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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.

Cohort studies have demonstrated a higher vulnerability in males towards ischemic and/or hypoxic-ischemic injury in infants born near- or full-term. Male sex was also associated with limited brain repair following neonatal stroke and hypoxia-ischemia, leading to increased incidence of long-term cognitive deficits compared to females with similar brain injury. As a result, the design of pre-clinical experiments considering sex as an important variable was supported and investigated because neuroprotective strategies to reduce brain injury demonstrated sexual dimorphism. While the mechanisms underlining these differences between boys and girls remain unclear, several biological processes are recognized to play a key role in long-term neurodevelopmental outcomes: gonadal hormones across developmental stages, vulnerability to oxidative stress, modulation of cell death, and regulation of microglial activation. This review summarizes the current evidence for sex differences in neonatal hypoxic-ischemic and/or ischemic brain injury, considering the major pathways known to be involved in cognitive and behavioral deficits associated with damages of the developing brain.

We previously demonstrated that fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, reduced the neurological deficit, the edema and the cerebral lesion induced by traumatic brain injury (TBI). In order to elucidate these beneficial effects, in the present study, we investigated, in the same TBI model, fenofibrate's effects on the inflammation and oxidative stress. Male Sprague Dawley rats were randomized in four groups: non-operated, sham-operated, TBI + vehicle, TBI + fenofibrate. TBI was induced by lateral fluid percussion of the temporoparietal cortex. Rats were given fenofibrate (50 mg/kg) or its vehicle (water containing 0.2% methylcellulose), p.o. 1 and 6 h after brain injury. A neurological assessment was done 24 h after TBI, then rats were killed and the brain COX2, MMP9 expression, GSx, GSSG levels were determined. The same schedule of treatment was used to evaluate the effect of fenofibrate on immunohistochemistry of 3NT, 4HNE and iNOS at 24 h post-injury. Our results showed that fenofibrate promotes neurological recovery by exerting anti-inflammatory effect evidenced by a decrease in iNOS, COX2 and MMP9 expression. In addition, fenofibrate showed anti-oxidant effect demonstrated by a reduction of markers of oxidative stress: loss of glutathione, glutathione oxidation ratio, 3NT and 4HNE staining. Our data suggest that PPARα activation could mediate pleiotropic effects and strengthen that it could be a promising therapeutic strategy for TBI.

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.

Traumatic brain injury (TBI) results in white matter injury (WMI) that is associated with neurological deficits. Neuroinflammation originating from microglial activation may participate in WMI and associated disorders. To date, there is little information on the time courses of these events after mild TBI. Therefore we investigated (i) neuroinflammation, (ii) WMI and (iii) behavioral disorders between 6 hours and 3 months after mild TBI. For that purpose, we used experimental mild TBI in mice induced by a controlled cortical impact. (i) For neuroinflammation, IL-1b protein as well as microglial phenotypes, by gene expression for 12 microglial activation markers on isolated CD11b+ cells from brains, were studied after TBI. IL-1b protein was increased at 6 hours and 1 day. TBI induced a mixed population of microglial phenotypes with both pro-inflammatory, anti-inflammatory and immunomodulatory markers from 6 hours to 3 days post-injury. At 7 days, microglial activation was completely resolved. (ii) Three myelin proteins were assessed after TBI on ipsi- and contralateral corpus callosum, as this structure is enriched in white matter. TBI led to an increase in 2',3'-cyclic-nucleotide 3'-phosphodiesterase, a marker of immature and mature oligodendrocyte, at 2 days post-injury; a bilateral demyelination, evaluated by myelin basic protein, from 7 days to 3 months post-injury; and an increase in myelin oligodendrocyte glycoprotein at 6 hours and 3 days post-injury. Transmission electron microscopy study revealed various myelin sheath abnormalities within the corpus callosum at 3 months post-TBI. (iii) TBI led to sensorimotor deficits at 3 days post-TBI, and late cognitive flexibility disorder evidenced by the reversal learning task of the Barnes maze 3 months after injury. These data give an overall invaluable overview of time course of neuroinflammation that could be involved in demyelination and late cognitive disorder over a time-scale of 3 months in a model of mild TBI. This model could help to validate a pharmacological strategy to prevent post-traumatic WMI and behavioral disorders following mild TBI.

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.

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) is a chronic pathology, inducing long-term deficits that remain understudied in pre-clinical studies. In this context, exploration, anxiety-like behavior, cognitive flexibility, and motor coordination were assessed until 5 and 10 months after an experimental TBI in the adult mouse, using two cohorts. In order to differentiate age, surgery, and remote gray and white matter lesions, three groups (unoperated, sham-operated, and TBI) were studied. TBI induced delayed motor coordination deficits at the pole test, 4.5 months after injury, that could be explained by gray and white matter damages in ipsilateral nigrostriatal structures (striatum, internal capsule) that were spreading to new structures between cohorts, at 5 versus 10 months after the injury. Further, TBI induced an enhanced exploratory behavior during stressful situations (active phase during actimetry test, object exploration in an open field), risk-taking behaviors in the elevated plus maze 5 months after injury, and a cognitive inflexibility in the Barnes maze that persisted until 9 months after the injury. These behavioral modifications could be related to the white and gray matter lesions observed in ipsi- and contralateral limbic structures (amygdala, hilus/cornu ammonis 4, hypothalamus, external capsule, corpus callosum, and cingular cortex) that were spreading to new structures between cohorts, at 5 months versus 10 months after the injury. The present study corroborates clinical findings on TBI and provides a relevant rodent chronic model which could help in validating pharmacological strategies against the chronic consequences of TBI.

Background Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation. Methods Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed. Results Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- ( ptgs2 , CD32 and CD86 ) and M2-like ( CD206 , Arg-1 and Lgals3 ) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2 + microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals. Conclusions Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.

The poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 has been reported to improve endothelial dysfunction in the peripheral system. We addressed the role of PJ34 on the vascular tone and vasoreactivity during development in the mouse brain. Blood flows were measured in the basilar trunk using ultrasonography. Cerebral vasoreactivity or vasodilation reserve was estimated as a percentage increase in mean blood flow velocities (mBFV) recorded under normoxia-hypercapnia in control and after PJ34 administration. Non-selective and selective eNOS and nNOS inhibitors were used to evaluate the role of NO-pathway into the hemodynamic effects of PJ34. PJ34 increased mBFVs from 15.8 ± 1.6 to 19.1 ± 1.9 cm/s (p = 0.0043) in neonatal, from 14.6 ± 1.4 to 16.1 ± 0.9 cm/s (p = 0.0049) in adult, and from 15.7 ± 1.7 to 17.5 ± 2.0 cm/s (p = 0.0024) in aged mice 48 h after administration. These PJ34 values were similar to those measured in age-matched control mice under normoxia-hypercapnia. This recruitment was mediated through the activation of constitutive NO synthases in both the neonatal (38.2 ± 6.7 nmol/min/mg protein) and adult (31.5 ± 4.4 nmol/min/mg protein) brain, as compared to age-matched control brain (6.9 ± 0.4 and 6.3 ± 0.7 nmol/min/mg protein), respectively. In addition, quite selective eNOS inhibitor was able to inhibit the recruitment. PJ34 by itself is able to increase cerebral blood flow through the NO-pathway activation at least over 48 h after a single administration.