Neuronal Overexpression of Heme Oxygenase‐1 Correlates with an Attenuated Exploratory Behavior and Causes an Increase in Neuronal NADPH Diaphorase Staining

Abstract

Heme oxygenase isozymes, HO‐1 (also known as hsp32) and HO‐2, are the source for the formation of the putative messenger molecule carbon monoxide (CO), reactive iron, and the in vitro antioxidant bilirubin. We have developed and characterized transgenic (Tg) mice that overexpress the stress protein in neurons in various brain regions. The Tg mice were generated by the use of rat HO‐1 cDNA under the control of the neuron‐specific enolase promoter. Except for a tendency to have an enlarged spleen, Tg mice did not show gross anatomical changes. Increase in HO‐1 mRNA, which was demonstrated by northern blot analysis and in situ hybridization, was accompanied by an increase in neuronal HO‐1 protein expression, shown by immunohistochemistry and western blotting, and an increase in HO activity. Expression of the transgene correlated with an attenuation of exploratory behavior and increased circling activity and coincided with enhanced neuronal NADPH diaphorase staining. Those changes were not accompanied by an increase in DNA damage or significant change in whole‐brain NO synthase activity. The HO‐1 Tg mice potentially represent a good model to examine the function of CO as a neuromodulator, iron as a gene regulator, and bile pigments as in vivo antioxidants.

Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment

“…63 Anesthetic agents have been shown to impair motivation in neonatal non-human primates while CO reduced exploratory behavior in transgenic mice that overexpress heme oxygenase. 64,65 Thus, it is possible that such effects may have contributed to the longer latency times seen on the first day of testing in the two higher CO concentration-exposed cohorts. Of note, the escape times were not significantly different from results of the other cohorts on the subsequent days of testing and approximated control values by Day 3, suggesting that potential defects were transient and could be overcome.…”

Induction of Heme Oxygenase-1 Is Involved in Carbon Monoxide-Mediated Central Cardiovascular Regulation

“…HO-1 normally shows only a limited distribution, but its synthesis can be selectively increased in certain neurons and glial cells through activation of heat shock elements by diverse stimuli. Conversely, HO-2 is widely distributed in the brain under all conditions (Maines et al, 1998).…”

“…Heme oxygenase (HO) is the rate-limiting enzyme responsible for the catabolism of heme and subsequent production of carbon monoxide (CO), biliverdin, and iron (Maines, 1997;Maines et al, 1998). To date, three isoforms of HO have been identified.…”

“…HO-3 is a 33-kDa protein that shares approximately 90% homology with HO-2 but exhibits a relatively low catalytic activity (McCoubrey et al, 1997). HO and its metabolic products have been implicated in the regulation of numerous biological processes (Maines, 1997;Maines et al, 1998). Among them, CO derived from HO activity has been shown to function as a neurotransmitter (Verma et al, 1993), a vasodilator (Furchgott and Jothianandan, 1991), and an endogenous modulator of the nitric oxide (NO)-cGMP signaling in brain (Ingi et al, 1996).…”

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

“…HO activity has been shown to be neuroprotective or anti-oxidative stress in various models of neural injury and disease [17,18]. The overexpression of HO-1 in neurons appears to be relatively resistant to glutamate, H 2 O 2 and other damage, such as amyloid-␤-mediated oxidative damage in vitro and in vivo [19][20][21][22]. HO-1 upregulation in astrocyte cells promotes intracellular oxidative stress, mitochondrial permeability transition, and mitochondrial iron deposition [23][24][25][26][27].…”