This study provides a proof-of-concept that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS. Further investigation of this therapeutic approach is warranted as some patients were excluded after randomization.

Remote ischaemic conditioning (RIC) triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuroprotection. RIC involves repetitive inflation and deflation of a blood pressure cuff on the limb, and is safe and feasible. The exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system seem to have critical roles. Early-phase clinical trials have already been conducted to test RIC in the prehospital setting in acute ischaemic stroke, and in subarachnoid haemorrhage for the prevention of delayed cerebral ischaemia. Furthermore, two small randomized clinical trials in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuroprotective activity. RIC represents a highly practical and translatable therapy for acute, subacute, and chronic neurological diseases with an ischaemic or inflammatory basis. In this Review, we consider the principles and mechanisms of RIC, evidence from preclinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury.

Symptomatic intracranial arterial stenosis (SIAS) is very common in octo-and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo-and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo-and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n=30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n=28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p<0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p<0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo-and nonagenarians with SIAS. A multicenter trial is ongoing.Clinical Trial Registration: www.clinicaltrials.gov, unique identifier: NCT01570231.

Nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) is an enzyme complex with the sole function of producing superoxide anion and reactive oxygen species (ROS) at the expense of NADPH. Vital to the immune system as well as cellular signaling, NOX is also involved in the pathologies of a wide variety of disease states. Particularly, it is an integral player in many neurological diseases, including stroke, TBI, and neurodegenerative diseases. Pathologically, NOX produces an excessive amount of ROS that exceed the body’s antioxidant ability to neutralize them, leading to oxidative stress and aberrant signaling. This prevalence makes it an attractive therapeutic target and as such, NOX inhibitors have been studied and developed to counter NOX’s deleterious effects. However, recent studies of NOX have created a better understanding of the NOX complex. Comprised of independent cytosolic subunits, p47-phox, p67-phox, p40-phox and Rac, and membrane subunits, gp91-phox and p22-phox, the NOX complex requires a unique activation process through subunit interaction. Of these subunits, p47-phox plays the most important role in activation, binding and translocating the cytosolic subunits to the membrane and anchoring to p22-phox to organize the complex for NOX activation and function. Moreover, these interactions, particularly that between p47-phox and p22-phox, are dependent on phosphorylation initiated by upstream processes involving protein kinase C (PKC). This review will look at these interactions between subunits and with PKC. It will focus on the interaction involving p47-phox with p22-phox, key in bringing the cytosolic subunits to the membrane. Furthermore, the implication of these interactions as a target for NOX inhibitors such as apocynin will be discussed as a potential avenue for further investigation, in order to develop more specific NOX inhibitors based on the inhibition of NOX assembly and activation.

The effect that exercise has on angiogenesis in the aging rat is unknown. We initiated this study with the intent to determine if exercise could induce angiogenesis in aging rats, as well as in adult rats reported previously. The markers we used to determine our endpoint were vascular endothelial growth factor (VEGF) and angiopoietin 1 and 2, as well as vascular density. Aged (22 month old) female Fisher 344 rats (n=16) were exercised on a treadmill 30 minutes each day for 3 weeks, or housed as non-exercised controls for the same duration. At the end of the exercise protocol, a significant (p<0.01) increase in the density of microvessels was found within the cerebral vasculature of the rats. Exercise was also associated with a significantly (p<0.01) increased mRNA expression of angiopoietin 1 and 2 in the aged cohort of rats. A mild but significant (p<0.01) increase in the four isoforms of VEGF mRNA (120, 144, 164, 188) were observed, with VEGF120 and VEGF144 being more markedly up-regulated than the other two. VEGF protein expression was also significantly (p<0.01) increased. This study demonstrates that angiogenesis can be induced in aging rats via exercise. The induced angiogenesis was associated with overexpression of angiogenic factors. These results support the hypothesis that an angiogenic response to chronic physical exercise is maintained with aging.

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The data support the notion that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular pathway cascade involving AQP-4 and MMP-9. Pharmacological blockade of this pathway in patients with TBI may provide a novel therapeutic strategy.

Previous treadmill exercise studies showing neuroprotective eVects have raised questions as to whether exercise or the stress related to it may be key etiologic factors. In this study, we examined diVerent exercise regimens (forced and voluntary exercise) and compared them with the eVect of stress-only on stroke protection. Adult male Sprague-Dawley rats (n = 65) were randomly assigned to treatment groups for 3 weeks. These groups included control, treadmill exercise, voluntary running wheel exercise, restraint, and electric shock. Levels of the stress hormone, corticosterone, were measured in the diVerent groups using ELISA. Animals from each group were then subjected to stroke induced by a 2-h middle cerebral artery (MCA) occlusion followed by 48-h reperfusion. Infarct volume was determined in each group, while changes in gene expression of stress-induced heat shock proteins (Hsp) 27 and 70 were compared using real-time PCR between voluntary and treadmill exercise groups. The level of corticosterone was signiWcantly higher in both stress (P < 0.05) and treadmill exercise (P < 0.05) groups, but not in the voluntary exercise group. Infarct volume was signiWcantly reduced (P < 0.01) following stroke in rats exercised on a treadmill. However, the amelioration of damage was not duplicated in voluntary exercise, even though running distance in the voluntary exercise group was signiWcantly (P < 0.01) longer than that of the forced exercise group (4,828 vs. 900 m). Furthermore, rats in the electric shock group displayed a signiWcantly increased (P < 0.01) infarct volume. Expression of both Hsp 27 and Hsp 70 mRNA was signiWcantly increased (P < 0.01) in the treadmill exercise group as compared with that in the voluntary exercise group. These results suggest that exercise with a stressful component, rather than either voluntary exercise or stress alone, is better able to reduce infarct volume. This exercise-induced neuroprotection may be attributable to up-regulation of stress-induced heat shock proteins 27 and 70.