Ion transporters in cerebral ischemic damage

Loss of ion homeostasis is a central hallmark in pathological changes during cerebral ischemia. Ischemia-induced perturbation of ion homeostasis includes accumulation of intracellular Na+ and Ca2+ , which subsequently activates many cell death events. Na+ and Ca2+ can enter into cells through ionotropic glutamate receptors (iGluR), voltage-gated Na+ and Ca2+ channels (VGSC and VGCC). However, role of ion transport proteins in disruption of Na+ and Ca2+ homeostasis is not well known. Na+-K+-Cl- cotransporter isoform 1 (NKCC1) and Na+-Ca2+ exchanger (NCX) are ubiquitously expressed in brain tissues. They are important in regulating of Na +, K+, Cl- and Ca2+ under physiological conditions. However, the role of NKCC1 and NCX in ischemic Na +, Ca2+ overload is not well understood.; In the first part of my thesis, I investigated the role of NKCC1 in cerebral ischemic injury in both white and grey matters using mouse transient middle cerebral artery occlusion (tMCAO) model. NKCC1-/- showed significantly less infarction and edema compared to NKCC1+/+ mice. Besides, less pronounced amyloid precursor protein (APP) accumulation is found in NKCC1 -/-mice. Our results suggest that NKCC1 activity contributes to both grey matter and white matter damage after brain ischemia.; Considerable research effort has been centered on grey matter changes in cerebral ischemic damage. In contrast, mechanisms underlying white matter ischemic damage are not extensively studied. White matter is composed of axons and oligodendrocytes. In the second part of my thesis, I further studied the role of NKCC1 and NCX in oligodendrocyte damage following AMPA-mediated excitotoxicity. Our results demonstrated that NKCC1 activity results in Na+ overload in oligodendrocytes and the excessive Na+ entry drives NCX working in the reverse mode and causes subsequent Ca2+ influx. Inhibition of NKCC1 activity can reduce excitotoxicity-mediated disruption of ion homeostasis.; In conclusion, NKCC1 contributes to Na+ homeostasis disturbance during ischemia. Moreover, NKCC1 is involved in Ca2+ homeostasis change through triggering the reverse mode operation of NCX. Inhibition of NKCC1 is protective in brain ischemia both in vivo and in vitro. These findings advance our understanding of the role of NKCC1 and NCX in cerebral ischemia. These ion transport proteins may be potential therapeutic targets for stroke treatment.