Neuroprotective and regenerative roles of intranasal Wnt-3a administration after focal ischemic stroke in mice

Abstract

Wnt signaling is a conserved pathway involved in expansion of neural progenitors and lineage specification during development. However, the role of Wnt signaling in the post-stroke brain has not been well-elucidated. We hypothesized that Wnt-3a would play an important role for neurogenesis and brain repair. Adult male mice were subjected to a focal ischemic stroke targeting the sensorimotor cortex. Mice that received Wnt-3a (2 µg/kg/day, 1 h after stroke and once a day for the next 2 days, intranasal delivery) had reduced infarct volume compared to stroke controls. Wnt-3a intranasal treatment of seven days upregulated the expression of brain-derived growth factor (BDNF), increased the proliferation and migration of neuroblasts from the subventricular zone (SVZ), resulting in increased numbers of newly formed neurons and endothelial cells in the peri-infarct zone. Both the molecular and cellular effects of Wnt-3a were blocked by the Wnt specific inhibitors XAV-939 or Dkk-1. In functional assays, Wnt-3a treatment enhanced the local cerebral blood flow (LCBF) in the peri-infarct, as well as improved sensorimotor functions in a battery of behavioral tests. Together, our data demonstrates that the Wnt-3a signaling can act as a dual neuroprotective and regenerative factor for the treatment of ischemic stroke.

Identification of Novel LncRNA Biomarkers and Construction of LncRNA-Related Networks in Han Chinese Patients with Ischemic Stroke

“…In rat cerebral cortical neurons, the ANXA1-p53 interaction in the nucleus was enhanced following oxygen-glucose deprivation-reoxygenation (OGD/R) and induced cell death [40]. The Wnt signaling pathway is involved in the development of the blood-brain barrier, contributed to stimulating neurogenesis, consolidating the blood-brain structure, and recovering cognitive brain functions after central nervous system injury [41][42][43]. Chang indicated that the Gpr124-Wnt signaling axis is essential for protecting blood-brain barrier function and vascular integrity [44].…”

WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury

“…On the other hand, intranasal delivery of proteins is believed to bypass the BBB in animal models [24], and our results demonstrate that this method of WNT3A delivery can produce a promising outcome on regeneration of injured brain neurons. The clinical efficacy of systemic or intranasal administration of protein drugs to the brain of TBI patients remains to be tested [25,26]. Alternatively, small-molecule activators of WNT3A, such as 6-bromoindirubin-3 -oxime (BIO), may be readily permeable to the BBB and could be considered for clinical use.…”

Rosiglitazone ameliorates tissue plasminogen activator‐induced brain hemorrhage after stroke

“…All animal experiments were approved by the Renji Hospital Institutional Animal Care and Use Committee and performed in accordance with the Institutional Guide for the Care and Use of Laboratory Animals. Focal cerebral ischemia was produced by intraluminal occlusion of the left middle cerebral artery (MCA) with a nylon monofilament suture as originally described with slight modifications . Male 2‐ to 3‐month‐old C57/B6 mice (25‐30 g each) were anesthetized with 1.5% isoflurane in a 30% O2/68.5% N2O mixture under spontaneous breathing.…”

“…Focal cerebral ischemia was produced by intraluminal occlusion of the left middle cerebral artery (MCA) with a nylon monofilament suture as originally described with slight modifications. 4,20,21 Male 2-to 3-month-old C57/B6 mice (25-30 g each) were anesthetized with 1.5% isoflurane in a 30% O2/68.5% N2O mixture under spontaneous breathing. Rectal temperature was controlled at 37°C during and after surgery via a temperature-regulated heating pad.…”