For decades, numerous pharmacological and non-pharmacological strategies have been evaluated without success to limit the consequences of the ischemic cascade, but more rarely the therapies were explored as add on remedies on individuals also receiving reperfusion therapies. It is plausible that these putative neuroprotectants never reached the ischemic brain in adequate concentrations. Currently, the concept of neuroprotection incorporates cerebral perfusion as an obligatory substrate upon which ischemic brain survival depends, and it is plausible that some of the compounds tested in previous neuroprotection trials might have resulted in more favorable results if reperfusion therapies had been co-administered. Nonetheless, pharmacological or mechanical thrombectomy are frequently powerless to fully reperfuse the ischemic brain despite achieving a high rate of recanalization. This review covers in some detail the importance of the microcirculation, and the barriers that may hamper flow reperfusion at the microcirculatory level. It describes the main mechanisms leading to microcirculatory thrombosis including oxidative/nitrosative stress and refers to recent efforts to ameliorate brain perfusion in combination with the co-administration of neuroprotectants mainly aimed at harnessing oxidative/nitrosative brain damage.
Antioxidants ; Brain ; Microcirculation ; Neuroprotection ; Neuroprotective Agents* ; Oxidative Stress ; Perfusion ; Reperfusion* ; Stroke ; Thrombectomy ; Thrombosis

Patent foramen ovale (PFO) closure, along with medical therapy, has emerged as the therapeutic gold standard in younger (<60-year-old) patients with a PFO-related stroke for preventing recurrent events. However, PFO management guidelines lack definite recommendations for older (>60 years) patients with a PFO-related cerebrovascular event, a complex group of patients who were mostly excluded from PFO closure clinical trials. Nevertheless, several studies have shown a higher prevalence of PFO among older patients with cryptogenic stroke, and its presence has been associated with an increased risk of recurrent events. Furthermore, older patients exhibit a higher prevalence of high-risk PFO anatomical features, present inherent age-related risk factors that might increase the risk of paradoxical embolism through a PFO, and have a higher incidence of ischemic events after a PFO-related event. Additionally, observational studies have shown the safety and preliminary efficacy of PFO closure in older PFO-related stroke patients. Yet, higher rates of recurrent cerebrovascular events and new-onset atrial fibrillation were observed in some studies among older patients compared to their younger counterparts. After careful case-by-case evaluation, including the assessment of hidden potential cardioembolic sources of a cryptogenic stroke other than PFO, transcatheter PFO closure might be a safe and effective therapeutic option for preventing recurrent thromboembolic events in patients >60 years with a high-risk PFO-associated stroke. Ongoing trials will provide important insights into the role of PFO closure in the elderly population.