Increased P2X7 Receptor Binding Is Associated With Neuroinflammation in Acute but Not Chronic Rodent Models for Parkinson’s Disease

Abstract

The purinergic P2X7 receptor is a key mediator in (neuro)inflammation, a process that is associated with neurodegeneration and excitotoxicity in Parkinson’s disease (PD). Recently, P2X7 imaging has become possible with [ 11 C]JNJ-(54173)717. We investigated P2X7 availability, in comparison with availability of the translocator protein (TSPO), in two well-characterized rat models of PD using in vitro autoradiography at multiple time points throughout the disease progression. Rats received either a unilateral injection with 6-hydroxydopamine (6-OHDA) in the striatum, or with recombinant adeno-associated viral vector overexpressing human A53T alpha-synuclein (α-SYN) in the substantia nigra. Transverse cryosections were incubated with [ 11 C]JNJ-717 for P2X7 or [ 18 F]DPA-714 for TSPO. [ 11 C]JNJ-717 binding ratios were transiently elevated in the striatum of 6-OHDA rats at day 14–28 post-injection, with peak P2X7 binding at day 14. This largely coincided with the time course of striatal [ 18 F]DPA-714 binding which was elevated at day 7–21, with peak TSPO binding at day 7. Increased P2X7 availability co-localized with microglial, but not astrocyte or neuronal markers. In the chronic α-SYN model, no significant differences were found in P2X7 binding, although in vitro TSPO overexpression was reported previously. This first study showed an increased P2X7 availability in the acute PD model in a time window corresponding with elevated TSPO binding and motor behavior changes. In contrast, the dynamics of TSPO and P2X7 were divergent in the chronic α-SYN model where no P2X7 changes were detectable. Overall, extended P2X7 phenotyping is warranted prior to implementation of P2X7 imaging for monitoring of neuroinflammation.

ATP Signaling Controlling Dyskinesia Through P2X7 Receptors

“…BBG prevented all these LID-associated dopaminergic alterations, which might eventually result from direct effects of P2X7R located in dopamine cells (Heine et al, 2007 ) and striatal dopamine terminals (Carmo et al, 2014 ). However, although the presence of P2X7R mRNA and protein in the striatum and substantia nigra is established (Amadio et al, 2007 ; Kaczmarek-Hajek et al, 2018 ; Crabbé et al, 2019 ; Gentile et al, 2019 ) and there is evidence for an increased P2X7R density in the striatum upon decreasing dopaminergic innervation (Ferrazoli et al, 2017 ; Crabbé et al, 2019 ), the cellular localization of P2X7R is essentially unknown, and there is no data currently available to ascribe the presence of P2X7R to different neuronal populations (e.g., D1R or D2R) in nigrostriatal pathways.…”

P2X7 Receptors Amplify CNS Damage in Neurodegenerative Diseases

“…Similarly, BBG also antagonized the hemiparkinsonian rotation behavior. In vitro autoradiography with [ 11 C]JNJ-717 to label P2X7Rs and [ 18 F]DPA-714 to label the microglial marker translocator protein demonstrated in rats receiving unilaterally 6-OH-DA, at day 14 post-injection a maximum P2X7R binding, in good temporal correlation with the maximum binding affinity of the microglial marker [ 185 ].…”

Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

“…PET ligand has also been used to measure the regional distribution of activated microglia in PD patients, showing neuroinflammation within the substantia nigra of the most affected hemisphere [66]. In addition, the P2X7 (P2X purinoceptor 7 receptor) PET ligand revealed microglial P2X7 availability in acute but not chronic rodent models of PD [67]. Taken together, all these findings demonstrate the key role of activated microglia in the regions critically involved in PD, which takes place early in PD development.…”