Abstract
Aims Stroke is a leading cause of morbidity and mortality. This study aimed to determine whether nicotinamide administration could improve remyelination after stroke and reveal the underlying mechanism. Methods Adult male C57BL/6J mice were intraperitoneally (i.p.) administered with nicotinamide (200 mg/kg, daily) or saline after stroke induced by photothrombotic occlusion of the middle cerebral artery. FK866 (3 mg/kg, daily, bis in die), an inhibitor of NAMPT, and ANA-12 (0.5 mg/kg, daily), an antagonist of tropomyosin-related kinase B (TrkB), were administered intraperitoneally 1 h before nicotinamide administration. Functional recovery, MRI, and histological assessment were performed after stroke at different time points. Results The nicotinamide-treated mice showed significantly lower infarct area 7 d after stroke induction and significantly higher fractional anisotropy (FA) in the ipsilesional internal capsule (IC) 14 d after stroke induction than the other groups. Higher levels of NAD+, BDNF, and remyelination markers were observed in the nicotinamide-treated group. FK866 administration reduced NAD+ and BDNF levels in the nicotinamide-treated group. ANA-12 administration impaired the recovery from stroke with no effect on NAD+ and BDNF levels. Furthermore, lesser functional deficits were observed in the nicotinamide-treated group than in the control group. Conclusions Nicotinamide administration improves remyelination after stroke via the NAD+/BDNF/TrkB pathway.
Highlights
Ischemic stroke is a leading cause of mortality and morbidity [1]
NAM Administration Led to Reduced Infarct Size, Increased Fractional Anisotropy Value, and Fiber Counts after Stroke
These results suggested a better recovery of myelination with NAM administration after stroke
Summary
Ischemic stroke is a leading cause of mortality and morbidity [1]. To date, recombinant tissue plasminogen activator (rtPA) is the only approved drug for the treatment of acute ischemic stroke with a 4.5 h window for therapeutic intervention after ischemic stroke onset [2,3,4,5,6]. Very few patients with acute ischemic stroke receive this therapy. As many as half of the patients with ischemic stroke receiving rtPA treatment survive and suffer longterm disability. The white matter, constituted of axons and glial cells including oligodendrocytes, astrocytes, and microglia, is vulnerable to ischemic insults and can be considerably damaged by brief focal ischemic episodes. White matter injury is the major cause of functional disability after ischemic stroke [9,10,11]. Myelin sheath has a vital role for cell interaction involving information exchange between oligodendrocytes and axons; it provides nutrition support for neurons and is important for the motor, sensory, and cognitive functions of the nervous system [13, 14]. We believe that it is important to develop an effective therapy to promote
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