjiti ili ukloniti simptome bolesti i omogućiti pacijentu da postigne što je moguće najvišu razinu kvalitete života. Pri planiranju zdravstvene njege bitno je pridržavati se načela zdravstvene njege, a to je da je skrb usmjerena isključivo prema pacijentu kao prema pojedincu, da mu se pristupa holistički gdje je pacijent u centru zbivanja te uključuje njegovo tijelo, um i duh. Parkinson's disease is a chronic progressive neurodegenerative disease characterized by the breakdown of dopaminergic neurons in the substantia nigra. The disease is manifested by the appearance of motor and non-motor symptoms and impairs the ability to move. The development of the disease is slow, so that the first symptoms can be noticed only after a few months or years after the onset of symptoms. The diagnosis of Parkinson's disease is generally made clinically, as there is no reliable test or examination that can confirm the disease. The basis of Parkinson's disease treatment is symptomatic treatment, so controlling motor symptoms and improving quality of life are the main goals of treatment. In patients with Parkinson's disease, a proper and balanced diet is a key factor in the effectiveness of therapy, as many antiparkinsonian drugs achieve better efficacy with adequate nutrition. Parkinson's disease greatly reduces the quality of life of the patient because its symptoms and complications prevent a person in his daily activities, so the goal of nursing care is to reduce or eliminate the symptoms of the disease and enable the patient to achieve the highest possible quality of life. When planning health care, it is important to adhere to the principles of health care, which is that care is directed exclusively to the patient as an individual, to be approached holistically where the patient is at the center of events and includes his body, mind and spirit.

Sažetak. Cilj: Prikazati ishod duboke moždane stimulacije (engl. Deep brain stimulation, DBS), tijekom vremenskog razdoblja od 2,5 godine, u sedamdeset osmogodišnje pacijentice koja boluje od Parkinsonove bolesti (PB) rezistentne na lijekove. Prikaz slučaja: Prikazujemo slučaj pacijentice u dobi od 74 godine koja je bila zainteresirana za DBS zbog PB-a rezistentnog na lijekove. Bolest se manifestirala u obliku tremora lijeve ruke i noge te je uvelike narušavala njezinu kvalitetu života. U dobi od 75 godina ugrađen joj je DBS u suptalamičke jezgre (engl. subthalamic nucleus, STN) obostrano. Na prvom poslijeoperacijskom kontrolnom pregledu ustanovljeno je da nakon stimulacije gotovo nije bilo tremora i govor je bio uredan. Stimulacije elektroda bile su postavljene desno (D 0- 2.1 V 90 μs 130 Hz) i lijevo (L 8- 0.8 V 90 μs 130 Hz). Tijekom 2,5 godine pacijentica je redovito kontrolirana i stimulacija elektroda bila je izmijenjena u dva navrata. Na zadnjem kontrolnom pregledu navela je da je nesmetano obavljala svakodnevne aktivnosti te se čak i bavila pletenjem, što prije nije mogla. Također, pacijentica je bila dobro kognitivno očuvana. Razina stimulacije elektroda iznosila je desno – D 0- 2.4 V 90 μs 130 Hz i lijevo – L 8- 1.0 V 90 μs 130 Hz. Zaključak: Kod pažljivo odabranih kandidata, koji duže godina boluju od PB-a rezistentnog na medikamentoznu terapiju, dob iznad 70 godina ne bi trebala predstavljati kontraindikaciju za DBS STN. Prikazani slučaj pokazuje da DBS STN može biti koristan u smanjenju simptoma i time značajno poboljšati kvalitetu života takvih pacijenata., Aim: To present the outcome of deep brain stimulation (DBS) through a time period of 2.5 years, in a seventy-eight-year-old female suffering from drug-resistant Parkinson’s disease (PD). Case report: We present the case of a 74-year-old patient who was interested in DBS due to drug-resistant PD. The disease manifested itself in the form of tremor of the left arm and leg and greatly impaired her quality of life. At the age of 75, she was embedded with DBS in the subthalamic nuclei (STN) bilaterally. At the first postoperative check-up, it was found that there was almost no tremor after stimulation and the speech was orderly. Electrode stimulations were placed on the right (D 0- 2.1 V 90 μs 130 Hz) and on the left (L 8- 0.8 V 90 μs 130 Hz). Over a period of 2.5 years, the patient was regularly monitored and electrode stimulation was changed twice. At the last check-up, she stated that she performed her daily activities without hindrance and in her free time she was even knitting, what she couldn’t do before. Also, the patient was well cognitively preserved. The level of electrode stimulation was right (D 0– 2.4 V 90 μs 130 Hz) and left (L 8- 1.0 V 90 μs 130 Hz). Conclusion: In carefully selected candidates, who have been suffering from drug-resistant PD for many years, age over 70 years should not be a contraindication for DBS STN. The presented case shows that DBS STN can be useful in reducing symptoms and thus significantly improve the quality of life in such patients.

Comorbidity is one of the most significant challenges in diagnostic and therapeutic procedures in clinical medicine, but also in scientific research and nosology. The occurrence of comorbidity that is secondary syndrome or disease raises the question of whether it is an accidental phenomenon, whether there may be a causal relationship with the primary disorder or whether it is simply synchronicity. Schizophrenia and Parkinson's disease are progressive and degenerative diseases of the central nervous system with overlapping neurobiological etiopathogenesis of dopaminergic system disorders. In schizophrenia, symptoms appear depending on the hypo or hyperactivity of dopamine, while in Parkinson's disease the syndrome is caused by hypodopaminergia. Regardless of early recognition, personalized treatment and duration of both diseases, the treatment outcome is very unfavorable due to the irreversible death of nerve cells of the dopaminergic system.

Parkinsonova bolest je progresivni poremećaj živčanog sustava koja stvara probleme u kretanju. Kao posljedica ove neurodegenerativne bolesti javlja se smrt dopaminergičnih neurona. Glavni pokazatelji da se radi o navedenoj bolesti su: tremor ruku ili nogu, posebno u mirovanju, rigiditet, bradikinezija i gubitak posturalnih refleksa. Od nemotoričkih simptoma javljaju se poremećaji raspoloženja poput depresije, anksioznosti i razdražljivosti. Kognitivne promjene poput problema s usredotočenom pažnjom i planiranjem, usporavanje misli, poteškoće u jeziku i pamćenju, promjene osobnosti. Velike probleme stvara i demencija koja je česta u osoba s Parkinsonovom bolesti. Prosječno javljanje bolesti je u 60. godini života. Čimbenici koji povećavaju rizik od nastanka bolesti su: muški spol, česte ozljede glave, izloženost pesticidima, upotreba vode iz izvora, život u ruralnim područjima i pozitivna obiteljska anamneza. U kliničkoj slici bolesti karakteristični su motorički simptomi. Dijagnoza se temelji na podacima prikupljenim tijekom zdravstvene povijesti pacijenta i tjelesne procjene; konkretno, najmanje dva kardinalna motorička znaka poput tremora u mirovanju i bradikinezija. Nakon dijagnoze, tretmani mogu pomoći u ublažavanju simptoma, ali bolest nije izlječiva. Liječenje podrazumijeva primjenu medikamentozne terapije te neurokirurški tretman. Važnu ulogu predstavlja bihevioralna terapija, fizikalni tretmani te tjelovježba i tehnike relaksacije. Cilj provedenog istraživanja bio je dobiti uvid u razinu informiranosti populacije o Parkinsonovoj bolesti. U istraživanju je sudjelovalo 338 ispitanika. Upitnik koji je sastavljen za potrebe ovog istraživanja sadrži 22 pitanja. Svrha rada je usporediti razinu informiranosti osoba koje su bile u neposrednom kontaktu s osobom oboljelom od Parkinsonove bolesti u odnosu na ispitanike koji nisu. Rezultati pokazuju da ne postoji statistički značajna razlika između ispitanika u razini informiranosti o Parkinsonovoj bolesti s obzirom na opća obilježja (spol, dob, razinu obrazovanja). Osobe koje su imale kontakt s oboljelima od Parkinsonove bolesti statistički se značajno ne razlikuju u nivou informiranosti o toj bolesti od osoba koje ne poznaju nijednu takvu oboljelu osobu. Nužno je poraditi na informiranosti populacije o PB bolesti jer će na taj način doći do ranijeg otkrivanja bolesti, bržeg započinjanja liječenja i omogućiti oboljelima duži niz godina samostalnog, zadovoljavajućeg funkcioniranja. Parkinson's disease is a progressive disorder of the nervous system that affects movement. As a consequence of this neurodegenerative disease, the death of dopaminergic neurons occurs. The main indicators that it is Parkinson's disease are: tremor / shaking of the hands, arms or legs, especially when hitting, rigidity-abnormal stiffness of limbs or body parts, instability of posture - disturbed balance or difficulty standing or walking, bradykinesia - gradual loss and slowing of spontaneous movements. Non-motor symptoms include schedule disorders such as depression, anxiety, and irritability. Cognitive changes such as problems with focused attention and planning, slowing of thoughts, difficulties in language and memory, personality changes. Dementia, which is a person with Parkinson's disease, also creates big problems. The average onset of the disease is around the 60s. Factors that increase the risk of developing the disease are: male gender, frequent head injuries, exposure to pesticides, use of spring water, life in rural areas, and a positive family history. In the clinical picture of the disease, the most characteristic are the motor symptoms. Diagnosis based on data collected during patients ’medical history and physical assessments; specifically, at least two cardinal motor signs such as resting tremor and bradykinesia. Once diagnosed, treatments can help alleviate symptoms, but the disease is not curable. In the treatment of the disease, drug therapy, neurosurgical treatment is used. Behavioral therapy, physical exercise treatments and relaxation techniques play an important role. The aim of the study was to gain insight into the knowledge of the general population about Parkinson's disease. The research was conducted online. 338 people participated. The questionnaire was compiled for the purposes of this research and contains 22 questions. The purpose of this paper is to compare the knowledge of people who have met a person with Parkinson's disease with the knowledge of those who have not met or been in contact with people with Parkinson's disease. The results show that there is no statistically significant difference between the respondents in the level of information about Parkinson's disease with regard to general characteristics (gender, age, level of education). People who have had contact with people with Parkinson's disease do not differ statistically significantly in the level of knowledge about the disease from people who do not know any such person. It is necessary to work on informing the population about PB disease, because in this way the disease will be detected earlier, treatment will be started faster and patients will be able to function independently and satisfactorily for many years.

Parkinsonova bolest (PB) je drugo po učestalosti neurodegenerativno oboljenje, koje karakteriše progresivna degeneracija i smrt dopaminergičkih (DA) neurona substantiae nigrae (SN) pars compacta, koji učestvuje u kontroli pokreta. Iako je etiologija PB u velikoj meri i dalje nedovoljno razjašnjena, rezultati brojnih eksperimentalnih studija, ukazali su da bi oksidativni stres, disfunkcija mitohondrija i ćelijskih sistema uključenih u homeostazu proteina, mogli biti odgovorni za degeneraciju i smrt DA neurona u SN. Ispitivanje uticaja neurotoksina MPP+ na neurone, je do danas ostao jedan od najznačajnijih modela za proučavanje molekularnih mehanizama oštećenja i smrti neurona. Cilj ovog istraživanja je bio da se ispita uloga oksidativnog stresa, kao i signalnih puteva unutarćelijsog energetskog senzora, adenozin monofosfatom aktivirane kinaze (AMPK), protein kinaze B/Akt - medijatora rasta i preživljavanja ćelija, autofagije, kao i njihovih interakcija, u modelu oštećenja neurona delovanjem MPP+. Istraživanje je sprovedeno na modelu ćelijske linije humanog neuroblastoma SH-SY5Y. Primena MPP+ je dovela do dozno i vremenski-zavisnog pada vijabiliteta i fragmentacije DNK, kome su prethodili porast oslobađanja superoksidnog anjona i depolarizacija unutrašnje mitohondrijalne membrane, kao i rana aktivacija signalnih puteva AMPK i Akt kinaze. Primena antioksidanasa, N-acetil cisteina ili butiliranog hidroksianizola, dovela je do delimičnog smanjenja citotoksičnog delovanja MPP+, koji je bio praćen padom nivoa aktivacije AMPK i Akt kinaze. Genska ili farmakološka inhibicija AMPK kinaze rezultirala je povećanom osetljivošću ćelija na MPP+, uz smanjenje aktivacije Akt kinaze, dok je farmakološka aktivacija AMPK rezultirala poboljšanim preživljavanjem ćelija tretiranih MPP+ toksinom. U uslovima farmakološke ili genske inhibicije Akt kinaze, ćelije su ispoljavale veću osetljivost na štetno dejstvo MPP+ toksina, uz povećanu produkciju superoksidnog anjona. Imunoblot analiza uticaja MPP+ na aktivnost mTOR signalnog puta, najvažijeg regulatora autofagije u ćeliji, pokazala je da MPP+ indukuje kasnu inhibiciju mTOR kompleksa 1 (mTORC1), kao i porast prevođenja proteina LC3-I (engl. Microtubule associated protein 1 light chain 3, LC3) u oblik vezan za autofagozome, LC3-II, što ukazuje na indukciju mTORC1-zavisne autofagije... characterized by the progressive degeneration and demise of the dopaminergic (DA) neurons in the substantia nigra (SN) pars compacta, part of the midbrain. Even though the etiology of PD is still insufficiently elucidated, research results implicate that oxidative stress, mitochondrial dysfunction and impairment of proein homeostasis cellular play an important role in DA neurons' degeneration and cell death. The MPP+ neurotoxic model has been widely used in study of molecular mechanismsm of neuronal demise in PD. The aim of this study was to assess the interaction between the signaling pathways of the main intracellular energy sensor, adenosine monophosphate activated kinase (AMPK), prosurvival protein kinase B/Akt, oxidative stress and autophagy in the effect of parkinsonian neurotoxin 1-methyl-4-phenyl piridinium (MPP+) The study was conducted on SH-SY5Y human neuroblastoma cell line. MPP+ caused the dose- and time- dependent decrease in cell viability and DNA fragmentation, preceded by increase in superoxide production (2 h) and subsequent inner mitochondrial membrane depolarization (8 h), accompanied by early activation of AMPK and Akt signaling pathways. The reactive oxygen species (ROS) scavengers, Nacetyl- L-cysteine and butylated hydroxyanisole partially alleviated the MPP+-induced cell death, causing decrease in phosphorylation levels of both AMPK and protein kinase B/Akt. Pharmacological or genetic AMPK inhibition further potentiated MPP+-induced ROS production and cell death, and diminished Akt phosphorylation, whereas AMPK activation exerted protective effects against MPP+-induced toxicity. Nevertheless, pharmacological or genetic inactivation of Akt caused an increase in MPP+-initiated oxidative stress and neurotoxicity, but failed to affect AMPK activation. Furthernore, MPP+ treatment at later time-points (16-24 h) inhibited the main autophagy repressor, mammalian target of rapamycin (mTOR), which was accompanied by the increased levels of the autophagy marker, microtubule-associated protein 1 light-chain 3B. On the other hand, the concentration of a selective autophagic target, sequestosome-1/p62, were increased in MPP+-treated cells, while levels of lysosomal-associated membrane protein 1 and cytoplasmic acidification were reduced, which suggested that MPP+- induced autophagy was associated with a decrease in autophagic flux...

PB je dosta kompleksna bolest. Utjecana je od strane velikog broja rizičnih faktora, no još uvijek joj se ne zna pravi uzrok. Prije nastupa same bolesti prethodi joj prodromalna faza u kojoj dominiraju NMS. PB čine i MS i NMS, a sama bolest zahvaća podosta šire neuroanatomsko područje no što se to prije mislilo, te se danas zna da PB ima puno opširniju kliničku sliku, no što se o njoj spominje u djelu dr. Parkinsona. Ova bolest predstavlja veliki izazov kako za bolesnika, tako i za bolnički tim. Nažalost temelj dijagnostike je još uvijek klinički kriterij, slikovne metode nam koliko toliko pomažu u diferencijalnoj dijagnostici, a na pravi biomarker bolesti se još uvijek čeka. Terapijski odgovor levodope i ostalih antiparkinsonika nakon nekoliko godina jenjava. Iako PB nema izliječenja, zahvaljujući suvremenoj terapiji, životni vijek oboljelih je vrlo sličan onome koji je i kod zdrave populacije, te kvaliteta života oboljelih je znatno poboljšana u odnosu na kojoj je razini bila prije ere antiparkinsonika. DBS se može smatrati još jednom prekretnicom koja poboljšava kvalitetu života oboljelih od PB, i to upravo onih bolesnika koji se nalaze u jako uznapredovaloj fazi bolesti., Parkinsons disease (PD) is quite a complex disease. It is influenced by a huge variety of risk factors, but we still don't know the true cause of it. Before the onset of the disease itself, it is preceded by a prodromal phase dominated by NMS. PD is comprised of MS and NMS, and the disease itself covers a much broader neuroanatomical area than previously thought, and it is nowadays known that PD has a much broader clinical picture than it is mentioned in Dr. Parkinson's work. This disease presents a great challenge for both the patient and the medical team. Unfortunately, the basis of diagnostics is still the clinical criteria, imaging methods are of minimal help with differential diagnosis, and we are still waiting on the discovery of the true biomarker of this disease. The therapeutic response of levodopa and other antiparkinsonics reduces with time. Although PD has no cure, but thanks to modern therapy, the life expectancy of patients is very similar to that of a healthy population, and the quality of life of patients is much improved compared to what it was before the antiparkinsonics era. DBS can be considered as another milestone that improves the quality of life of patients with PD, particularly those patients who are in a very advanced stage of the disease.