Regulation of Neurogenesis and Apoptosis through the NHE1 in Lithium-treated Rat Dentate gyrus

Kim, Young Jae; Jung, Yong Wook

Abstract

Lithium-induced neuroprotection are complex and may include the neurogenesis and anti-apoptotic events. Recently, several studies have suggested the possibility that replacement of external Na+ with lithium which induced activations of sodium transporters such as the Na+/H+ exchanger 1 (NHE1) and electrogenic Na+/HCO3 -cotransporter (eNBC). Thus, alteration of sodium transporters could be associated with neurogenesis and anti-apoptotic actions of lithium even though the drug's therapeutic mechanisms remain obscure. The present study was undertaken to examine the changes of protein of NHE1 and eNBC after lithium treatment in normal and ischemic rats can regulate neurogenesis and/or apoptosis in dentate gyrus (DG). Lithium treatment was produced by pellet of standard diet containing 60 mmol/dL lithium for 25 days. The serum concentrations of lithium were found to be 0.76+/-0.2 mEq/L which is therapeutic dose of clinical practice. Immunoblotting analyses revealed that the NHE1 was significantly increased (259+/-8% of controls, n=4, P<0.01) whereas eNBC was unchanged (103+/-8%) compared with controls (n=4) after lithium treatment. Immunohistochemical studies demonstrated that bromodeoxyuridine (BrdU)-positive cells in the lithium-treated DG(n=3) were significantly higher compared with those in controls (n=3). In ischemia-reperfusion rats (n=6), terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining revealed apoptotic granule cells with ischemia-reperfusion rats while no apoptotic granule cells were showed with pretreatment of lithium. These findings suggest that significant increase of NHE1 after lithium treatment may at least partly contribute the neurogenesis and anti-apoptosis of DG via increased intracellular pH and volume increase. Therefore, lithium treatment may have therapeutic potential for ischemic stroke via neurogenesis and anti-apoptotic actions