Article
Role of Cav2.1 P/Q Ca2+ channels in the development of posttraumatic brain damage
Search Medline for
Authors
-
Nicole A. Terpolilli
- Neurochirurgie, Klinikum der Universität München - Standort Grosshadern, München, Germany; Institut für Chirurgische Forschung, Klinikum der Universität München - Standort Grosshadern, München, Germany
-
Reinhard Dolp
- Neurochirurgie, Klinikum der Universität München - Standort Grosshadern, München, Germany; Institut für Chirurgische Forschung, Klinikum der Universität München - Standort Grosshadern, München, Germany
-
K. Waehner
- Neurochirurgische Klinik, Mannheim, Germany
-
Michel D. Ferrari
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
-
Arn M. J. M. van den Maagdenberg
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands; Neurochirurgische Klinik, Mannheim, Germany
-
Nikolaus Plesnila
- Institut für Schlaganfall- und Demenzforschung, Klinikum der Universität München - Standort Grosshadern, München, Germany
| Published: | June 8, 2016 |
|---|
Outline
Text
Objective: Traumatic brain injury (TBI) accounts for numerous deaths in industrialized countries. It remains unclear why some patients fare worse than others. So far, only a few risk factors are known that adversely influence outcome. Patients suffering from Familial Hemiplegic Migraine were reported to develop severe brain edema and coma after minor TBI. A number of those affected have missense-mutations in the CACNA1A gene encoding the neuronal voltage-gated Cav2.1-(P/Q-type)-Ca2+-channel which causes a gain of function. The aim of this study was to evaluate the effect of two CACNA1a-mutations (severe phenotype: S218L, mild phenotype: R192Q) on posttraumatic brain damage. We also investigated the role of the Cav2.1-channel in non-transgenic animals after TBI in order to evaluate whether the channels play a role in the pathogenesis of secondary brain damage in genetically healthy subjects.
Method: CACNA1a transgenic mice (S218L homozygous/heterozygous/wt mice, R192Q homozygous/wt mice) were subjected to mild controlled cortical impact trauma (CCI). Acute and chronic posttraumatic changes were observed with special focus on Cortical Spreading Depressions (CSD) and brain edema formation. In a second set of experiments, C57 bl/6 mice received Eudesmol, a highly selective Cav2.1 channel blocker 10 minutes before trauma by icv. injection in order to evaluate the role of the channel in non-transgenic animals.
Results: CACNA1a mutant mice had a significantly higher incidence of posttraumatic CSDs after CCI than wildtype litter mates. The effect was gene-dose-dependent. All transgenic animals had significantly elevated posttraumatic brain damage; particularly brain water content, a surrogate parameter for brain edema formation, was markedly increased. Pharmacological inhibition of the P/Q channel significantly reduced edema formation and improved neurological outcome in C57 bl/6 mice after CCI.
Conclusions: CACNA1a gene mutations resulting in a gain of function of the Cav2.1 P/Q-Ca2+-channel massively increase posttraumatic brain damage dependent on the extent of the dysfunction. Transgenic mice showed a significantly higher occurrence of CSDs indicating that CSDs are triggered through Cav2.1 P/Q-Ca2+ channels and result in secondary brain damage. Inhibition of the channel in non-transgenic mice significantly reduced edema formation. CACNA1a mutations may therefore be a risk factor for adverse outcome after TBI. Furthermore, the channel might be a promising target for neuroprotective therapies after TBI.
