Therapeutic effects of D4F, an ApoA-I mimetic peptide, in aged mice subjected to ischemic stroke

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Background: D-4F, an ApoA-I mimetic peptide, improves the functional properties of high density lipoprotein cholesterol and has anti-inflammation effects. Ischemic stroke is a primary cause of mortality and disability in the aged population. In this study, we investigated the therapeutic effects and mechanisms underlying the beneficial effects of D4F in aged mice subjected to ischemic stroke. Methods: A total of 24 aged (~24 months) C57BL/6J male mice were subjected to photochemical distal middle cerebral artery occlusion (dMCAo). Treatment was initiated at 24 hours after dMCAo with: 1) PBS; 2) D4F (16mg/kg/day, intraperitoneal injection) daily for 4 weeks until sacrifice at 28 days post stroke (n=12/group). Immunostaining, Luxol fast blue staining, PCR and Western blot measurements were performed. One-way Analysis of Variance was employed for statistical analysis. Results: Compared to PBS-control stroke mice, D4F treatment in aged stroke mice significantly (p<0.05): 1) reduced the mortality post dMCAo (50% vs 12.5%) and decreased ischemic lesion volume ratio (13% vs 9%); 2) improved the neurological functional outcome identified by the mNSS (Modified Neurological Severity Score) and foot-fault test as well as improved cognitive functions evaluated by Novel object cognitive test, Odor test and Three-chamber sociability test; 3) decreased white matter/axonal damage tested by Luxol fast blue and Bielschowsky silver staining; 4) increased oligodendrogenesis and synaptic plasticity measured by NG2 and NF200 expression in the ischemic brain; 5) increased vascular density in the ischemic border of ischemic brain measured by von Willebrand staining; 6) decreased glial scar formation identified by reducing GFAP positive cells as well as decreased IBA-1 expression in the IBZ; 7) as well as decreased inflammatory factor TLR4 and thrombin, but increased IL-10 gene expression in the ischemic brain. Conclusions: D4F treatment decreases ischemic lesion, glial scar formation and neuroinflammation, and promotes WM/axonal and neurovascular remodeling as well as improves neurological and cognitive function in aged ischemic stroke mice. D4F not only induces neuroprotective effect, but also promotes neurorestorative effects in aged ischemic stroke mice.




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