Clinical neuroscienceApocynin improves outcome in experimental stroke with a narrow dose range
Section snippets
Experimental procedures
All reagents were obtained from Sigma-Aldrich (St. Louis, MO, USA), except where noted. Animals were obtained from Jackson Laboratories (Bar Harbor, ME, USA).
Apocynin penetrates the intact BBB
Texas Red–labeled apocynin administered to uninjured mice was readily detected 3 h later in the brain (Fig. 1A). In comparison, injection of Texas Red led to little detection of the fluorescent label (Fig. 1B). Thus, after systemic administration, apocynin is capable of crossing the BBB and entering the brain.
Apocynin reduces infarct size, but not at higher doses
Compared with vehicle-treated animals, apocynin 2.5 mg/kg significantly reduced infarct volume by about 40% (84.6±30.6 mm3 vs. 139.4±35.7 mm3, P<0.05). However, at higher doses, apocynin
Discussion
In this study, we show that apocynin at a dose of 2.5 mg/kg given just prior to reperfusion, or 1.5 h after ischemia onset, resulted in reduced infarct volume, BBB disruption and cerebral hemorrhage, and improved neurological outcome. We also found that in this model of stroke, O·− is largely generated by neurons and some microglia/monocytes, with no generation in brain vascular endothelial cells. Apocynin at protective doses markedly reduced O·− in the brain. Interestingly, apocynin at higher
Conclusions
In conclusion, our data showed that apocynin, a NOX inhibitor, reduces infarct volume, cerebral hemorrhage, and BBB disruption and improves neurological function following experimental stroke but with a narrow therapeutic window. We suggest that this is a relevant therapeutic target, but safer inhibitors should be developed.
Acknowledgments
This work was supported by NIH NINDS grant R01 NS40516 (M.A.Y.), P50 NS014543 (M.A.Y.), P01 NS37520 (M.A.Y.), and an American Heart Association Established Investigator Award (M.A.Y.).
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2021, NeuroscienceCitation Excerpt :In addition, activation of NOX and subsequent NOX-dependent ROS production could cause microglial proliferation and inflammatory reaction, which further exacerbates the injury (Brown, 2007). Inhibition of NOX could mitigate brain injury and improve neurological outcome in tMCAO animal model (Tang et al., 2008). Hence, NOX has been treated as an important therapeutic target in the management of ischemic stroke (Tang et al., 2008, 2012; Liu et al., 2015; Tian et al., 2016).