2. Academic Validation
  3. Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE

  • Oxid Med Cell Longev. 2020 Oct 7:2020:6801587. doi: 10.1155/2020/6801587.
Xiao Hu 1 2,  Shirong Li 1 2,  Desislava Met Doycheva 2,  Lei Huang 2 3,  Cameron Lenahan 2 4,  Rui Liu 1 2,  Juan Huang 2 5,  Ling Gao 2 6,  Jiping Tang 2,  Gang Zuo 2 7,  John H Zhang 2 3 8
Affiliations

Affiliations

  • 1 Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550002, China.
  • 2 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA.
  • 3 Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92350, USA.
  • 4 Burrell College of Osteopathic Medicine, Las Cruces, NM 88003, USA.
  • 5 Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China.
  • 6 Department of Neurosurgery, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou, Hainan 570208, China.
  • 7 Department of Neurosurgery, Taicang Hospital Affiliated to Soochow University, Taicang, Suzhou, Jiangsu 215400, China.
  • 8 Department of Anesthesiology, Loma Linda University, Loma Linda, CA 92350, USA.
PMID: 33101590 DOI: 10.1155/2020/6801587
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.

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