Fatty acid amide hydrolase inhibitor URB597 may protect against kainic acid-induced damage to hippocampal neurons: Dependence on the degree of injury

- The structure of neuronal mitochondria, ER, and nuclei altered after KA-evoked SE.
- A correlation between the severity of SE and neuronal damage was established.
- Nonconvulsive SE-induced injury was prevented or diminished by URB597.
- URB597 failed to reverse most of alterations after convulsive seizures.

ObjectiveStatus epilepticus (SE) provokes changes, which lead to neuronal alterations. Endocannabinoids (eCBs) can affect the neuronal survival during excitotoxicity and brain damage. Using a kainic acid (KA)-induced experimental SE model, we investigated whether cellular changes entail damage to endoplasmic reticulum (ER), mitochondria, and nuclei in hippocampal cells (CA1 field), and whether these alterations can be diminished by treatment with URB597, an inhibitor of eCB enzymatic degradation.Material and methodsSE was induced in Wistar rats by the microinjection of KA into the lateral ventricle. URB597 or a vehicle (10% DMSO) were injected in the same way into the brain of animals 24 h after the KA infusion and then daily for the next nine days. The behavior of animals was controlled visually and recorded with a video system. The intensity of SE significantly varied in different animals. Convulsive (stages 3-5 according to the Racine scale) and nonconvulsive seizures (mainly stages 1, 2 and rarely 3, 4) were recognized.ResultsTwo weeks after SE, a significant loss of hippocampal cells occurred in animals with KA injections. In survived cells, ultrastructural alterations in ER, mitochondria, and nuclei of hippocampal neurons were observed. The degree of cell injury depended on the severity of SE. Alterations evoked by moderate seizures were prevented or diminished by URB597, but strong seizures induced mostly irreversible damage.ConclusionsThe beneficial impact of the FAAH inhibitor URB597 can give impetus to the development of novel neuroprotective strategies.