title: Tozasertib attenuates neuronal apoptosis via DLK/JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats.
abstract: Since tozasertib is neuroprotective for injured optic nerve, this study is intended to test whether tozasertib reduces early brain injury after subarachnoid hemorrhage (SAH) in a rat model.
  
  
  
  Two hundred sixteen (216) male Sprague-Dawley rats were randomly subjected to endovascular perforation model of SAH and sham group. SAH grade, neurological score, and brain water content were measured at 24 and 72 h after SAH. Dual leucine zipper kinase (DLK) and its downstream factors, JNK-interacting protein 3 (JIP3), MA2K7, p-JNK/JNK (c-Jun N-terminal kinase), and apoptosis related proteins cleaved caspase-3 (CC-3), Bim, Bcl-2, and cleaved caspase-9 (CC-9) were analyzed by western blot at 24 h after SAH. Apoptotic cells were detected by terminal deoxynucleotid transferase-deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). DLK small interfering RNA (siRNA), JIP3 siRNA and MA2K7 siRNA, the JNK, p38MAPK, and MEK inhibitors SP600125, SB203580, and PD98059 were used for intervention.
  
  
  
  Tozasertib reduced neuronal apoptosis, attenuated brain edema and improved neurobehavioral deficits 24 and 72 h after SAH. At 24 h After SAH, DLK/JIP3/MA2K7/p-JNK/CC-3 expressions were elevated markedly and tozasertib reduced DLK, MA2K7/p-JNK/CC-3 expressions but enhanced JIP3 expression. In the presence of tozasertib, DLK/JIP3/MA2K7 siRNA and SP600125, SB203580 and PD98059 deteriorated the neurobehavioral deficits, brain edema and increased the expression of CC-3. SAH potentiated the expression of Bim, CC-9, and CC-3 but reduced Bcl-2, while tozasertib reduced expression of Bim, CC-9, and CC-3 but enhanced Bcl-2.
  
  
  
  Tozasertib reduced neuronal apoptosis and improved outcome possibly via DLK/JIP3/MA2K7/JNK pathways after SAH.
authors.affiliation: Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurosurgery, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yin
authors.affiliation: Department of Neurosurgery, Hospital of the University of Electronic Science and Technology of China, Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Xiao-Chuan
authors.initials: XC
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zongduo
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Departments of Anesthesiology and Physiology, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010879:Piperazines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000201:enzymology / Q000517:prevention & control; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020930:MAP Kinase Kinase Kinases; D009419:Nerve Tissue Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C554781:mapk8ip3 protein, rat; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C090757:mitogen-activated protein kinase kinase kinase 12
keywords: Apoptosis; DLK; Early brain injury; Subarachnoid hemorrhage; Tozasertib