Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: Magnetic resonance imaging

Epilepsia. 2016 Jan;57(1):59-69. doi: 10.1111/epi.13246. Epub 2015 Dec 22.


Objective: The mammalian target of rapamycin (mTOR) pathway has received increasing attention as a potential antiepileptogenic target. Treatment with the mTOR inhibitor rapamycin after status epilepticus reduces the development of epilepsy in a rat model. To study whether rapamycin mediates this effect via restoration of blood-brain barrier (BBB) dysfunction, contrast-enhanced magnetic resonance imaging (CE-MRI) was used to determine BBB permeability throughout epileptogenesis.

Methods: Imaging was repeatedly performed until 6 weeks after kainic acid-induced status epilepticus in rapamycin (6 mg/kg for 6 weeks starting 4 h after SE) and vehicle-treated rats, using gadobutrol as contrast agent. Seizures were detected using video monitoring in the week following the last imaging session.

Results: Gadobutrol leakage was widespread and extensive in both rapamycin and vehicle-treated epileptic rats during the acute phase, with the piriform cortex and amygdala as the most affected regions. Gadobutrol leakage was higher in rapamycin-treated rats 4 and 8 days after status epilepticus compared to vehicle-treated rats. However, during the chronic epileptic phase, gadobutrol leakage was lower in rapamycin-treated epileptic rats along with a decreased seizure frequency. This was confirmed by local fluorescein staining in the brains of the same rats. Total brain volume was reduced by this rapamycin treatment regimen.

Significance: The initial slow recovery of BBB function in rapamycin-treated epileptic rats indicates that rapamycin does not reduce seizure activity by a gradual recovery of BBB integrity. The reduced BBB leakage during the chronic phase, however, could contribute to the decreased seizure frequency in post-status epilepticus rats treated with rapamycin. Furthermore, the data show that CE-MRI (using step-down infusion with gadobutrol) can be used as biomarker for monitoring the effect of drug therapy in rats.

Keywords: Blood-brain barrier; Contrast-enhanced magnetic resonance imaging; Epileptogenesis; Rapamycin; Status epilepticus; Temporal lobe epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / adverse effects*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / physiopathology*
  • Brain / metabolism
  • Brain / pathology
  • Capillary Permeability / drug effects
  • Disease Models, Animal
  • Electroencephalography
  • Excitatory Amino Acid Agonists / toxicity
  • Follow-Up Studies
  • Kainic Acid / toxicity
  • Magnetic Resonance Imaging
  • Male
  • Phospholipids / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sirolimus / adverse effects*
  • Sirolimus / blood
  • Status Epilepticus / blood
  • Status Epilepticus / chemically induced
  • Status Epilepticus / drug therapy*
  • Sulfur Hexafluoride / metabolism
  • Time Factors
  • Video Recording


  • Anticonvulsants
  • Excitatory Amino Acid Agonists
  • Phospholipids
  • contrast agent BR1
  • Kainic Acid
  • Sirolimus
  • Sulfur Hexafluoride