Adenosine 5′-triphosphate outflow increases after an ischemic insult in the brain and may induce the expression of P2X₇receptors in resting microglia, determining its modification into an activated state. To assess the effects of P2X₇receptor blockade in preventing microglia activation and ameliorating brain damage and neurological impairment, we delivered the P2 unselective antagonist Reactive Blue 2 to rats after middle cerebral artery occlusion. In sham-operated animals, devoid of brain damage, double immunofluorescence verified the absence of P2X₇immunoreactivity on resting microglia, astrocytes, and neurons, identified, respectively, by OX-42, glial fibrillary acid protein, and neuronal nuclei (NeuN) immunoreactivity. After ischemia, vehicle-treated rats showed monolateral sensorimotor deficit and tissue damage in striatum and frontoparietal cortex. Moreover, P2X₇immunoreactivity was de novo expressed on activated microglia in infarcted and surrounding areas, as well as on a reactive form of microglia, resting in shape but P2X₇immunoreactive, present in ipsi- and contralateral cingulate and medial frontal cortex. Reactive Blue 2 improved sensorimotor deficit and restricted the volume of infarction, without preventing the expression of P2X₇, but inducing it in the microglia of contralateral frontal and parietal cortex and striatum, which had lost reciprocal connections with the remote infarct area. De novo expression of P2X₇occurred in both activated and reactive microglia, suggesting their differentiated roles in the area of infarct and in remote regions. Reactive Blue 2 reduced ischemic brain damage, likely blocking the function of activated microglia in the infarct area, but in the remote brain regions promoted the expression of P2X₇on reactive microglia, developing defense and reparative processes.

Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.

Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy.

Background: The accumulation of α‐synuclein (α‐syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α‐syn–dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α‐syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α‐syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression.Objectives: We aimed to determine the consequences of a prolonged α‐syn overexpression on somatodendritic morphology and functions of SNpc DA neurons.Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch‐clamp recordings, and in vivo DA microdialysis measurements in a 12‐ to 13‐month‐old transgenic rat model overexpressing the full‐length human α‐syn (Snca^+/+) and age‐matched wild‐type rats.Results: Aged Snca^+/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/inactivating voltage‐gated K⁺ channels and Ca²⁺‐ and voltage‐activated large conductance K⁺ channels. These intrinsic currents underlie the repolarization/afterhyperpolarization phase of action potentials, thus affecting neuronal excitability.Conclusions: Besides clarifying α‐syn–induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.