Study of purinergic receptors antagonism in the inflammatory process and microglial cells activation using in vitro and in vivo models of Parkinsons Disease

• Grant number: 19/26852-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): February 01, 2020
• Effective date (End): January 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Ágatha Oliveira Giacomelli
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases, AP.TEM

Abstract

Among the processes involved in neurodegeneration in Parkinson's Disease (PD) is the accumulation of ubiquitinized alpha-synuclein proteins, which lead to cellular metabolic disorders. These processes trigger ATP release and inflammatory responses with recruitment and activation of resident microglia, exacerbating the secretion of proinflammatory cytokines that can induce cell death. This activation is involved in both beneficial processes, by triggering protection mechanisms against oxidative stress, and pro-apoptotic processes involving the production of ROS, cytokines and proinflammatory prostaglandins. The release of ATP and alpha synuclein resulting from cell death, neuroinflammation and the injurious process amplify, accumulating microglia around alpha synuclein aggregates and increasing the release of proinflammatory cytokines. Part of this action occurs due to ATP binding and activation of P2X7 purinergic receptors, whose antagonism has been shown to be effective in preventing and reversing the dopaminergic deficit observed in animal models of PD. In addition, results from our laboratory show that this antagonism using Brilliant Blue G (BBG) induces neuroregeneration associated with reduced microglial activity and inflammatory response. However, the mechanisms involved in this effect have not yet been elucidated. Therefore, studies are needed to elucidate the role of BBG in the observed neuroregeneration. In addition to P2X7R, data from our laboratory show that P2Y6R antagonism with the drug MRS2578 protects dopaminergic neuron death in an animal model of 6-OHDA-induced PD. P2Y6R is known to be involved in the phagoptosis process of viable neurons by microglial cells. Studies of exosomes have shown interesting results in PD. BV-2 microglial cells submitted to alpha-synuclein showed greater release of exosomes and consequent increase in cortical neuron death, a possible indication of involvement in neurodegeneration observed in PD. Knowing that alpha-synuclein is transferred between cells of PD patients through exosomes, and that SH-SY5Y cells submitted to alpha-synuclein transfer this protein to healthy cells by the same method, elucidating a way to slow the spread of alpha-synuclein by exosomes may be a potential target against worsening neurodegeneration and in cell transplantation as a therapy for PD. In addition, results show that the release of IL-1² and caspase-1 by exosomes may be mediated by P2X7R activation, indicating that the antiinflammatory effect of BBG may involve decreased exosome release. In vitro, tooth pulp stem cell-derived exosomes were able to restrict 6-OHDA-induced dopaminergic neuron death. Considering that P2X7R and P2Y6R antagonism has shown promising results against dopaminergic deficit induced by 6-OHDA injection, study this effect in the animal model of alpha-synuclein injection, whose neurodegeneration and inflammation are triggered by other molecular mechanisms, complements and reinforces the therapeutic potential of these drugs. Knowing that these receptors are widely involved in microglial cells responses in neurodegenerative processes, elucidating the involvement of inflammation and microglial activation may be interesting not only in the development of alternative therapies but also in elucidating the molecular basis of the disease. Finally, since PD patients have reduced neurogenic capacity, combining anti-inflammatory therapies with cell transplantation therapy could create an immunomodulated microenvironment favorable to cell repopulation, repair of the lesion site and consequent reversal (or decrease) of the injury. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SEMEANO, ANA T.; TOFOLI, FABIANO A.; CORREA-VELLOSO, JULIANA C.; DE JESUS SANTOS, ANA P.; OLIVEIRA-GIACOMELLI, AGATHA; CARDOSO, RAFAELA R.; PESSOA, MATEUS A.; DA ROCHA, EDROALDO LUMMERTZ; RIBEIRO, GUSTAVO; FERRARI, MERARI F. R.; et al. Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells. STEM CELL REVIEWS AND REPORTS, v. 18, n. 4, p. 18-pg., 2022-03-24. (18/07366-4, 19/26852-0, 16/14513-8, 13/08028-1, 18/07592-4, 13/08135-2)

OLIVEIRA-GIACOMELLI, AGATHA; PETIZ, LYVIA LINTZMAIER; ANDREJEW, ROBERTA; TURRINI, NATALIA; SILVA, JEAN BEZERRA; SACK, ULRICH; ULRICH, HENNING. Role of P2X7 Receptors in Immune Responses During Neurodegeneration. FRONTIERS IN CELLULAR NEUROSCIENCE, v. 15, MAY 26 2021. (18/08426-0, 19/24553-5, 18/07366-4, 19/26852-0, 20/10725-6)

PILLAT, MICHELI MAINARDI; OLIVEIRA-GIACOMELLI, AGATHA; DAS NEVES OLIVEIRA, MONA; ANDREJEW, ROBERTA; TURRINI, NATALIA; BARANOVA, JULIANA; LAH TURNSEK, TAMARA; ULRICH, HENNING. Mesenchymal stem cell-glioblastoma interactions mediated via kinin receptors unveiled by cytometry. Cytometry Part A, v. 99, n. 2, SI, JAN 2021. (18/07366-4, 20/10725-6, 12/50880-4, 19/24553-5, 19/26852-0)

PILLAT, MICHELI MAINARDI; OLIVEIRA-GIACOMELLI, AGATHA; DAS NEVES OLIVEIRA, MONA; ANDREJEW, ROBERTA; TURRINI, NATALIA; BARANOVA, JULIANA; LAH TURNSEK, TAMARA; ULRICH, HENNING. Mesenchymal stem cell-glioblastoma interactions mediated via kinin receptors unveiled by cytometry. Cytometry Part A, v. 99, n. 2, p. 12-pg., 2021-01-13. (12/50880-4, 20/10725-6, 19/24553-5, 19/26852-0, 18/07366-4)

GLASER, TALITA; OLIVEIRA-GIACOMELLI, AGATHA; PETIZ, LYVIA LINTZMAIER; RIBEIRO, DEIDIANE ELISA; ANDREJEW, ROBERTA; ULRICH, HENNING. Antagonistic Roles of P2X7 and P2Y2 Receptors in Neurodegenerative Diseases. FRONTIERS IN PHARMACOLOGY, v. 12, p. 7-pg., 2021-04-12. (18/08426-0, 18/17504-5, 19/24553-5, 19/26852-0, 15/13345-1, 18/07366-4)

RIBEIRO, DEIDIANE ELISA; OLIVEIRA-GIACOMELLI, AGATHA; GLASER, TALITA; ARNAUD-SAMPAIO, VANESSA F.; ANDREJEW, ROBERTA; DIECKMANN, LUIZ; BARANOVA, JULIANA; LAMEU, CLAUDIANA; RATAJCZAK, MARIUSZ Z.; ULRICH, HENNING. Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology. MOLECULAR PSYCHIATRY, v. 26, n. 4, DEC 2020. (18/17504-5, 19/24553-5, 15/19128-2, 15/13345-1, 19/26852-0, 18/07366-4)

GLASER, TALITA; ANDREJEW, ROBERTA; OLIVEIRA-GIACOMELLI, AGATHA; RIBEIRO, DEIDIANE ELISA; MARQUES, LUCAS BONFIM; YE, QING; REN, WEN-JING; SEMYANOV, ALEXEY; ILLES, PETER; TANG, YONG; et al. Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington's and Parkinson's Disease. NEUROSCIENCE BULLETIN, v. 36, n. 11, SI, p. 1299-1314, NOV 2020. (18/17504-5, 19/24553-5, 15/13345-1, 19/26852-0, 18/07366-4)

DUARTE-SILVA, EDUARDO; ULRICH, HENNING; OLIVEIRA-GIACOMELLI, AGATHA; HARTUNG, HANS-PETER; MEUTH, SVEN G.; PEIXOTO, CHRISTINA ALVES. The adenosinergic signaling in the pathogenesis and treatment of multiple sclerosis. FRONTIERS IN IMMUNOLOGY, v. 13, p. 10-pg., 2022-07-28. (18/07366-4, 18/08426-0, 19/26852-0)

GLASER, TALITA; ANDREJEW, ROBERTA; OLIVEIRA-GIACOMELLI, AGATHA; RIBEIRO, DEIDIANE ELISA; MARQUES, LUCAS BONFIM; YE, QING; REN, WEN-JING; SEMYANOV, ALEXEY; ILLES, PETER; TANG, YONG; et al. Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington's and Parkinson's Disease. NEUROSCIENCE BULLETIN, v. 36, n. 11, p. 16-pg., 2020-10-07. (18/17504-5, 19/24553-5, 15/13345-1, 19/26852-0, 18/07366-4)