P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective/ Neuroregenerative Effects in an Animal Model of Parkinson’s Disease

Oliveira-Giacomelli, Ágatha; Albino, Carolina M.; Souza, Héllio Danny Nóbrega de; Corrêa-Velloso, Juliana; Santos, Ana Paula de Jesus; Baranova, Juliana; Ulrich, Henning

doi:10.3389/fncel.2019.00476

Cited by 44 publications

(43 citation statements)

References 59 publications

(79 reference statements)

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“…Animal models of PD show that the P2X7 receptor is involved in disease development, especially in microglial cell activation. In an animal model of nigrostriatal injury induction by 6-OH dopamine (6-OHDA), a toxic dopamine analog, striatal gene expression of the P2X7 receptor gradually increased over 5 weeks after injury (Oliveira-Giacomelli et al, 2019). Neuroprotective effects of P2X7 receptor antagonism were observed after pretreating animals with A-438079.…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…Treatment of neuronal-differentiated SH-SY5Y cells, an in vitro model of dopaminergic neurons, with BBG protected cells from 6-OHDA-induced synaptotoxicity and death (Carmo et al, 2014;Oliveira-Giacomelli et al, 2019). In addition, assays with wild-type and α-synuclein mutants of microglial cells showed that α-synuclein activated microglial P2X7 receptors, inducing NADPH oxidase, modulating the PI3K/AKT signaling pathway and increasing oxidative stress (Jiang et al, 2015).…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…Additionally, it is suggested that P2X7 receptor inhibition may also promote neuroregeneration of dopaminergic neurons when given 1 week after 6-OHDA-induced injury ( Ferrazoli et al, 2017 ; Oliveira-Giacomelli et al, 2019 ). Administration of BBG (50 mg/kg) in rats during 7 days, starting 1 week after injury, augmented the number of substantia nigra dopaminergic neurons ( Ferrazoli et al, 2017 ).…”

Section: P2x7 Receptor Roles In Neurodegenerative Diseasesmentioning

confidence: 99%

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The P2X7 Receptor: Central Hub of Brain Diseases

Andrejew

Oliveira-Giacomelli

Ribeiro

et al. 2020

Front. Mol. Neurosci.

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108

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The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.

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Section: Parkinson's Diseasementioning

confidence: 99%

Section: Parkinson's Diseasementioning

confidence: 99%

Section: P2x7 Receptor Roles In Neurodegenerative Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

The P2X7 Receptor: Central Hub of Brain Diseases

Andrejew

Oliveira-Giacomelli

Ribeiro

et al. 2020

Front. Mol. Neurosci.

Self Cite

108

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“…The protective effect of BBG treatment against 6-OH-DA-induced hemiparkinsonian symptoms including microglial activation in the substantia nigra [ 186 ] and striatum [ 187 ] was repeatedly confirmed. BBG attenuated the oxidative stress (lipid peroxidase and superoxide dismutase activities), as well as the deterioration of mitochondrial integrity (changes in mitochondrial membrane potential and mitochondrial complex-I, II, III and IV-activities) [ 187 ].…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Illéš

2020

IJMS

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ATP is a (co)transmitter and signaling molecule in the CNS. It acts at a multitude of ligand-gated cationic channels termed P2X to induce rapid depolarization of the cell membrane. Within this receptor-channel family, the P2X7 receptor (R) allows the transmembrane fluxes of Na+, Ca2+, and K+, but also allows the slow permeation of larger organic molecules. This is supposed to cause necrosis by excessive Ca2+ influx, as well as depletion of intracellular ions and metabolites. Cell death may also occur by apoptosis due to the activation of the caspase enzymatic cascade. Because P2X7Rs are localized in the CNS preferentially on microglia, but also at a lower density on neuroglia (astrocytes, oligodendrocytes) the stimulation of this receptor leads to the release of neurodegeneration-inducing bioactive molecules such as pro-inflammatory cytokines, chemokines, proteases, reactive oxygen and nitrogen molecules, and the excitotoxic glutamate/ATP. Various neurodegenerative reactions of the brain/spinal cord following acute harmful events (mechanical CNS damage, ischemia, status epilepticus) or chronic neurodegenerative diseases (neuropathic pain, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis) lead to a massive release of ATP via the leaky plasma membrane of neural tissue. This causes cellular damage superimposed on the original consequences of neurodegeneration. Hence, blood-brain-barrier permeable pharmacological antagonists of P2X7Rs with excellent bioavailability are possible therapeutic agents for these diseases. The aim of this review article is to summarize our present state of knowledge on the involvement of P2X7R-mediated events in neurodegenerative illnesses endangering especially the life quality and duration of the aged human population.

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“…Oliveira-Giacomelli et al (2019) tested the effects of P2Y6 and P2X7 in preventing or reversing PD behavior and dopaminergic levels in male Sprague Dawley rat models using 7 µg/µL of 6-OHDA dose injected unilaterally into the right midforebrain of two-month-old male Sprague Dawley rats. The motor changes confirmed after the 1st week of 6-OHDA lesion, behavioral analysis data showed no significant rotational behavior before 6-OHDA lesion, and significant behavioral changes were observed only after 1st, 3rd, and 5th week of 6-OHDA lesion where the number of rotations which increased in a time-dependent manner [ 94 ].…”

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective/ Neuroregenerative Effects in an Animal Model of Parkinson’s Disease

Cited by 44 publications

References 59 publications

The P2X7 Receptor: Central Hub of Brain Diseases

The P2X7 Receptor: Central Hub of Brain Diseases

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

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