P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions, the extensive release of ATP induces sustained P2X7 receptor activation, culminating in induction of proinflammatory pathways with inflammasome assembly and cytokine release. These inflammatory conditions, whether occurring peripherally or in the central nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS, resulting in brain parenchyma infiltration. For instance, despite common effects on cytokine release, P2X7 receptor signaling is also associated with metalloproteinase secretion and activation, as well as migration and differentiation of T lymphocytes, monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate the pathogenesis of Multiple Sclerosis and Parkinson’s and Alzheimer’s disease, mainly through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7 receptor activation contributes to neurodegenerative disease progression beyond its known effects on the CNS. This review discusses how P2X7 receptor activation mediates responses of peripheral immune cells within the inflamed CNS, as occurring in the aforementioned diseases.

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Hydrogels of poly(vinyl alcohol) (PVA)/sodium alginate (SA), and magnetic nanoparticles (MNPs) were prepared by solvent casting in the absence and in the presence of magnets, in order to obtain MNPs...

Aim: Excitotoxicity results from unusually increased activation of excitatory amino acid receptors leading to neuronal death. Since glutamate is the main excitatory neurotransmitter in the central nervous system, it is also the most common excitotoxicity trigger. This uncontrolled neuronal response participates in various neurodegenerative diseases, such as ischemia, hypoglycemia, Huntington’s, Parkinson’s and Alzheimer’s disease. Thus, the investigation in the field expanded a lot in the past decade, leading to in vitro modelling adaptations. However, much performed work on glutamate-induced excitotoxicity is methodologically inconsistent in the literature. The field lacks reproducibility, which is one of the main fundaments of empirical science. In this regard, the literature was summarized and the main methodological features were critically evaluated, aiming to guide the researchers that are starting in the field. Methods: Published data since 1985 from PUBMED were collected and analyzed to observe which in vitro experimental conditions of excitotoxicity were reproducible. The suggested methods were based on the characteristics of excitotoxicity, such as abnormal intracellular calcium mediated signaling, mitochondria impairment, reactive oxygen species accumulation and cell death. Various conditions and comparative controls were used to design the standard investigation of excitotoxicity, such as culture medium content (presence of glutamate and aspartate), time interval of induction and the concentration of the inductor, based on the most reproducible published ones. Results: Our results and critical analysis point to some experimental conditions to consider, such as primary cultured neurons are more sensitive to glutamate and the response obtained is more robust than in other models; excitotoxicity mediated effects are better observed one hour following the stimulus; the culture medium should contain low levels of glutamate or aspartate or glycine. Online available phosphoproteomic data on excitotoxicity using the primary cortical neurons in vitro model supported the same conditions proposed by us. Conclusions: This manuscript will facilitate the design of any research for excitotoxic or neuroprotective compounds in physiological and pathophysiological conditions by standardizing and improving experimental conditions.

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