Targeting Heme Oxygenase-1 for Neuroprotection and Neuroinflammation in Neurodegenerative Diseases

Abstract

Heme oxygenase-1 (HO-1), an enzyme degrading heme to carbon monoxide, free iron, and biliverdin, participates in the cell defence against oxidative stress and it has been speculated that it might be a new therapeutic target for neuroprotection. In this review, we discuss recent findings on the regulation of the HO-1 gene, Hmox1, in the brain with particular focus on the transcription factors Nrf2 and HIF-1. Functional polymorphisms in Hmox1 have been associated with high risk for Alzheimers and Parkinsons disease. Hence, we review the current knowledge on the role of HO-1 and its enzymatic products on these two pathologies as well as ischemic brain injury. HO-1 modulates the inflammatory response in several scenarios, and therefore we discuss its role in modulation of the innate immune cell of the brain, microglia. From the therapeutic side, the blood brain barrier represents an obstacle to directly modulate heme oxygenase activity, but drugs activating the transcription actor Nrf2, which have a very diverse molecular structure, may be good candidates to induce HO-1 in concert with other antioxidant and detoxification enzymes. A more complete understanding on the mechanisms regulating HO-1 expression in brain cells and how these mechanisms are involved in neuropathological changes will be essential to develop these new therapeutic approaches. Keywords: Heme oxygenase-1, oxidative stress, Alzheimer's disease, Parkinson's disease, stroke, inflammation, immunomodulation, carbon monoxide, free iron, biliverdin, neuroprotection, HO-1 gene, Hmox1, polymorphisms, ischemic brain injury, blood brain barrier, microglia, antioxidant, detoxification enzymes, neuropathological changes, inflammation immunomodulation, central nervous system (CNS), reactive oxygen species (ROS), bilirubin, arteriosclerotic lesions, ferroxidase, neurodegenerative diseases, redox homeostasis, neuroinflammation, lipopolysaccharide (LPS), heat shock protein, astrocytes, cerebroprotective, erythroid 2-related factor 2 (Nrf2), antioxidant-response element (ARE), hypoxia-response element (HRE), hydroxylases (PHDs), ubiquitin-proteaseome, iron chelators, 2-OG analogues (DMOG), neuroprotective effect, hypoxia responsive element (HRE), dimethyloxaloylglycine, dopaminergic nigrostriatal injury, guanylyl cyclase, cyclic GMP, noradrenergic neurons, cholinergic neurotransmission, circadian rhythms, hypothalamus, muscarinic receptors, metalloporphirins, tumor necrosis factor (TNF), interleukin-1β (IL-1β), macrophage inflammatory protein-1β (MIP-1β), carbon-monoxide, –, releasing molecules (CORM-2, kernicterus, a-tocopherol, anatomopathological features, dopaminergic neurons, a-synuclein aggregates, bradykinesia, akinesia, nicotinamide adenine dinucleotide phosphate (NADPH), senile plaques, Amyloid precursor protein (APP), excitotoxic neurotransmitter (glutamate), nordihydroguaiaretic acid (NDGA), Larrea tridentate