Hypoxic preconditioning protects against oxidative injury in the central nervous system

Oxidative stress resulting from an imbalance between free radical formation and antioxidative defensive systems has been proposed as one of the mechanisms underlying central nervous system (CNS) neurodegenerative diseases, including Parkinsonism and stroke. Hypoxic preconditioning (HP) reportedly exerts a better protection than other traditional therapies, in large part because the blood brain barrier limits drug permeability to the CNS. Several in vivo animal models have been employed to investigate the effect of HP on CNS neurodegenerative diseases, including microinfusion of transition metals into the substantia nigra for Parkinson?s disease, transient occlusion of middle cerebral artery followed by reperfusion for cortical infarction and local infusion of kainic acid into the hippocampus for epilepsy/brain trauma. Oxidative responses include elevation in free radical formation and lipid peroxidation, depletion of neurotransmitters, as well as neuronal death mediated through necrosis and apoptosis. Neuroprotective effects of HP on oxidative injury in the biological organisms are mediated via multiple mechanisms. The HP: 1) reduces free radical formation; 2) attenuates the depleted glutathione content and the reduced superoxide dismutase activity in response to oxidative stress; 3) ameliorates the elevated lipid peroxidation; 4) inhibits α-synuclein aggregation, a putative pathological protein commonly found the degenerating neurons in the CNS; 5) reduces the elevated heme oxygenase-1, a chaperone protein in response to oxidative stress; 6) prevents neuronal death via inhibiting both necrosis and apoptosis; and 7) inhibits apoptosis through mitochondrial and endoplasmic reticulum pathways. In conclusion, hypoxic preconditioning has protective effects on oxidative injury in the CNS. Moreover, the neuroprotective mechanisms underlying HP include inhibiting elevation in chaperone proteins, attenuating protein aggregation and preventing necrosis and apoptosis via both mitochondria and endoplasmic reticulum in the CNS.