Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats.
Traumatic brain injury (TBI) initiates a complex cascade of neurochemical and signaling changes that leads to neuronal apoptosis, which contributes to poor outcomes for patients with TBI. Previous study indicates that calcium-sensing receptor (CaSR) activation contributes to neuron death in focal cerebral ischemia-reperfusion mice, however, its role in neuronal apoptosis after TBI is not well-established. Using a controlled cortical impact model in rats, the present study was designed to determine the effect of CaSR inhibitor NPS2390 upon neuronal apoptosis after TBI. Rats were randomly distributed into three groups undergoing the sham surgery or TBI procedure, and NPS2390 (1.5 mg/kg) was infused subcutaneously at 30 min and 120 min after TBI. All rats were sacrificed at 24 h after TBI. Our data indicated that NPS2390 significantly reduced the brain edema and improved the neurological function after TBI. In addition, NPS2390 decreased caspase-3 levels and the number of apoptotic neurons. Furthermore, NPS2390 up-regulated anti-apoptotic protein Bcl-2 expression and down-regulated pro-apoptotic protein Bax, and reduced subsequent release of cytochrome c into the cytosol. In summary, this study indicated that inhibition of CaSR by NPS2390 attenuates neuronal apoptosis after TBI, in part, through modulating intrinsic apoptotic pathway.
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China.
Zhaoliang
Z
Xue
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China.
Zhengfei
Z
Song
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China.
Yingfeng
Y
Wan
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China.
Kun
K
Wang
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China.
Lianjie
L
Mo
Department of Neurosurgery, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University School of Medicine, China. Electronic address: s2012neurosurgery@163.com.
Yirong
Y
Wang
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D055104:Infusions, Subcutaneous; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C569355:2-quinoxaline-carboxamide-N-adamantan-1-yl; C494828:Bax protein, rat; C000617196:Bcl2 protein, rat; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D044169:Receptors, Calcium-Sensing; D051028:bcl-2-Associated X Protein; C473605:extracellular calcium cation-sensing receptor, rat; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D000218:Adamantane
Calcium-sensing receptor (CaSR); NPS2390; Neuronal apoptosis; Traumatic brain injury