Potential implications of heme oxygenase in neurodegenerative diseases
Heme oxygenase: Heme oxygenase is the only enzyme in the body that can degrade heme, and it generates different metabolites with specific actions: iron, biliverdin/bilirubin, and carbon monoxide. Heme, or iron protoporphyrin IX, is a prooxidant. Following subarachnoid hemorrhage, for example, it plays a significant role in detoxifying the brain. Within a cell, after different stress conditions, heme is released from heme-containing enzymes and can reach micromolar concentrations. Heme is not recycled and must be degraded. Using mice with deletion of the HO2 gene, we found an approximate twice greater infarct size after induced cerebral ischemia.
Biliverdin and bilirubin: Biliverdin and bilirubin have been generally associated with neurotoxicity in newborn babies. Dr. Doré has proposed that, at low concentrations, these can be significant antioxidants. Using primary neuronal cultures, he showed that nanomolar concentrations of BR appear to be neuroprotective against oxidative stress. In order to test this hypothesis in vivo, he has shown that HO2 knockout mice have greater infarct after transient cerebral ischemia and have greater damage after stereotaxic injection of NMDA. He is now interested in testing new ways to deliver free bilirubin in the brain into order to stay within the physiological protective levels.
Carbon monoxide: Another metabolite of HO reaction is carbon monoxide. The field of CO is still quite controversial. CO is a gas, which has been postulated to be an important neurotransmitter. Because it is a gas, it does not accumulate within vesicles and can readily diffuse to activate its targets. Due to its stability and its relatively long half-life, it can travel longer distances. Carbon monoxide can modulate soluble guanylate cyclase and influence the production of cGMP. For these reasons, it has been postulated that it plays a role in modulating long-term potentiation and influencing memory. Observation of significant differences in the expression levels of the HO2 in aged cognitively impaired rodents is interesting. Additionally, it has been demonstrated that CO can activate the MAP kinase pathway and limit apoptotic-like cell death. This could also partially explain the protective effect found in the HO2-/- mice using in vivo and in vitro models. The goal now is to test whether low levels of CO can be protective using in vivo models of neurotoxicity.
Iron: It is known that iron levels are tightly regulated in order to keep cellular homeostasis and that heme oxygenase appears to control iron efflux from the cell and determines the rate of programmed cell death. One of Dr. Doré’s future objectives is to investigate the cellular mechanism by which heme oxygenase can regulate the iron level within a cell.
- Doré S.Decreased activity of the anti-oxidant heme-oxygenase enzyme: implications in ischemia and in Alzheimer’s disease. Free Radical Res 32:1276-82, 2002.
- Doré S*, Takahashi M*, Ferris CD, Tomita T, Sawa A, Wolosker H, Borchelt DR, Iwatsubo T, Kim SH, Thinakanan G, Sissodia S, Snyder SH. Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer’s disease. Neuron 28:461-73, 2000.
- Doré S, Takahashi M, Ferris CD, Zakhary R, Hester LD, Guastella D, Snyder SH. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci U S A 96:2445-50, 1999.