Calcium-sensing receptor antagonist NPS2390 attenuates neuronal apoptosis though intrinsic pathway following traumatic brain injury in rats

• Published in: Biochemical and biophysical research communications 2017-04, Vol.486 (2), p.589-594
• Main Authors: Xue, Zhaoliang, Song, Zhengfei, Wan, Yingfeng, Wang, Kun, Mo, Lianjie, Wang, Yirong
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Animals; Apoptosis - drug effects; bcl-2-Associated X Protein - antagonists & inhibitors; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain Edema - drug therapy; Brain Edema - genetics; Brain Edema - metabolism; Brain Edema - pathology; Brain Injuries, Traumatic - drug therapy; Brain Injuries, Traumatic - genetics; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - pathology; Calcium-sensing receptor (CaSR); Caspase 3 - genetics; Caspase 3 - metabolism; Cytochromes c - antagonists & inhibitors; Cytochromes c - secretion; Gene Expression Regulation; Infusions, Subcutaneous; Male; Neuronal apoptosis; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; NPS2390; Proto-Oncogene Proteins c-bcl-2 - agonists; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - antagonists & inhibitors; Receptors, Calcium-Sensing - genetics; Receptors, Calcium-Sensing - metabolism; Signal Transduction; Traumatic brain injury
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.03.097

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. •Potential roles of CaSR inhibitor NPS2390 were explored in experimental traumatic brain injury.•Inhibiting CaSR activation by NPS2390 significantly decreased brain edema and improved neurological deficits.•Inhibiting CaSR activation by NPS2390 significantly reduced the number of apoptotic neurons.•Inhibiting CaSR activation by NPS2390 regulated intrinsic apoptotic-associated protein expression.