Article
Role of acid sensing ion channel 1a in the development of posttraumatic brain damage and functional outcome after experimental traumatic brain injury
Rolle des acid-sensing ion channels 1a auf posttrauamtischen Hirnschaden und funktionelles Outcome nach experimentellem Schädel-Hirn-Trauma
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Authors
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Shiqi Cheng
- Klinikum der Ludwig-Maximilians-Universität München, Institut für Schlaganfall- und Demenzforschung, München, Deutschland; Klinikum der Ludwig-Maximilians-Universität München, München, Deutschland
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Maria Wostrack
- Technische Universität München, Neurochirurgie, München, Deutschland
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Florian Ringel
- Universitätsmedizin Mainz, Neurochirurgie, Mainz, Deutschland
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Nikolaus Plesnila
- Klinikum der Ludwig-Maximilians-Universität München, Institut für Schlaganfall- und Demenzforschung, München, Deutschland; Klinikum der Ludwig-Maximilians-Universität München, München, Deutschland
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Nicole Angela Terpolilli
- Klinikum der Ludwig-Maximilians-Universität München, Neurochirurgie, München, Deutschland; Klinikum der Ludwig-Maximilians-Universität München, Institut für Schlaganfall- und Demenzforschung, München, Deutschland; Klinikum der Ludwig-Maximilians-Universität München, München, Deutschland
| Published: | June 26, 2020 |
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Outline
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Objective: Traumatic brain injury (TBI) is a leading cause of death and disability among young adults and children and a major risk factor for neurodegenerative diseases and early-onset dementia. The mechanisms involved in the development of long-term consequences of TBI are not fully understood yet. Acid-sensing ion channel 1a is a voltage gated Na+- and Ca2+channel located on the postsynaptic membrane of neurons in both central and peripheral nervous system; in the CNS, it is involved in mediating – among other things – synaptic plasticity. It also seems to be implicated in the development of post-ischemic brain damage. The role of ASIC1a in traumatic brain injury, especially for long-term consequences of TBI, has not been evaluated yet. In the current study, we investigated the effect of ASIC1a on lesion progression and functional outcome up to six months after experimental traumatic brain injury in a transgenic mouse model.
Methods: Male ASIC1a transgenic miceand their wildtype littermates were subjected to TBI using the controlled cortical impact model.Brain water content was assessed by the wet weight-dry weight method 24 hours after TBI. Body weight and motor function were measured 3 days before surgery, then 1, 3, 7, 14, 60, 90 and 180 days after TBI. Behavioral tests assessing memory and depression like behavior were performed 60, 90, and 180 days after CCI. Lesion volume was longitudinally observed with serial MRI scans 14, 60, 90, and 180 days after TBI. At the end of the observation period (180 days after TBI), brains were harvested for histological evaluation.
Results: ASIC1a deficiency did not affect survival rate, body weight, or fine motor skills after CCI. Brain edema formation 24 hours after TBI was significantly lower in homozygous ASIC1a animals compared to wildtype controls. Furthermore, homozygous ASIC1a mice showed significantly reduced lesion volume from 60 to 180 days and reduced hippocampal damage at 180 days after TBI, in MR as well as in histological assessment at six months after TBI. This translated into improved cognitive function at 180 days (as measured by Barnes Maze testing) and reduced depression-like behavior 60 to 180 days after TBI.
Conclusion: ASIC1a deficiency reduced brain edema formation early after TBI, significantly reduced posttraumatic brain damage and improved neurological outcome in the chronic phase after experimental traumatic brain injury. ASIC1a may therefore be a promising therapeutic target after TBI.
