P2X7 Receptors as a Therapeutic Target in Cerebrovascular Diseases

Shortage of oxygen and nutrients in the brain induces the release of glutamate and ATP that can cause excitotoxicity and contribute to neuronal and glial damage. Our understanding of the mechanisms of ATP release and toxicity in cerebrovascular diseases is incomplete. This review aims at summarizing current knowledge about the participation of key elements in the ATP-mediated deleterious effects in these pathologies. This includes pannexin-1 hemichannels, calcium homeostasis modulator-1 (CALHM1), purinergic P2X7 receptors, and other intermediaries of CNS injury downstream of ATP release. Available data together with recent pharmacological developments in purinergic signaling may constitute a new opportunity to translate preclinical findings into more effective therapies in cerebrovascular diseases.This study was supported by grants from CONACYT-Mexico No. 252121 and PAPIITUNAM-Mexico No. IN203519 to ROA laboratory; by Spanish Ministry of Education and Science/FEDER (SAF2016-75292-R), Basque Government (IT1203/19), CIBERNED, Eranet-Neuron and Universidad del Pais Vasco to CM's laboratory. AC-M is a researcher from Catedras-CONACYT commissioned at Instituto de Neurobiologia at Universidad Nacional Autonoma de Mexico (UNAM)

N-butyl-β-carboline-3-carboxylate (β-CCB) systemic administration promotes remyelination in the cuprizone demyelinating model in mice

Abstract Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug