Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms.

Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A_2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia. Indeed, A_2BRs participate in the early glutamate-mediated excitotoxicity responsible for neuronal and synaptic loss in the CA1 hippocampus. On the contrary, later after ischemia, the same receptors have a protective role in tissue damage and functional impairments, reducing inflammatory cell infiltration and neuroinflammation by central and/or peripheral mechanisms. Of note, demyelination following brain ischemia, or autoimmune neuroinflammatory reactions, are also profoundly affected by A_2BRs since they are expressed by oligodendroglia where their activation inhibits cell maturation and expression of myelin-related proteins. In conclusion, data in the literature indicate the A_2BRs as putative therapeutic targets for the still unmet treatment of stroke or demyelinating diseases.

Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation. Moreover, OPCs are crucial players in neuro-glial communication as they receive synaptic inputs from neurons and express ion channels and neurotransmitter/neuromodulator receptors that control their maturation. Ion channels are recognized as attractive therapeutic targets, and indeed ligand-gated and voltage-gated channels can both be found among the top five pharmaceutical target groups of FDA-approved agents. Their modulation ameliorates some of the symptoms of MS and improves the outcome of related animal models. However, the exact mechanism of action of ion-channel targeting compounds is often still unclear due to the wide expression of these channels on neurons, glia, and infiltrating immune cells. The present review summarizes recent findings in the field to get further insights into physio-pathophysiological processes and possible therapeutic mechanisms of drug actions.

Alzheimer’s disease (AD) is a neurodegenerative process responsible for almost 70% of all cases of dementia. The clinical signs consist in progressive and irreversible loss of memory, cognitive, and behavioral functions. The main histopathological hallmark is the accumulation of amyloid-ß (Aß) peptide fibrils in the brain. To date, the origin of Aß has not been determined. Recent studies have shown that the gut microbiota produces Aß, and dysbiotic states have been identified in AD patients and animal models of AD. Starting from the hypothesis that maintaining or restoring the microbiota’s eubiosis is essential to control Aß’s production and deposition in the brain, we used a mixture of probiotics and prebiotics (symbiotic) to treat APPPS1 male and female mice, an animal model of AD, from 2 to 8 months of age and evaluated their cognitive performances, mucus secretion, Aβ serum concentration, and microbiota composition. The results showed that the treatment was able to prevent the memory deficits, the reduced mucus secretion, the increased Aβ blood levels, and the imbalance in the gut microbiota found in APPPS1 mice. The present study demonstrates that the gut–brain axis plays a critical role in the genesis of cognitive impairment, and that modulation of the gut microbiota can ameliorate AD’s symptomatology.

BACKGROUND: Basic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, although clinical evidence remains conflicting. The TRICS BASIC study (Multicenter Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke) investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. METHODS: Multicenter, multispecies, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary end point was a good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary end points were infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Preenrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment, and intention-to-treat analysis were applied. RESULTS: The trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across 7 laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared with controls, at 48 hours postischemia (55% versus 36%; odds ratio, 2.2 [95% CI, 1.23–4.4]; P =0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference, −0.38 [95% CI, −0.70 to −0.05]; P =0.024). Health monitoring indicated no major safety concerns, and postoperative analgesia requirements were lower in RIC-treated mice. CONCLUSIONS: Surgically induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity. REGISTRATION: URL: https://www.preclinicaltrials.eu ; Unique identifier: PCTE0000177.