**2.3 Reoxygenation injury**

H2O2 production has been noted to increase extensively in brain tissues during reoxygenation after CO intoxication (Zhang and Piantadosi 1992). Salicylate hydroxylation products and 2,3- and 2,5-dihydroxybenzoic acid are also significantly increased during reoxygenation. During this period, CO still binds to cytochrome c oxidase and inhibits the mitochondrial electron transport chain. If the reaction exists in iron-rich regions such as the basal ganglia, it causes persistent acidosis and active iron, which can further damage cells (Zhang and Piantadosi 1992).

#### **2.4 Mechanisms related to central nervous system (CNS) injury 2.4.1 Acute CNS injury**

In animal models, an initial cerebral blood flow increment after CO exposure is thought to maintain the baseline energy state (MacMillan 1975). A change of blood flow depends on both the reaction of the cerebrovasculature and cardiac function in CO intoxication. In either failure of cerebrovasculature dilatation or impairment of cardiac pumping function, there is no compensatory blood supply increase in the status of acute carboxyhemoglobin elevation and oxyhemoglobin reduction. (Raub and Benignus 2002). After initially compensated hyperperfusion, focal hypoperfusion has been noted in several studies (Choi, Lee et al. 1992; Choi and Lee 1993) which might be related to clinical manifestation (Sesay, Bidabe et al. 1996). Hypoperfusion over the basal ganglion (Sesay, Bidabe et al. 1996; Kao, Hung et al. 1998), cerebral cortical (Choi, Lee et al. 1992; Kao, Hung et al. 1998), and white matter (WM) (Sesay, Bidabe et al. 1996) areas have been noticed. Cerebral WM and the globus pallidum (GPi) were noted to have relatively low cerebral blood flow after acute CO intoxication in one animal study (Okeda, Matsuo et al. 1987).

Hypoxia in the CNS induces decreased adenosine-5'-triphosphate, influx of Ca2+ and Na+, release of glutamate, noradrenaline and acetylcholine and causes cell swelling and death (Weinachter, Blavet et al. 1990; Kluge 1991). Increased glutamate with both neuronal necrosis and apoptosis was noted immediately after CO intoxication in one animal study (Piantadosi, Zhang et al. 1997). However, how hypoxia affects the CNS in the acute stage of CO intoxication has not been well established (Piantadosi, Zhang et al. 1997; Gorman, Drewry et al. 2003). Aside from changes of cerebral blood flow and hypoxia, increasing intracranial pressure and brain tissue necrosis have been noted in animals and humans after acute CO intoxication (Jiang and Tyssebotn 1997; Piantadosi, Zhang et al. 1997; Uemura, Harada et al. 2001; Lo, Chen et al. 2007).

### **2.4.2 Chronic CNS injury**

354 Neuroimaging – Cognitive and Clinical Neuroscience

CO competes with oxygen in binding with hemoglobin to form carboxyhemoglobin. The affinity between CO and hemoglobin is 200 times higher than that of oxygen (Ernst and Zibrak 1998; Piantadosi 2002; Weaver 2009). The production of carboxyhemoglobin shifts the oxygen-hemoglobin curve to the left and dissociates oxygen from hemoglobin (Ernst and Zibrak 1998). These reactions consequently reduce oxygen delivery to tissues and result

In brief, CO intoxication leads to oxidative stress through the following mechanisms:

1. CO increases cytosolic heme levels leading to increased heme oxygenase-1 protein, causing intracellular oxidative stress and direct cellular injury (Ernst and Zibrak 1998;

2. CO binds to cytochrome c oxidase and impairs mitochondrial function. Cytochrome c oxidase is one of the mitochondrial complexes involved in electric chain transport and is essential for energy production. Binding of CO to cytochrome c oxidase can lead to activation of hypoxia-inducible factor 1α or production of reactive oxygen species with direct cellular injury. Related downstream reactions include apoptosis, lipid peroxidation, lymphocyte proliferation, inflammation and necrosis (Weaver 2009). 3. CO binds to platelet heme protein and induces biogenesis of nitric oxide peroxynitrite, consequently leading to enhanced adhesion of neutrophils to the vascular lining, neutrophil aggregation and release of myeloperoxidase. All of these reactions not only trigger inflammatory processes but also produce more reactive oxygen species (Ernst

H2O2 production has been noted to increase extensively in brain tissues during reoxygenation after CO intoxication (Zhang and Piantadosi 1992). Salicylate hydroxylation products and 2,3- and 2,5-dihydroxybenzoic acid are also significantly increased during reoxygenation. During this period, CO still binds to cytochrome c oxidase and inhibits the mitochondrial electron transport chain. If the reaction exists in iron-rich regions such as the basal ganglia, it causes persistent acidosis and active iron, which can further damage cells

In animal models, an initial cerebral blood flow increment after CO exposure is thought to maintain the baseline energy state (MacMillan 1975). A change of blood flow depends on both the reaction of the cerebrovasculature and cardiac function in CO intoxication. In either failure of cerebrovasculature dilatation or impairment of cardiac pumping function, there is no compensatory blood supply increase in the status of acute carboxyhemoglobin elevation and oxyhemoglobin reduction. (Raub and Benignus 2002). After initially compensated hyperperfusion, focal hypoperfusion has been noted in several studies (Choi, Lee et al. 1992; Choi and Lee 1993) which might be related to clinical manifestation (Sesay, Bidabe et al. 1996). Hypoperfusion over the basal ganglion (Sesay, Bidabe et al. 1996; Kao, Hung et al.

**2.4 Mechanisms related to central nervous system (CNS) injury** 

**2. Mechanisms of CO intoxication** 

in a hypoxic microenvironment.

and Zibrak 1998; Weaver 2009).

**2.3 Reoxygenation injury** 

(Zhang and Piantadosi 1992).

**2.4.1 Acute CNS injury** 

**2.1 Tissue hypoxia** 

**2.2 Oxidative stress** 

Weaver 2009).

The pathogenesis of delayed CNS injury in CO intoxication is complicated. Hypoperfusion (Sesay, Bidabe et al. 1996; Watanabe, Nohara et al. 2002; Chu, Jung et al. 2004) and hypoxia (Opeskin and Drummer 1994) still play an important role. Demyelination (Murata, Kimura et al. 2001; Kamijo, Soma et al. 2007; Ide and Kamijo 2008), cytotoxic edema (Kim, Chang et al. 2003; Chu, Jung et al. 2004; Kwon, Chung et al. 2004), hemorrhage (Ramsey 2001) and infarction (Schwartz, Hennerici et al. 1985; Sung, Yu et al. 2010) have also been associated with delayed neurological deficits. Hypoperfusion and cytotoxic edema in delayed CNS injury have been noted in WM areas and the cerebral cortex (Chu, Jung et al. 2004), and ischemia and necrosis have been noted in the globus pallidus (Chang, Han et al. 1992). Although demyelination and axonal damage might co-exist in CO intoxication, demyelination more than axonal damage is suggested in the literature (Chang, Han et al. 1992; Murata, Kimura et al. 2001; Kamijo, Soma et al. 2007; Ide and Kamijo 2008).

### **2.5 Other mechanisms**

CO also inhibits a number of proteins essential for cells. Myoglobin in the heart and skeletal muscle systems, neuroglobin in the brain, cytochrome P450 (Weiner 1986), dopamine and tryptophan oxygenase (Raub and Benignus 2002) have all been reported to be affected. A high CO concentration transforms xanthine dehydrogenase to xanthine oxidase and produces more free radicals in tissues (Piantadosi, Tatro et al. 1995). Inhibiting the normal function of these intracellular proteins causes further damage or systemic injury in CO intoxication.
