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Minimal Traumatic Brain Injury in Mice: Protease-Activated Receptor 1 and Thrombin-Related Changes
Zeev Itsekson-Hayosh1,2, Efrat Shavit-Stein1,2, Aviva Katzav2
11 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv, Israel .
Abstract:
Minimal traumatic brain injury (mTBI) is partially defined by the existence of retrograde amnesia and is associated with microscopic bleeds containing activated coagulation factors. In a previous study, we have found that mTBI immediately releases thrombin-like activity in the brain, which induces amnesia by activating protease-activated receptor 1 (PAR-1) and blocking long-term potentiation (LTP). In the present study, we assessed the effects of mTBI on thrombin and PAR-1 levels in the brain using the same model. After the immediate elevation, thrombin activity returned to baseline 1 h post-trauma and increased again 72 h later (42% relative to control; p < 0.005). These changes were associated with a significant increase in PAR-1 levels 24 (17%; p < 0.05) and 72 h (20%; p < 0.05) post-trauma. Interestingly, the late elevation in thrombin-like activity was also associated with elevation of the major central nervous system thrombin inhibitor, protease nexin-1, 72 h post-mTBI (10%; p < 0.005). When thrombin was injected into brain ventricles, an increased sensitivity to seizure-like activity was detected at 72 h post-mTBI. The results are compatible with astrocyte activation post-mTBI resulting in increased thrombin secretion, PAR-1 expression, and seizure sensitivity.
Insights
Minimal traumatic brain injury (mTBI) causes amnesia by activating thrombin and protease-activated receptor 1 (PAR-1). This study reveals delayed thrombin increases and PAR-1 expression post-mTBI, linked to heightened seizure sensitivity.
Area of Science:
- Neuroscience
- Traumatic Brain Injury Research
- Coagulation Factor Studies
Background:
- Minimal traumatic brain injury (mTBI) is characterized by amnesia and microscopic brain bleeds with activated coagulation factors.
- Previous research linked immediate post-mTBI thrombin activity to amnesia via protease-activated receptor 1 (PAR-1) and blocked long-term potentiation (LTP).
Purpose of the Study:
- To investigate the temporal effects of mTBI on brain thrombin and PAR-1 levels.
- To explore the relationship between mTBI, thrombin, PAR-1, and seizure sensitivity.
Main Methods:
- Utilized a validated mTBI model to assess thrombin and PAR-1 levels at various time points post-injury.
- Measured thrombin activity, PAR-1 expression, and protease nexin-1 levels.
- Administered direct ventricular thrombin injection to evaluate seizure-like activity post-mTBI.
Main Results:
- Thrombin activity initially increased, returned to baseline, then rose significantly at 72 hours post-mTBI (42%).
- Protease-activated receptor 1 (PAR-1) levels significantly increased at 24 hours (17%) and 72 hours (20%) post-trauma.
- A late increase in thrombin was associated with elevated protease nexin-1 (10%) at 72 hours post-mTBI.
- Thrombin injection post-mTBI induced increased seizure-like activity at 72 hours.
Conclusions:
- mTBI leads to biphasic changes in thrombin activity and sustained increases in PAR-1 expression.
- Astrocyte activation post-mTBI may drive increased thrombin secretion and PAR-1 expression.
- These molecular changes are associated with heightened seizure sensitivity following mTBI.
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