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Updated: Jul 23, 2026
Acute Brain Trauma in Mice Followed By Longitudinal Two-photon Imaging
Published on: April 6, 2014
Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain
Ursula Felderhoff-Mueser1, Marco Sifringer, Stefanie Pesditschek
1Department of Neonatology, Charité Children's Hospital, Humboldt University, 13353 Berlin, Germany.
Abstract:
Trauma triggers diffuse apoptotic neurodegeneration in the developing rat brain. To explore the pathogenesis of this phenomenon we investigated the involvement of three possible mechanisms: death receptor activation, activation of the intrinsic apoptotic pathway by cytochrome c release into the cytoplasm, and changes in trophic support provided by endogenous neurotrophins. We detected a decrease in the expression of bcl-2 and bcl-x(L), two antiapoptotic proteins that decrease mitochondrial membrane permeability, an increase in cytochrome c immunoreactivity in the cytosolic fraction, and an activation of caspase-9 in brain regions which show apoptotic neurodegeneration following percussion brain trauma in 7-day-old rats. Increase in the expression of the death receptor Fas was revealed by RT-PCR analysis, Western blotting, and immunohistochemistry, as was activation of caspase-8 in cortex and thalamus. Apoptotic neurodegeneration was accompanied by an increase in the expression of BDNF and NT-3 in vulnerable brain regions. The pancaspase inhibitor z-VAD.FMK ameliorated apoptotic neurodegeneration with a therapeutic time window of up to 8 h after trauma. These findings suggest involvement of intrinsic and extrinsic apoptotic pathways in neurodegeneration following trauma to the developing rat brain. Upregulation of neurotrophin expression may represent an endogenous mechanism that limits this apoptotic process.
Insights
Traumatic brain injury in young rats triggers apoptosis via intrinsic and extrinsic pathways. Neurotrophin upregulation may offer a protective mechanism against this neurodegeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Traumatic brain injury (TBI) in developing brains can cause widespread neurodegeneration.
- The precise molecular mechanisms driving this apoptosis are not fully understood.
Purpose of the Study:
- To investigate the roles of death receptor activation, intrinsic apoptosis, and neurotrophin support in TBI-induced neurodegeneration in the developing rat brain.
- To identify potential therapeutic targets for mitigating TBI-related brain damage.
Main Methods:
- Percussion brain trauma was induced in 7-day-old rats.
- Apoptosis markers, including caspase activation and cytochrome c release, were assessed.
- Expression levels of antiapoptotic proteins (bcl-2, bcl-xL), death receptors (Fas), caspases (caspase-8, caspase-9), and neurotrophins (BDNF, NT-3) were analyzed using RT-PCR, Western blotting, and immunohistochemistry.
- The efficacy of a pancaspase inhibitor (z-VAD.FMK) was evaluated.
Main Results:
- Trauma induced apoptotic neurodegeneration in vulnerable brain regions.
- Evidence of both intrinsic (decreased bcl-2/bcl-xL, increased cytosolic cytochrome c, activated caspase-9) and extrinsic (increased Fas, activated caspase-8) apoptotic pathway activation was observed.
- Upregulation of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) expression was detected.
- The pancaspase inhibitor z-VAD.FMK significantly reduced apoptotic neurodegeneration up to 8 hours post-trauma.
Conclusions:
- Both intrinsic and extrinsic apoptotic pathways are critically involved in neurodegeneration following trauma to the developing rat brain.
- Upregulation of neurotrophin expression appears to be an endogenous protective response against trauma-induced apoptosis.
