o:39126 Efekti repetitivne transkranijalne magnetne stimulacije na neurodegeneraciju, neuroinflamaciju i komponente purinskog signalnog sistema u modelu parkinsonove bolesti izazvane 6-hidroksidopaminom kod pacova doktorska disertacija Effects of repetitive transcranial magnetic stimulation on neurodegeneration, neuroinflammation and components of the purinergic signaling system in a 6-hydroxydopamine rat model of Parkinson's disease : doctoral dissertation sr Parkinsonova bolest (PB) predstavlja složeno, multisistemsko neurodegenerativno oboljenje koje beleži značajan rast globalne prevalence i opterećenja na zdravstveni sistem, dok terapijske strategije koje bi usporile ili zaustavile progresiju ove bolesti i dalje predstavljaju veliki izazov. Tačan uzrok koji pokreće kaskadu događaja koja dovodi do degeneracije dopaminskih (DA) neurona u regionu crne supstance i razvoja kliničke slike ove bolesti koja uključuje brojne motorne i nemotorne simptome i dalje nije jasno definisan, ali ono što je sigurno je postojanje složene interakcije genetičkih i sredinskih faktora. Mehanizmi patogeneze PB uključuju akumulaciju α-sinukleina, mitohondrijsku disfunkciju, oksidativni stres i neuroinflamaciju, koji dovode do degeneracije DA neurona i smanjenja nivoa dopamina, ali i drugih neurotransmitera. S obzirom na ograničenja trenutnih terapijskih strategija, današnja istraživanja se usmeravaju ka inovativnim pristupima kao što je repetitivna transkranijalna magnetska stimulacija (rTMS). rTMS je oblik neinvazivne stimulacije mozga koji pokazuje značajan potencijal u različitim patološkim stanjima. Predmet istraživanja ove doktorske disertacije bio je ispitivanje efekata 21-dnevnog tretmana rTMS-om na neurodegeneraciju u eksperimentalnom modelu PB izazavanom unilateralnom aplikacijom 6-hidroksidopamina (6-OHDA) u region crne supstance pacova, kao i uloga purinskog i glutamatnog signalnog sistema u tim efektima, sa ciljem da se proceni potencijalni terapijski efekat izabranog protokola u PB. Rezultati dobijeni u okviru ove disertacije ukazuju da je već nakon prve nedelje stimulacije tretman doveo do značajnih poboljšanja u pogledu motornih i nemotornih simptoma. Neuroprotektivni efekti rTMS-a su primećeni kroz povećanu ekspresiju tirozin-hidroksilaze, koja je uključena u sintezu dopamina, i povećanje nivoa dopamina i serotonina. Nadalje, rTMS je uzrokovao promene u ekspresiji ADP-zavisnih receptora u smeru koji ukazuje na potencijalnu ulogu u neuroprotekciji. Primećeno je smanjenje ekspresije i aktivnosti enzima eN/CD73 i ADA1, kao i povećanje u ekspresiji A1R i smanjenje u ekspresiji A2A receptora. Dodatno, rTMS je doveo do promena u komponentama glutamatnog signalnog sistema, uključujući povećanu ekspresiju GluN1 i GluN2A, kao i smanjenu ekspresiju GluN2B subjedinica NMDA receptora, što može pozitivno uticati na preživljavanje DA neurona. Uočeno je i povećanje antioksidativnih markera u tkivnim homogenatima ispitivanih struktura, ali i u serumu. Navedene promene ukazuju da primena iTBS-a utiče na regulaciju ključnih neurotransmitera, kao i na modulaciju komponenti purinskog i glutamatnog sistema, da ispoljava neuroprotektivni efekat, ali i povećani potencijal antioksidativnog kapaciteta što ukazuje da izabrani rTMS protokol može da utiče povoljno na ključne patofiziološke procese uključene u PB. Parkinson's disease (PD) is a complex, multisystemic neurodegenerative disorder whose global prevalence and burden on the healthcare system has increased significantly. At the same time therapeutic strategies to slow or halt the progression of the disease remain a major challenge. The exact cause that triggers the cascade of events leading to the degeneration of dopaminergic neurons in the substantia nigra and the development of the clinical picture of the disease, which includes numerous motor and non-motor symptoms, is still not clearly defined. However, a complex interplay of genetic and environmental factors is recognizable. Pathogenic mechanisms of PD include accumulation of α-synuclein, mitochondrial dysfunction, oxidative stress and neuroinflammation leading to degeneration of dopaminergic neurons and a decrease in dopamine levels as well as other neurotransmitters. Given the limitations of current therapeutic strategies, research has turned to innovative approaches such as repetitive transcranial magnetic stimulation (rTMS), a form of non-invasive brain stimulation that shows significant potential in various pathological conditions. This dissertation investigated the effects of 21days rTMS treatment on neurodegeneration in an experimental animal model of PD induced by unilateral administration of 6-hydroxydopamine (6-OHDA) in the substantia nigra, and the role of the purinergic and glutamatergic signaling systems in these effects, with the ultimate goal of evaluating the potential therapeutic effect of the chosen protocol in PD. The results of this dissertation show that rTMS led to significant improvements in motor and non-motor symptoms already after the first week of stimulation. The neuroprotective effects of iTBS were observed through increased expression of tyrosine hydroxylase, a marker for dopaminergic neurons, and increased dopamine and serotonin levels. In addition, rTMS decreased the expression of P2X7 receptors and led to changes in the expression of ADP-dependent receptors, also suggesting a possible role in neuroprotection. A reduction in the expression and activity of the enzymes eN/CD73 and ADA1 as well as changes in the expression of A1R and A2A receptors were observed. In addition, treatment with iTBS resulted in changes in the components of the glutamatergic signaling system, including increased expression of GluN1 and GluN2A and decreased expression of the GluN2B subunits of NMDA receptors, which may have a positive effect on the survival of dopaminergic neurons. An increase in antioxidant markers in tissue homogenates of the investigated structures as well as in serum was also observed. These changes indicate that rTMS influences the regulation of key neurotransmitters, as well as the components of the purinergic and glutamatergic signaling system, and has a neuroprotective effect and a potential to increase antioxidant capacity, leading to the conclusion that iTBS can positively influence important pathophysiological processes involved in PD. Biološke nauke - Neurobiologija / Biology- Neurobiology Datum odbrane: 25.09.2024. Parkinsonova bolest, neurodegeneracija, 6-hidroksidopamin, repetitivna transkranijalna magnetna stimulacija (rTMS), stimulacija teta praskovima (iTBS), neuroprotekcija, neuromodulacija, NMDA receptor, purinska signalizacija Parkinson's disease, neurodegeneration, 6-hydroxydopamine, repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation (iTBS), neuroprotection, neuromodulation, NMDA receptor, purinergic signaling 577.3:616.858(043.3) 91552100 156692489 91552101 10398 2026-05-28T07:19:15.053Z 45 no 46 Milica, 1993- Zeljković Jovanović 119833865 2024 63 mentor Danijela, 1973- Laketa 12860263 2024 63 mentor Milorad, 1993- Dragić 58855689 2024 63 član komisije Nadežda, 1967- Nedeljković 12744551 2024 63 član komisije Ivanka, 1968- Marković 12765287 2024 63 član komisije Jasna, 1962- Šaponjić 15092839 2024 63 član komisije Miroslav, 1972- Živić 12074599 2024 63 član komisije Ivana, 1973- Stevanović 77269769 2024 120 str. 22872161 http://phaidrabg.bg.ac.rs/o:39126 no yes 12 2026-05-28T07:19:15.320Z 70 11 1066841 1066872 Parkinsonova bolest, neurodegeneracija, 6-hidroksidopamin, repetitivna transkranijalna magnetna stimulacija (rTMS), stimulacija teta praskovima (iTBS), neuroprotekcija, neuromodulacija, NMDA receptor, purinska signalizacija Parkinson's disease, neurodegeneration, 6-hydroxydopamine, repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation (iTBS), neuroprotection, neuromodulation, NMDA receptor, purinergic signaling 577.3:616.858(043.3) 1738 11A02 2024