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Lacosamide is a new antiepileptic drug which is widely used to treat partial-onset seizures. In this study, we examined the neuroprotective effect of lacosamide against transient ischemic damage and expressions of antioxidant enzymes such as Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPX) in the hippocampal cornu ammonis 1 (CA1) region following 5 min of transient global cerebral ischemia in gerbils. We found that pre-treatment with 25 mg/kg lacosamide protected CA1 pyramidal neurons from transient global cerebral ischemic insult using hematoxylin-eosin staining and neuronal nuclear antigen immunohistochemistry. Transient ischemia dramatically changed expressions of SOD1, SOD2 and GPX, not CAT, in the CA1 pyramidal neurons. Lacosamide pre-treatment increased expressions of CAT and GPX, not SOD1 and 2, in the CA1 pyramidal neurons compared with controls, and their expressions induced by lacosamide pre-treatment were maintained after transient cerebral ischemia. In brief, pre-treatment with lacosamide protected hippocampal CA1 pyramidal neurons from ischemic damage induced by transient global cerebral ischemia, and the lacosamide-mediated neuroprotection may be closely related to increases of CAT and GPX expressions by lacosamide pre-treatment.

Tanshinone I (TsI), a lipophilic diterpene extracted from Danshan (Radix Salvia miltiorrhizae), exerts neuroprotection in cerebrovascular diseases including transient ischemic attack. In this study, we examined effects of TsI on cell proliferation and neuronal differentiation in the subgranular zone (SGZ) of the mouse dentate gyrus (DG) using Ki-67, BrdU and doublecortin (DCX) immunohistochemistry. Mice were treated with 1 and 2 mg/kg TsI for 28 days. In the 1 mg/kg TsI-treated-group, distribution patterns of BrdU, Ki-67 and DCX positive ((+)) cells in the SGZ were similar to those in the vehicle-treated-group. However, in the 2 mg/kg TsI-treated-group, double labeled BrdU(+)/NeuN(+) cells, which are mature neurons, as well as Ki-67(+), DCX(+) and BrdU(+) cells were significantly increased compared with those in the vehicle-treated-group. On the other hand, immunoreactivities and protein levels of Wnt-3, β-catenin and serine-9-glycogen synthase kinase-3β (p-GSK-3β), which are related with morphogenesis, were significantly increased in the granule cell layer of the DG only in the 2 mg/kg TsI-treated-group. Therefore, these findings indicate that TsI can promote neurogenesis in the mouse DG and that the neurogenesis is related with increases of Wnt-3, p-GSK-3β and β-catenin immunoreactivities.

Ischemic preconditioning (IPC) induced by sublethal transient cerebral ischemia could reduce neuronal damage/death following a subsequent lethal transient cerebral ischemia. We, in this study, compared expressions of interleukin (IL)-2 and tumor necrosis factor (TNF)-α as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines in the gerbil hippocampal CA1 region between animals with lethal ischemia and ones with IPC followed by lethal ischemia. In the animals with lethal ischemia, pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region were dead at 5 days post-ischemia; however, IPC protected the CA1 pyramidal neurons from lethal ischemic injury. Expressions of all cytokines were significantly decreased in the SP after lethal ischemia and hardly detected in the SP at 5 days post-ischemia because the CA1 pyramidal neurons were dead. IPC increased expressions of anti-inflammatory cytokines (IL-4 and IL-13) in the stratum pyramidale of the CA1 region following no lethal ischemia (sham-operation), and the increased expressions of IL-4 and IL-13 by IPC were continuously maintained is the SP of the CA1 region after lethal ischemia. However, pro-inflammatory cytokines (IL-2 and TNF-α) in the SP of the CA1 region were similar those in the sham-operated animals with IPC, and the IL-4 and IL-13 expressions in the SP were maintained after lethal ischemia. In conclusion, this study shows that anti-inflammatory cytokines significantly increased and longer maintained by IPC and this might be closely associated with neuroprotection after lethal transient cerebral ischemia.

Calcium binding proteins play important roles in all aspects of neural functioning in the central nervous system. In the present study, we examined age-related changes of three different calcium binding proteins calbindin-D28k (CB), calretinin (CR) and parvalbumin (PV) immunoreactivities in the striatum of young (1 month), adult (6 months) and aged (24 months) ages in three species of rodents (mouse, rat and gerbil) using immunohistochemistry and Western blotting. Our results show that the number of CB-immunoreactive neurons was highest in the adult mouse and rat; however, in the gerbil, the number of CB-immunoreactive neurons was not significantly different from each group although the CB immunoreactivity was significantly decreased in the aged group compared with the adult group. The number of CR-immunoreactive neurons in the striatum was significantly highest in all the adult groups, and, especially, the number of CR-immunoreactive neurons and CR immunoreactivity in the aged gerbil were significantly decreased in the aged group compared with the other groups. Finally, we did not found any significant difference in the number of PV-immunoreactive neurons in the striatum with age among the three rodents. On the other hand, we found that protein levels of three calcium binding proteins in all the mouse groups were similar to the immunohistochemical data. These results indicate that the distribution pattern of calcium binding proteins is different according to age; the adult might show an apparent tendency of high expression in the striatum.

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor of the immunoglobulin superfamily that has been implicated in multiple neuronal and inflammatory stress processes. In this study, we examined changes in RAGE immunoreactivity and its protein levels in the gerbil hippocampus (CA1-3 regions) after 5 min of transient global cerebral ischemia. The ischemic hippocampus was stained with cresyl violet, neuronal nuclei (a neuron-specific soluble nuclear antigen) antibody and Fluoro-Jade B (a marker for neuronal degeneration). 5 days after ischemia-reperfusion, delayed neuronal death occurred in the stratum pyramidale of the CA1 region. RAGE immunoreactivity was not detected in any regions of the CA1-3 regions of the sham-group; the immunoreactivity was markedly increased only in the CA1 region from 3 days after ischemia-reperfusion. On the other hand, RAGE immunoreactivity was newly expressed in astrocytes, not in microglia. Western blot analysis showed that RAGE protein level was highest at 5 days post-ischemia. In brief, both the RAGE immunoreactivity and protein level were distinctively increased in astrocytes in the ischemic CA1 region from 3 days after transient cerebral ischemia. These results indicate that the increase of RAGE expression in astrocytes after ischemia-reperfusion may be related to the ischemia-caused activation of astrocytes in the ischemic CA1 region.