Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice

• Increased BBB permeability was caused by the neovascularization in the acute phase after SE.
• Pro-inflammatory responses in hippocampus enhanced in the acute phase after SE.
• The angiogenesis and pro-inflammatory responses coincided with the BBB leakage in hippocampus.
• LEV inhibited the BBB failure associated with angiogenesis and pro-inflammatory responses.
• LEV may be key to developing new prophylactic therapies for post-brain insult epilepsy.

Our previous study showed that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam might prevent the development of spontaneous recurrent seizures via the inhibition of neurotoxicity induced by brain edema events. In the present study, we determined the possible molecular and cellular mechanisms of LEV treatment after termination of SE. To assess the effect of LEV against the brain alterations after SE, we focused on blood-brain barrier (BBB) dysfunction associated with angiogenesis and brain inflammation. The consecutive treatment of LEV inhibited the temporarily increased BBB leakage in the hippocampus two days after SE. At the same time point, the LEV treatment significantly inhibited the increase in the number of CD31-positive endothelial immature cells and in the expression of angiogenic factors. These findings suggested that the increase in neovascularization led to an increase in BBB permeability by SE-induced BBB failure, and these brain alterations were prevented by LEV treatment. Furthermore, in the acute phase of the latent period, pro-inflammatory responses for epileptogenic targets in microglia and astrocytes of the hippocampus activated, and these upregulations of pro-inflammatory-related molecules were inhibited by LEV treatment. These findings suggest that LEV is likely involved in neuroprotection via anti-angiogenesis and anti-inflammatory activities against BBB dysfunction in the acute phase of epileptogenesis after SE.