Some of the energy saving afforded by myelination is offset by AC220 nmr the cost of maintaining the resting potential of oligodendrocytes, which is estimated to be high (Harris and Attwell, 2012). Loss of myelin has important consequences for the white matter tracts. In addition to the brain dysfunction caused by slowing down the transmission of axon potentials, demyelination threatens

the integrity of the axons and leads to axonal loss (Franklin and Ffrench-Constant, 2008 and Matute and Ransom, 2012). Several factors contribute to the demise of the axons. Oligodendrocytes release growth factors, such as IGF-1 and glial cell-derived neurotrophic factor that support the survival of axons (Wilkins et al., 2003). Thus, loss of myelin deprives the axons of trophic support and increases their vulnerability. In addition, demyelination exposes the axons to the deleterious effects of

cytokine and free radicals in the hypoxic white matter, which may impair axonal energy production leading to failure of the Na+/K+ ATPase. The resulting accumulation of intracellular Na+ reverses the operation of the Na+/ Ca2+ exchanger, resulting in intracellular Ca2+ accumulation (Matute and Ransom, 2012 and Stys et al., 1992). Furthermore, the adaptive upregulation of voltage-dependent Na+ channels (VNa+) in the denuded internodal axoplasm, attempting to preserve impulse propagation in demyelinated axons, leads to Na+ entry and aggravates the energy deficit and Ca2+ overload. Upregulation Buparlisib Megestrol Acetate of VNa+1.2 channels

increases the activity of the Na+/K+ ATPase, stressing further the energy budget of the marginally perfused white matter (Trapp and Stys, 2009). In turn, excess intracellular Ca2+ activates protease dependent processes that lead to microtubule fragmentation and perturbation of axonal flow (Franklin and Ffrench-Constant, 2008 and Matute and Ransom, 2012). Attempts to remyelinate are present in the damaged white matter in leukoaraiosis (Jonsson et al., 2012). Oligodendrocytes are responsible for the formation and maintenance of the myelin sheet. A large pool of oligodendrocyte progenitor cells (OPC) is present in the brain, which goes through several stages of development before becoming mature and competent to lay down myelin (Fancy et al., 2011a). However, in demyelinating diseases, including leukoaraiosis, axons fail to fully remyelinate (Franklin and Ffrench-Constant, 2008). Several factors are thought to be responsible (Figure 7). First, OPC in the late stage of development are particularly susceptible to injury in conditions of chronic hypoxia and oxidative stress existing in the ischemic white matter (Back et al., 2011, Back et al., 2002, Fernando et al., 2006 and French et al., 2009).