Neuroreport · 2025
Protective effects of alectinib on germinal matrix hemorrhage-induced neonatal brain injury.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Yin Xuhui, Wang Yiheng, Zhang Xiaoli, Zhu Xixiao, Zhao Bing-Qiao
Аннотация
OBJECTIVE: This study aimed to investigate the role of alectinib in a neonatal mouse model of germinal matrix hemorrhage (GMH).
METHODS: We induced GMH in postpartum day 5 mouse pups by injecting collagenase into the germinal matrix. Alectinib was administered intraperitoneally after GMH induction. Western blot, immunofluorescence staining, and quantitative PCR were performed to explore the effects of alectinib on oxidative stress, microglial number, proinflammatory cytokines expression, blood-brain barrier (BBB) damage, and cortical neuron loss. Cresyl violet and Prussian blue staining were used to detect the ventricular size, cerebral cortical atrophy, and hemorrhage burden. Novel object recognition and rotarod tests were used to determine the neurological function.
RESULTS: We found that anaplastic lymphoma kinase (ALK) was upregulated in the perihematomal areas following GMH and was presented in endothelial cells. Treatment with alectinib resulted in a reduction in oxidative stress, as shown by decreasing generation of reactive oxygen species, lipid peroxidation, and oxidative DNA at 3 days after GMH. Alectinib also attenuated the number of microglia, levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, loss of BBB integrity ZO-1 and claudin-5, and disruption of BBB. These effects of alectinib were accompanied by reduced hemorrhage burden, cortical neuron loss and cerebral cortical atrophy, and improved motor coordination, cognitive and memory impairments at 23 days after GMH.
CONCLUSION: Our data revealed that alectinib reduced oxidative stress, microglia number, and BBB permeability, thereby alleviating secondary brain injury in GMH. Therapies that inhibit ALK signaling may confer neuroprotection against GHM.
METHODS: We induced GMH in postpartum day 5 mouse pups by injecting collagenase into the germinal matrix. Alectinib was administered intraperitoneally after GMH induction. Western blot, immunofluorescence staining, and quantitative PCR were performed to explore the effects of alectinib on oxidative stress, microglial number, proinflammatory cytokines expression, blood-brain barrier (BBB) damage, and cortical neuron loss. Cresyl violet and Prussian blue staining were used to detect the ventricular size, cerebral cortical atrophy, and hemorrhage burden. Novel object recognition and rotarod tests were used to determine the neurological function.
RESULTS: We found that anaplastic lymphoma kinase (ALK) was upregulated in the perihematomal areas following GMH and was presented in endothelial cells. Treatment with alectinib resulted in a reduction in oxidative stress, as shown by decreasing generation of reactive oxygen species, lipid peroxidation, and oxidative DNA at 3 days after GMH. Alectinib also attenuated the number of microglia, levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, loss of BBB integrity ZO-1 and claudin-5, and disruption of BBB. These effects of alectinib were accompanied by reduced hemorrhage burden, cortical neuron loss and cerebral cortical atrophy, and improved motor coordination, cognitive and memory impairments at 23 days after GMH.
CONCLUSION: Our data revealed that alectinib reduced oxidative stress, microglia number, and BBB permeability, thereby alleviating secondary brain injury in GMH. Therapies that inhibit ALK signaling may confer neuroprotection against GHM.