Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects
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Updated: Oct 2, 2026
Acute Brain Trauma in Mice Followed By Longitudinal Two-photon Imaging
Published on: April 6, 2014
Tatsuro Mori1, Xiaoying Wang, Jae-Chang Jung
1Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Abstract:
The authors provide the first in vitro and in vivo evidence that perturbations in mitogen-activated protein kinase (MAPK) signal-transduction pathways are involved in the pathophysiology of traumatic brain injury. In primary rat cortical cultures, mechanical trauma induced a rapid and selective phosphorylation of the extracellular signal-regulated kinase (ERK) and p38 kinase, whereas there was no detectable change in the c-jun N-terminal kinase (JNK) pathway. Treatment with PD98059, which inhibits MAPK/ERK 1/2, the upstream activator of ERK, significantly increased cell survival in vitro. The p38 kinase and JNK inhibitor SB203580 had no protective effect. Similar results were obtained in vivo using a controlled cortical impact model of traumatic injury in mouse brain. Rapid and selective upregulation occurred in ERK and p38 pathways with no detectable changes in JNK. Confocal immunohistochemistry showed that phospho-ERK colocalized with the neuronal nuclei marker but not the astrocytic marker glial fibrillary acidic protein. Inhibition of the ERK pathway with PD98059 resulted in a significant reduction of cortical lesion volumes 7 days after trauma. The p38 kinase and JNK inhibitor SB203580 had no detectable beneficial effect. These data indicate that critical perturbations in MAPK pathways mediate cerebral damage after acute injury, and further suggest that ERK is a novel therapeutic target in traumatic brain injury.
Insights
Mitogen-activated protein kinase (MAPK) pathways, specifically extracellular signal-regulated kinase (ERK), are implicated in traumatic brain injury. Inhibiting ERK signaling in vitro and in vivo reduced brain damage and improved cell survival after injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Traumatic brain injury (TBI) involves complex cellular signaling pathways.
- Mitogen-activated protein kinase (MAPK) pathways are crucial in cellular responses to stress.
Purpose of the Study:
- To investigate the role of MAPK signaling pathways in TBI pathophysiology.
- To determine if targeting specific MAPK pathways could offer therapeutic benefits for TBI.
Main Methods:
- Primary rat cortical cultures and a controlled cortical impact mouse model were used.
- Mechanical trauma was applied, and MAPK pathway activation (ERK, p38, JNK) was assessed.
- Pharmacological inhibitors (PD98059 for ERK, SB203580 for p38/JNK) were administered.
Main Results:
- Mechanical trauma selectively activated ERK and p38 pathways, but not JNK, in vitro and in vivo.
- Inhibition of ERK with PD98059 significantly increased neuronal survival in vitro and reduced lesion volume in vivo.
- Inhibition of p38/JNK with SB203580 showed no protective effects.
Conclusions:
- MAPK pathway perturbations, particularly ERK activation, play a significant role in TBI-induced brain damage.
- Targeting the ERK pathway represents a potential therapeutic strategy for mitigating secondary injury after TBI.
