Analysis of proliferating neuronal progenitors and immature neurons in the human hippocampus surgically removed from control and epileptic patients.

Adult neurogenesis in the mammalian hippocampus is a well-known phenomenon. However, it remains controversial as to what extent adult neurogenesis actually occurs in the adult human hippocampus, and how brain diseases, such as epilepsy, affect human adult neurogenesis. To address these questions, we analyzed immature neuronal marker-expressing (PSA-NCAM+) cells and proliferating neuronal progenitor (Ki67+/HuB+/DCX+) cells in the surgically removed hippocampus of epileptic patients. In control patients, a substantial number of PSA-NCAM+ cells were distributed densely below the granule cell layer. In epileptic patients with granule cell dispersion, the number of PSA-NCAM+ cells was reduced, and aberrant PSA-NCAM+ cells were found. However, the numbers of Ki67+/HuB+/DCX+ cells were very low in both control and epileptic patients. The large number of PSA-NCAM+ cells and few DCX+/HuB+/Ki-67+ cells observed in the controls suggest that immature-type neurons are not recently generated neurons, and that the level of hippocampal neuronal production in adult humans is low. These results also suggest that PSA-NCAM is a useful marker for analyzing the pathology of epilepsy, but different interpretations of the immunohistochemical results between humans and rodents are required.

Epileptic focus stimulation and seizure control in the rat model of kainic acid-induced limbic seizures.

The inhibitory effects of deep brain stimulation (DBS) were investigated in a rat model of kainic acid (KA)-induced limbic status epilepticus. Wistar rats were injected with 1.0 microg KA into the left amygdala after stereotactic implantation of a guide cannula and electrodes. Bipolar rectangular pulses of 0.1 msec duration and 0.1-0.3 mA amplitude were applied intermittently to the left amygdala (10 Hz or 130 Hz), left ventral hippocampus (10 Hz), and left dorsomedial thalamus (130 Hz). Seizure frequency was evaluated by video electroencephalography monitoring and compared to control animals that did not receive DBS. All rats developed limbic status epilepticus 60-90 minutes after KA injection. Seizure frequency was significantly reduced by 10 Hz stimulation of the amygdala and by 130 Hz stimulation of the dorsomedial thalamus. No significant effects were observed with other types of stimulation. Seizure behaviors or duration of seizure were not changed significantly by DBS treatment. DBS of an epileptic focus may attenuate KA-induced limbic seizures, depending on the stimulation sites and parameters.

Endothelial microsomal prostaglandin E synthase-1 exacerbates neuronal loss induced by kainate.

Prostaglandin E(2) (PGE(2)) is increased in the brain after kainic acid (KA) treatment. We previously demonstrated that KA also induces PG synthase cyclooxygenase-2 (COX-2) expression rapidly in neurons of the brain and slowly in astrocytes and endothelia. Prevention of KA-induced neuronal damage by nonneuronal COX-2 inhibition suggests a novel modulatory mechanism for neuronal injury by nonneuronal PGs. It remains unclear, however, which PG synthase is responsible for this modulation following COX-2 synthesis after neuronal insult. In addition, the PG receptor subtype that is involved in neuronal loss remains controversial. Here we demonstrate that microinjection of KA induces microsomal prostaglandin E synthase-1 (mPGES-1) in venous endothelial cells but not in neurons or astrocytes. We found that mPGES-1 plays a central role in delayed production of PGE(2) and that mPGES-1-deficient mice exhibit significantly less neuronal loss induced by KA. Furthermore, KA injection caused an increase in the immunoreactivity for the EP3 receptor in the astrocytic endfeet that surround vascular endothelia. Neurons form intimate interactions with astrocytes via glutamate, and astrocytes contact vascular endothelia through endfeet. These findings suggest that endothelial cells may control neuronal excitotoxicity, most likely by regulating astrocytes via inducible PGE(2).

Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region.

Injection of kainic acid (KA) into the brain causes severe seizures with hippocampal neuron loss. KA has been shown to immediately induce cyclooxygenase-2 (COX-2) expression in hippocampal neurons, indicating that neuronal COX-2 might be involved in neuronal death. In this study, however, we reveal that the delayed COX-2 induction in non-neuronal cells after KA injection plays an important role in hippocampal neuron loss rather than early COX-2 expression in neurons. We find that KA microinjection into the hemilateral hippocampus shows a later induction of COX-2 expression in non-neuronal cells, such as endothelial cells and astrocytes. In the KA-injected side, PGE2 concentration gradually increases and peaks at 24 h after injection, when non-neuronal COX-2 expression also peaks. When this delayed PGE2 elevation is prevented by selective COX-2 inhibitor NS398, it can block hippocampal cell death. Moreover, COX-2 knockout mice are also resistant to neuronal death after KA treatment. These findings indicate that delayed PGE2 production by non-neuronal COX-2 may facilitate neuronal death after seizure. Inhibition of COX-2 to an extent similar to PGE2 elevation after onset of seizure may be useful to prevent neuronal death.