D-4F Treatment Improves Neurological Outcome And Attenuates Cardiac Deficits In Aged Mice Subject To Ischemic Stroke

Background and purpose: Ischemic stroke is a leading cause of mortality and disability globally,especially in the aging population.Emerging evidence indicates that there exists a brain-heart axis with cardiac dysfunction ensuing after injury to the brain even in the absence of primary cardiac disease.The aging population are likely more vulnerable to such post-stroke cardiac complications.D-4F is an apolipoprotein-A1 mimetic peptide that improves neurological recovery after stroke in young non-diabetic mice as well as in young rats with type 1 diabetes.In this study,we investigate the therapeutic effects of D-4F on the ischemic brain as well as on heart after stroke in aged mice.Methods: Aged(24 months),male,C57BL/6J mice were subjected to photothrombotic stroke model and randomized to receive one of the following treatments: 1)phosphate buffered saline(PBS,vehicle control)or 2)D-4F(16mg/Kg,i.p).Treatments were initiated at 24 hours after stroke and administered once daily till sacrifice.A battery of neurological and cognitive tests was conducted,and mice were sacrificed at 28 days after stroke for immunohistochemical evaluation of brain and heart.Inflammatory factor expression was evaluated in ischemic brain and heart tissue using PCR and western blot assay.Results: In aged mice subjected to stroke,compared to PBS treatment,D-4F treatment significantly decreases early mortality at 7 days and reduces lesion volume at 28 days after stroke.Compared to PBS treatment,D-4F treatment significantly improves poststroke neurological outcome evaluated by modified neurological severity score,adhesive removal test and foot-fault tests.D-4F treatment also improves cognitive outcome evaluated by novel object recognition test,novel odor recognition test and three chamber sociability test in aged mice subjected to stroke.D-4F treatment in aged mice subject to stroke significantly increases vascular density and tight junction protein expression,promotes white matter remodeling indicated by increased axon and myelin density,greater neurofilament NF200 expression and increased number of oligodendrocyte progenitor cells,and significantly decreases glial activation,M1 macrophage numbers and inflammatory factor expression such as toll like receptor 4(TLR4)as well as decreased amyloid-beta and thrombin expression in ischemic brain compared to PBS treatment stroke mice.D-4F treatment also significantly decreases cardiac interstitial fibrosis,oxidative stress,autophagy marker Beclin-1(delete??)and thrombin expression compared to PBS-treated mice.Conclusions: D-4F treatment promotes neurorestorative effects in the brain and improves neurological and cognitive outcome after stroke in aged mice.D-4F treatment also attenuates cardiac inflammation and pathological cardiac remodeling post-stroke in aged mice.