Heme oxygenase‐1 and heme oxygenase‐2 have distinct roles in the proliferation and survival of olfactory receptor neurons mediated by cGMP and bilirubin, respectively

Abstract

Heme oxygenase (HO) is implicated in protection against oxidative stress, proliferation and apoptosis in many cell types, including neurons. We utilized olfactory receptor neurons (ORNs) as a model to define the roles of HO-1 and HO-2 in neuronal development and survival, and to determine the mediators of these effects. The olfactory system is a useful model as ORNs display neurogenesis post-natally and do not contain nitric oxide synthase (NOS) activity, which could confound results. HO isoforms were expressed in ORNs during embryogenesis and post-natally. Mice null for either HO-1 or HO-2 displayed decreased proliferation of neuronal precursors. However, apoptosis was increased only in HO-2 null mice. Cyclic GMP immunostaining was reduced in ORNs in both genotypes, providing direct evidence that HO mediates cGMP production in vivo. Bilirubin immunostaining was reduced only in HO-2 null mice. These roles for HO-1 and HO-2 were confirmed using detergent ablation of the epithelium to observe increased neurogenesis of ORNs after target disruption in HO null mice. Primary cultures of ORNs revealed that proliferative and survival effects of HO were mediated through cGMP and bilirubin, respectively. These results support a role for HO, the CO-cGMP signaling system and bilirubin in neurodevelopment and in response to injury. Keywords: development, heme oxygenase-1, heme oxygenase-2, neurogenesis, nitric oxide synthase, olfactory epithelium.

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

“…The beneficial effect of HO-1 is in general agreement with many prior observations in neural and nonneural systems (Chen et al, 2003;Clark et al, 2000;Turner et al, 1999).…”

Cerebroprotective Functions of HO-2

“…In the normal brain and in cerebral vessels, HO-1 is undetectable, with the exception of few neuronal populations, mainly olfactory and hippocampal neurons [37][38][39][40][41][42]. In sharp contrast to other tissues, brain and cerebrovascular HO-1 is not readily induced by oxidative stress, with the exception of very limited array of strong pro-oxidant signals.…”

“…The cerebral infarction volume was greatly increased in HO2-KO mice as well as in WT mice with SnPP-inhibited HO-2 enzymatic activity [47]. In a model of glutathione depletion-induced oxidative injury, brain neuronal damage and olfactory neuronal death were also greatly aggravated in HO2-KO mice [37].…”

“…Abundant HO-2 expression in the brain has been detected in a variety of species, including mice, rats, pigs, and humans. In newborn and mature animals, HO-2 is expressed in neurons [37,38,43,[46][47][48][49][50][51][52][53][54], glia [20,55], and cerebral vessels [1,3,20,40]. In cerebral vessels, HO-2 is detected in both endothelial and in smooth muscle cells [1,20].…”

Potential Application of Tetrahydroxystilbene Glucoside in Treatment of Alzheimer’s Disease

“…Other studies found that TSG facilitated tetanus stimulationinduced hippocampal long-term potentiation through activation of NMDA receptor in the hippocampal CA1 region of normal mice; phosphorylation of CaMKII and activation of ERK1/2 cascades possibly mediated TSG-induced enhancement [76] . There are also investigations suggested that TSG attenuated lipopolysaccharide (LPS)-mediated induction of pro-inflammatory factors in microglia through reducing binding activity of NF-κB [57] , and attenuated LPSinduced NADPH oxidase activation and subsequent reactive oxygen species production [49] ; while microglia are believed to mediate development of AD and that neurons injury is usually secondary to microglia activation [77][78][79][80] . …”