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Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms
Erwin A van Vliet1, Willem M Otte2,3, Wytse J Wadman4
1Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Objective:
Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activity during the chronic epileptic phase. Given rapamycin's role in growth and immune response, the potential therapeutic effects of rapamycin after status epilepticus with emphasis on brain inflammation and brain vasculature were investigated.
Methods:
Seven weeks after kainic acid-induced status epilepticus, rats were perfusion fixed and (immuno)histochemistry was performed using several glial and vascular markers. In addition, an in vitro model for the human BBB was used to determine the effects of rapamycin on transendothelial electrical resistance as a measure for BBB integrity.
Results:
(Immuno)histochemistry showed that local blood vessel density, activated microglia, and astrogliosis were reduced in rapamycin-treated rats compared to vehicle-treated rats. In vitro studies showed that rapamycin could attenuate TNFα-induced endothelial barrier breakdown.
Significance:
These data suggest that rapamycin improves BBB function during the chronic epileptic phase by a reduction of local brain inflammation and blood vessel density that can contribute to a milder form of epilepsy.
Insights
Rapamycin, an mTOR inhibitor, reduces blood-brain barrier leakage and neuroinflammation after status epilepticus, potentially leading to milder epilepsy. This study investigated its effects on brain vasculature and inflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Vascular Biology
Background:
- Blood-brain barrier (BBB) leakage is implicated in epilepsy development post-status epilepticus.
- The mammalian target of rapamycin (mTOR) inhibitor rapamycin has shown promise in reducing BBB leakage and seizures.
Purpose of the Study:
- To investigate the therapeutic effects of rapamycin on brain inflammation and vasculature after status epilepticus.
- To determine rapamycin's impact on BBB integrity and associated epilepsy progression.
Main Methods:
- Post-kainic acid-induced status epilepticus in rats, (immuno)histochemistry was used to assess glial and vascular markers.
- An in vitro human BBB model evaluated rapamycin's effect on transendothelial electrical resistance.
Main Results:
- Rapamycin treatment reduced local blood vessel density, activated microglia, and astrogliosis in rats.
- In vitro, rapamycin attenuated TNFα-induced endothelial barrier disruption.
Conclusions:
- Rapamycin enhances BBB function during chronic epilepsy by decreasing neuroinflammation and blood vessel density.
- These effects suggest rapamycin can contribute to a milder form of epilepsy post-status epilepticus.
