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A mechanistic model of calcium homeostasis leading to occurrence and propagation of secondary brain injury.

Jiang-Ling SongM Brandon WestoverRui Zhang
Published in: Journal of neurophysiology (2022)
Secondary brain injury (SBI) refers to new or worsening brain insult after primary brain injury (PBI). Neurophysiological experiments show that calcium (Ca 2+ ) is one of the major culprits that contribute to neuronal damage and death following PBI. However, mechanistic details about how alterations of Ca 2+ levels contribute to SBI are not well characterized. In this paper, we first build a biophysical model for SBI related to calcium homeostasis (SBI-CH) to study the mechanistic details of PBI-induced disruption of CH, and how these disruptions affect the occurrence of SBI. Then, we construct a coupled SBI-CH model by formulating synaptic interactions to investigate how disruption of CH affects synaptic function and further promotes the propagation of SBI between neurons. Our model shows how the opening of voltage-gated calcium channels (VGCCs), decreasing of plasma membrane calcium pump (PMCA), and reversal of the Na + /Ca 2+ exchanger (NCX) during and following PBI, could induce disruption of CH and further promote SBI. We also show that disruption of CH causes synaptic dysfunction, which further induces loss of excitatory-inhibitory balance in the system, and this might promote the propagation of SBI and cause neighboring tissue to be injured. Our findings offer a more comprehensive understanding of the complex interrelationship between CH and SBI. NEW & NOTEWORTHY We build a mechanistic model SBI-CH for calcium homeostasis (CH) to study how alterations of Ca 2+ levels following PBI affect the occurrence and propagation of SBI. Specifically, we investigate how the opening of VGCCs, decreasing of PMCA, and reversal of NCX disrupt CH, and further induce the occurrence of SBI. We also present a coupled SBI-CH model to show how disrupted CH causes synaptic dysfunction, and further promotes the propagation of SBI between neurons.
Keyphrases
  • brain injury
  • room temperature
  • subarachnoid hemorrhage
  • cerebral ischemia
  • risk assessment
  • spinal cord
  • white matter
  • resting state