The Wnt/Frizzled signaling pathway participates in many
inflammation-linked diseases. However, the inflammatory response mediated by the Wnt/Frizzled signaling pathway in experimental
subarachnoid hemorrhage has not been thoroughly investigated. Consequently, in this study, we examined the potential role of the Wnt/Frizzled signaling pathway in early
brain injury in rat models of
subarachnoid hemorrhage. Simultaneously, possible neuroprotective mechanisms were also investigated. Experimental
subarachnoid hemorrhage rat models were induced by injecting autologous blood into the prechiasmatic cistern. Experiment 1 was designed to examine expression of the Wnt/Frizzled signaling pathway in early
brain injury induced by
subarachnoid hemorrhage. In total, 42 adult rats were divided into
sham (injection of equivalent volume of saline), 6-, 12-, 24-, 48-, 72-hour, and 1-week
subarachnoid hemorrhage groups. Experiment 2 was designed to examine neuroprotective mechanisms of the Wnt/Frizzled signaling pathway in early
brain injury induced by
subarachnoid hemorrhage. Rats were treated with recombinant human Wnt1 (rhwnt1), small interfering Wnt1 (siwnt1)
RNA, and
monoclonal antibody of Frizzled1 (anti-Frizzled1) at 48 hours after
subarachnoid hemorrhage. Expression levels of Wnt1, Frizzled1, β-
catenin,
peroxisome proliferator-activated receptor-γ, CD36, and active nuclear factor-κB were examined by western blot assay and immunofluorescence staining. Microglia type conversion and inflammatory
cytokine levels in brain tissue were examined by immunofluorescence staining and
enzyme-linked
immunosorbent assay. Our results show that compared with the
sham group, expression levels of Wnt1, Frizzled1, and β-
catenin were low and reduced to a minimum at 48 hours, gradually returning to baseline at 1 week after
subarachnoid hemorrhage. rhwnt1 treatment markedly increased Wnt1 expression and alleviated
subarachnoid hemorrhage-induced early
brain injury (within 72 hours), including cortical cell apoptosis,
brain edema, and neurobehavioral deficits, accompanied by increasing
protein levels of β-
catenin, CD36, and
peroxisome proliferator-activated receptor-γ and decreasing
protein levels of nuclear factor-κB. Of note, rhwnt1 promoted M2-type microglia conversion and inhibited release of inflammatory
cytokines (
interleukin-1β,
interleukin-6, and
tumor necrosis factor-α). In contrast, siwnt1
RNA and anti-Frizzled1 treatment both resulted in an opposite effect. In conclusion, the Wnt/Frizzled1 signaling pathway may participate in
subarachnoid hemorrhage-induced early
brain injury via inhibiting the inflammatory response, including regulating microglia type conversion and decreasing inflammatory
cytokine release. The study was approved by the Animal Ethics Committee of Anhui Medical University and First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (approval No. LLSC-20180202) in May 2017.