Abstract
Oxidative stress (OS) and neuronal apoptosis are major pathological processes after hypoxic-ischemic encephalopathy (HIE). Colony stimulating factor 1 (CSF1), binding to CSF1 receptor (CSF1R), has been shown to reduce neuronal loss after hypoxic-ischemia- (HI-) induced brain injury. In the present study, we hypothesized that CSF1 could alleviate OS-induced neuronal degeneration and apoptosis through the CSF1R/PLCG2/PKA/UCP2 signaling pathway in a rat model of HI. A total of 127 ten-day old Sprague Dawley rat pups were used. HI was induced by right common carotid artery ligation with subsequent exposure to hypoxia for 2.5 h. Exogenous recombinant human CSF1 (rh-CSF1) was administered intranasally at 1 h and 24 h after HI. The CSF1R inhibitor, BLZ945, or phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, was injected intraperitoneally at 1 h before HI induction. Brain infarct volume measurement, cliff avoidance test, righting reflex test, double immunofluorescence staining, western blot assessment, 8-OHdG and MitoSOX staining, Fluoro-Jade C staining, and TUNEL staining were used. Our results indicated that the expressions of endogenous CSF1, CSF1R, p-CSF1R, p-PLCG2, p-PKA, and uncoupling protein2 (UCP2) were increased after HI. CSF1 and CSF1R were expressed in neurons and astrocytes. Rh-CSF1 treatment significantly attenuated neurological deficits, infarct volume, OS, neuronal apoptosis, and degeneration at 48 h after HI. Moreover, activation of CSF1R by rh-CSF1 significantly increased the brain tissue expressions of p-PLCG2, p-PKA, UCP2, and Bcl2/Bax ratio, but reduced the expression of cleaved caspase-3. The neuroprotective effects of rh-CSF1 were abolished by BLZ945 or U73122. These results suggested that rh-CSF1 treatment attenuated OS-induced neuronal degeneration and apoptosis after HI, at least in part, through the CSF1R/PLCG2/PKA/UCP2 signaling pathway. Rh-CSF1 may serve as therapeutic strategy against brain damage in patients with HIE.
Highlights
Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating disease with high morbidity and mortality
The results showed that p-CSF1 receptor (CSF1R), CSF1R, Colony stimulating factor 1 (CSF1), p-phospholipase C-gamma 2 (PLCG2), p-protein kinase A (PKA), and uncoupling protein2 (UCP2) were increased in a time-dependent manner after HI peaked at 24 h (P < 0:05) when compared with the sham group (Figure 2)
Our results showed that CSF1R and CSF1 were expressed on neurons in rat pups from all groups at 48 h after HI (Figure 3(a))
Summary
Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating disease with high morbidity and mortality. It is the primary cause of poor outcomes in infants and leads to lifelong neurodevelopmental disorders, such as cerebral palsy, cognitive deficits, visual dysfunction, hearing impairments, and epilepsy [1,2,3]. The overproduction of ROS directly damaged neurons and resulted in neuronal apoptosis and indirectly caused neuronal degeneration by regulating mitochondrial pathways, DNA repair enzymes, and transcription factors [10]. Among many factors involved in the pathogenesis of neonatal HIE [11], OS plays a crucial role in the neuronal degeneration and apoptosis [12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
