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Microglia are immune brain cells involved in neuroinflammation. They express a lot of proteins on their surface such as receptors that can be activated by mediators released in the microglial environment. Among these receptors, purinergic receptor expression could be modified depending on the activation status of microglia. In this review, we focus on P2Y receptors and more specifically on P2RY12 that is involved in microglial motility and migration, the first step of neuroinflammation process. We describe the purinergic receptor families, P2RY12 structure, expression and physiological functions. The pharmacological and genetic tools for studying this receptor are detailed thereafter. Last but not least, we report the contribution of microglial P2RY12 to neuroinflammation in acute and chronic brain pathologies in order to better understand P2RY12 microglial role.

Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children and adolescents or in the elderly, and it is well known that immune responses and the neuroregenerative capacities of the brain, among other factors, vary over a lifetime. Thus, age-at-injury can influence the consequences of TBI. Furthermore, age-at-injury also influences the pharmacological effects of drugs. However, the post-TBI inflammatory, neuronal and functional consequences have been mostly studied in experimental young adult animal models. The specificity and the mechanisms underlying the consequences of TBI and pharmacological responses are poorly understood in extreme ages. In this review, we detail the variations of these age-dependent inflammatory responses and consequences after TBI, from an experimental point of view. We investigate the evolution of microglial, astrocyte and other immune cells responses, and the consequences in terms of neuronal death and functional deficits in neonates, juvenile, adolescent and aged male animals, following a single TBI. We also describe the pharmacological responses to anti-inflammatory or neuroprotective agents, highlighting the need for an age-specific approach to the development of therapies of TBI.

Traumatic brain injury (TBI) leads to a deleterious neuroinflammation, originating from microglial activation. Monitoring microglial activation is an indispensable step to develop therapeutic strategies for TBI. In this study, we evaluated the use of the 18-kDa translocator protein (TSPO) in positron emission tomography (PET) and cellular analysis to monitor microglial activation in a mild TBI mouse model. TBI was induced on male Swiss mice. PET imaging analysis with [ 18 F]FEPPA, a TSPO radiotracer, was performed at 1, 3 and 7 days post-TBI and flow cytometry analysis on brain at 1 and 3 days post-TBI. PET analysis showed no difference in TSPO expression between non-operated, sham-operated and TBI mice. Flow cytometry analysis demonstrated an increase in TSPO expression in ipsilateral brain 3 days post-TBI, especially in microglia, macrophages, lymphocytes and neutrophils. Moreover, microglia represent only 58.3% of TSPO + cells in the brain. Our results raise the question of the use of TSPO radiotracer to monitor microglial activation after TBI. More broadly, flow cytometry results point the lack of specificity of TSPO for microglia and imply that microglia contribute to the overall increase in TSPO in the brain after TBI, but is not its only contributor.

Background At the Faculty of Pharmacy of Paris, we conducted a pharmacology tournament in 2021 and 2022, named “Pharmacotrophy”, to offer a game-, team- and competitive-based learning innovation based on fun and challenge. This article aims to (1) provide a detailed overview of the organisation of “Pharmacotrophy,” (2) present and compare feedback from both students and teachers, and (3) assess the impact of student participation on their exam marks. Methods “Pharmacotrophy” took place in 2021 and 2022 over a two-week period at the beginning of the exam revision phase. It involved a combination of remote matches using the online quiz creation tool Kahoot!® and in-person matches. Teams, consisting of three students from the 4th or 5th year, participated in several selection rounds leading up to the final match. The questions covered various topics from the pharmacology curriculum. Using an anonymous online survey, we collected the feedback from students and teacher regarding the organisation of the tournament and the interest and difficulty of the different type of questions. We retrospectively compared the exam marks of 4th year students who took part in “Pharmacotrophy” (n 2021  = 19 and n 2022  = 20) with those of the rest of the 4th year (n 2021  = 315–320 and n 2022  = 279–281), both in the year before “Pharmacotrophy” and just after the tournament. Results Students highlighted the educational benefits of team-based and game-based learning. This novel approach positively and constructively motivated students to review pharmacology. Additionally, students appreciated the establishment of a trust-based relationship with their teachers. All students had a similar pharmacology level based on their exam results in the year before “Pharmacotrophy.” After the tournament, participants had marks 20.1% higher in pharmacology questions compared to non-participants ( p  = 0.02), while they had comparable overall levels, as evidenced by their final grade averages and marks in non-pharmacology questions. Moreover, participants who advanced further in the competition achieved higher marks in pharmacology questions compared to those who were eliminated early in the tournament. Conclusion The implementation of “Pharmacotrophy” provided students with an enjoyable way to review pharmacology coursework and revived the interest in pharmacology for some. Specifically, participating in “Pharmacotrophy” led to an increase in pharmacology marks for students who were not among the top performers in the class or did not excel in pharmacology in the previous year. This study quantified the pedagogical value of this innovative curriculum in terms of knowledge acquisition.

Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y(1) and P2Y(12). In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y(12) pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y(12) antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment.

Milk fat globule-EGF 8 (MFGE8) plays important, nonredundant roles in several biological processes, including apoptotic cell clearance, angiogenesis, and adaptive immunity. Several recent studies have reported a potential role for MFGE8 in regulation of the innate immune response; however, the precise mechanisms underlying this role are poorly understood. Here, we show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell-induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β(3) and P2X7 receptor interactions in primed cells. Itgb3 deficiency in macrophages abrogated the inhibitory effect of MFGE8 on ATP-induced IL-1β production. In a setting of postischemic cerebral injury in mice, MFGE8 deficiency was associated with enhanced IL-1β production and larger infarct size; the latter was abolished after treatment with IL-1 receptor antagonist. MFGE8 supplementation significantly dampened caspase-1 activation and IL-1β production and reduced infarct size in wild-type mice, but did not limit cerebral necrosis in Il1b-, Itgb3-, or P2rx7-deficient animals. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production.

This study investigated the expression of deiodinases of thyroid hormones in the rat brain after transient occlusion of the middle cerebral artery. The activity of type 2 deiodinase (D2), which catalyzes the deiodination of thyroxine into the more active thyroid hormone 3,5,3′-triiodothyronine, was strongly increased by cerebral ischemia at 6 and 24 hours in the striatum and at 24 hours in the cerebral cortex. The activity of type 3 deiodinase, which catalyzes the inactivation of thyroid hormones, was not affected by ischemia. In situ hybridization showed, as soon as 6 hours, an upregulation of the expression of D2 mRNA in the ipsilateral striatum, which disappeared at 24 hours. In the ipsilateral cortex, the induction of D2 mRNA started at 6 hours, was increased at 24 hours and finally declined at 72 hours. These results were confirmed by reverse transcription-PCR for D2 mRNA in the striatum and cerebral cortex. The upregulation of D2 mRNA after ischemia was mainly localized in astrocytic cell bodies. These results show that D2 is rapidly induced in astrocytes after ischemic stroke. Future work will include the exploration of the role of the upregulation of this enzyme, responsible for local 3,5,3′-triiodothyronine production as a neuroprotective mechanism in the brain.

Benefits from thrombolysis with recombinant tissue plasminogen activator (rt-PA) after ischemic stroke remain limited due to a narrow therapeutic window, low reperfusion rates, and increased risk of hemorrhagic transformations (HT). Experimental data showed that rt-PA enhances the post-ischemic activation of poly(ADP-ribose)polymerase (PARP) which in turn contributes to blood-brain barrier injury. The aim of the present study was to evaluate whether PJ34, a potent PARP inhibitor, improves poor reperfusion induced by delayed rt-PA administration, exerts vasculoprotective effects, and finally increases the therapeutic window of rt-PA. Stroke was induced by thrombin injection (0.75 UI in 1 μl) in the left middle cerebral artery (MCA) of male Swiss mice. Administration of rt-PA (0.9 mg kg−1) or saline was delayed for 4 h after ischemia onset. Saline or PJ34 (3 mg kg−1) was given intraperitoneally twice, just after thrombin injection and 3 h later, or once, 3 h after ischemia onset. Reperfusion was evaluated by laser Doppler, vascular inflammation by immunohistochemistry of vascular cell adhesion molecule-1 (VCAM-1) expression, and vasospasm by morphometric measurement of the MCA. Edema, cortical lesion, and sensorimotor deficit were evaluated. Treatment with PJ34 improved rt-PA-induced reperfusion and promoted vascular protection including reduction in vascular inflammation (decrease in VCAM-1 expression), HT, and MCA vasospasm. Additionally, the combined treatment significantly reduced brain edema, cortical lesion, and sensorimotor deficit. In conclusion, the combination of the PARP inhibitor PJ34 with rt-PA after cerebral ischemia may be of particular interest in order to improve thrombolysis with an extended therapeutic window.

Background Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. Methods and results ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y.sub.1 and P2Y.sub.12 . In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y.sub.12 pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. Conclusions We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y.sub.12 antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment.

Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y.sub.1 and P2Y.sub.12 . In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y.sub.12 pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y.sub.12 antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment.