Ischaemic stroke leads to oxygen depletion in the brain, which has several cellular and molecular

consequences that affect neuronal and glial function in addition to vascular alterations and
inflammation. Neuronal function relies on the continuous availability of ATP (which in turn requires a
continuous sup of oxygen and glucose to the brain). When this supply is interrupted, as in stroke,
neurons can no longer maintain their transmembrane gradient, leading to the impairment of
neuronal signalling. In addition, anoxic depolarization (that is, sudden, progressive neuronal
depolarization during states of inadequate blood supply to the brain) at presynaptic terminals leads
to neurotransmitter release51. The clearing of excitatory neurotransmitters from the synaptic cleft is
an active, energy-dependent process; thus, neurotransmitter concentrations (including glutamate)
increase during ischaemic stroke.

Particular properties of the N-methyl-d-aspartate (NMDA) receptor cause additional problems. At

typical resting membrane potentials, conductance through the open NMDA receptor is limited as the
channel is blocked by extracellular magnesium. However, upon depolarization, the magnesium is
removed and conduction is substantially higher52, leading to calcium influx and the secondary
release of large amounts of calcium from intracellular stores53,54. The resulting increased
intracellular calcium concentration leads to the activation of several calcium-dependent processes
such as the activation of neuronal nitric oxide synthase with consequent free radical production55,
and the initiation of cell death processes including apoptosis, necrosis, necroptosis and autophagy.
Degeneration of distant nerve fibres (that is, Wallerian degeneration) in tracts that serve the
infarcted brain (such as the corticospinal tract for motor weakness) occurs in animal models56 and
can be detected using diffusion tensor imaging in humans, in whom changes in early fractional
anisotropy predict long-term clinical outcome57. These systems are well defined in rodent models of
stroke, and interfering with NMDA signalling58, neuronal nitric oxide synthase activity59 and p53
activation following DNA damage6