Regulation of haeme oxygenase‐1 for treatment of neuroinflammation and brain disorders

Abstract

Injury to the CNS elicits a host defense reaction that utilizes astrocytes, microglia, neurons and oligodendrocytes. Neuroinflammation is a major host defense mechanism designed to restore normal structure and function after CNS insult, but like other forms of inflammation, chronic neuroinflammation may contribute to pathogenesis. The inducible haeme oxygenase isoform, haeme oxygenase-1 (HO-1), is a phase 2 enzyme upregulated in response to electrophilic xenobiotics, oxidative stress, cellular injury and disease. There is emerging evidence that HO-1 expression helps mediate the resolution of inflammation, including neuroinflammation. Whether this is solely because of the catabolism of haeme or includes additional mechanisms is unclear. This review provides a brief background on the molecular biology and biochemistry of haeme oxygenases and the actions of haeme, bilirubin, iron and carbon monoxide in the CNS. It then presents our current state of knowledge regarding HO-1 expression in the CNS, regulation of HO-1 induction in neural cells and discusses the prospect of pharmacological manipulation of HO-1 as therapy for CNS disorders. Because of recognized species and cellular differences in HO-1 regulation, a major objective of this review is to draw attention to areas where gaps exist in the experimental record regarding regulation of HO-1 in neural cells. The results indicate the HO-1 system to be an important therapeutic target in CNS disorders, but our understanding of HO-1 expression in human neural cells is severely lacking.

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

“…HO-1 is an inducible enzyme with proven anti-inflammatory and cytoprotective activities, but little is known about its regulation of expression in primary human brain cells. 30 Thus, our results have important implications for human CNS diseases.…”

Inhibition of neuroinflammation in BV2 microglia by the biflavonoid kolaviron is dependent on the Nrf2/ARE antioxidant protective mechanism

“…The expression of the antioxidant protein HO-1 has been shown to mediate the resolution of neuroinflammation [24]. We were therefore in evaluating whether activation of HO-1 might be contributing to the anti-neuroinflammatory effects of kolaviron.…”

Prevention of Both Neutrophil and Monocyte Recruitment Promotes Recovery after Spinal Cord Injury

“…It is likely that the end products of heme degradation influence outcome. For example, whereas bilirubin may function as a potent antioxidant, the generation of ferrous iron may potentiate damage by reacting with hydrogen peroxide to produce highly reactive hydroxyl radicals that lead to oxidative stress and cell death (Liu et al, 2002;Mautes et al, 2000;Syapin, 2008). In SCI in which there is overt intraparenchymal hemorrhage, increased HO-1 activity may become cytotoxic as a result of the generation of excess iron that overwhelms mechanisms regulating iron homeostasis (Lee et al, 2010).…”