Effects Of Lamotrigine On Neurogenesis In The Dentate Gyrus Of Adult Rats

Objective Neurogenesis continues to occur throughout life in the adult mammalian brain, including humans. Subgranular zone (SGZ) of hippocampal dentate gyrus (DG) is a widely studied neurogenic region. Mounting evidence suggests that neurogenesis in the adult hippocampus contributes to structural plasticity and hippocampal function, including learning and memory.Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, which needs to be controlled with medication for 2-3 years. Recurrent epilepsy could induce severe cognitive impairment, which probably results from epilepsy-induced aberrant neurogenesis in DG. Recent studies indicated that Lamotrigine (LTG), as a new anti-epileptic drug, can improve cognition function of patients with epilepsy. Little is known about the effects of lamotrigine on the neurogenesis in the SGZ after epilepsy. In this study, we employed LiCl-pilocarpine-induced temporal lobe epilepsy rat model, used 5-bromodeoxyuridine (BrdU) to label newborn cells, and sought to examine the effects of lamotrigine on the neurogenesis in the SGZ after seizures induced by lithium-pilocarpine. Methods Adult SD rats were randomly divided into four groups: control group, LTG group, seizure group and seizure + LTG group. All animals were injected BrdU (i.p.) at 6 days after seizures and were killed 24h and 28 days after injection. Using immunohistochemistry, we examined the proliferation of neural progenitor cells and observed the survival, migration and differentiation of newborn cells in adult epileptic hippocampus.Results 1. Using BrdU-staining, we calculated the number of BrdU-positive cells in the DG and found a significant increase of BrdU-positive cells in epileptic rats, comparing to normal and LTG group (P<0.05). After administration of LTG, the number of BrdU-positive cells decreased significantly compared with seizure group (P<0.05).2. The number of BrdU positive cells in DG increased significantly in seizure and seizure + LTG groups, compared with normal and LTG groups (P<0.05). After seizures, LTG treatment did not affect the number of hippocampal BrdU positive cells.3. Using DCX staining, we found that only few newborn neurons migrated into dentate hilus in normal and LTG groups. However, a large number of ectopic newborn neurons appeared in the hilus after seizures. LTG treatment did not affect seizures-induced aberrant migration of newborn neurons.4. We co-labeled BrdU/NeuN using immunofluorescence and observed that the ratio of neuronal differentiation of newborn cells did not reveal a statistical difference in all groups.Conclusions 1. After seizures, LTG treatment effectively decreased the aberrant proliferation of hippocampal neural progenitor cells. 2. Although LTG administration suppressed the aberrant proliferation of neural progenitor cells, we found that there was no difference between seizure and seizure + LTG groups at 28d after BrdU injection. The result indicated that LTG could promote the survival of neuronal progenitors after epilepsy in the DG. 3. LTG treatment did not reduce aberrant migration of newborn neurons into the hilus after epilepsy. 4. LTG administration did not affect differentiation ratio of newborn neurons after epilepsy.