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

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. British Journal of Pharmacology (2008) 155 , 623–640; doi: 10.1038/bjp.2008.342 ; published online 15 September 2008