cAMP production mediated through P2Y11-like receptors in rat striatum due to severe, but not moderate, carbon monoxide poisoning
Highlights
► A threshold for stimulation of striatal cAMP production in CO poisoning. ► Close relationship between cAMP and hydroxyl radical production in CO poisoning. ► CO-induced cAMP production mediated by P2Y11-like receptors.
Introduction
Carbon monoxide (CO) is well known as a toxic gas, which binds to hemoglobin more strongly than does O2, forming carboxyhemoglobin (COHb) and interfering with the supply of O2 to tissues. Therefore, the brain, which strongly demands O2 to function, is vulnerable to CO poisoning. Injuries in the brain are salient in the cerebral cortex, globus pallidus, hippocampus, and caudate putamen, accompanying neuropsychological disorders, such as parkinsonism and amnesia, in humans (Choi and Cheon, 1999, Gale et al., 1999, Ginsberg, 1980, O’Donnell et al., 2000) and experimental animals (Ishimaru et al., 1992, Nabeshima et al., 1991). We found that CO poisoning stimulated generation of hydroxyl radical (•OH), the most toxic of the reactive oxygen species (ROS), in rat striatum (Hara et al., 2004), which could play a role in brain injury due to CO poisoning as well as brain ischemia and trauma (Gilgun-Sherki et al., 2002, Leker and Shohami, 2002, Lewén et al., 2000). Interestingly, •OH production was evident in rats with over 70% COHb due to 3000 ppm CO, but not those with approximately 50% COHb due to 1000 ppm CO, suggesting that severe, though not moderate, CO poisoning stimulates the generation of •OH (Hara et al., 2011). Therefore, a threshold is likely to exist for CO-induced •OH production.
An increase in an intracellular second messenger, cAMP, in the brain is a well-recognized event in response to brain ischemia and hypoxia/anoxia (Palmer, 1985). The increase could be attributed to activation of adenylate cyclase mediated through a stimulatory guanine nucleotide-binding protein (Gs) coupled with receptors of various neurotransmitters and neuromodulators, including dopamine, noradrenaline, serotonin (5-HT), histamine, adenosine and prostaglandins (Tanaka, 2001), which are increased in the extracellular fluid in response to brain insults (Adachi, 2005, Cheng et al., 2000, Hagberg et al., 1987, Stevens and Yaksh, 1988, Thaminy et al., 1997, Yang et al., 2007). Prado et al. (1992) reported that the cAMP increase in rat striatum due to brain ischemia was attenuated by SCH23390, an antagonist of the DA receptors coupled to Gs (Missale et al., 1998). The antagonist also attenuated striatal damage following brain ischemia in newborn piglets (Yang et al., 2007). Therefore, activation of the cAMP signaling pathways mediated through the dopamine system might at least in part play a deleterious role in the brain damage (Prado et al., 1992, Yang et al., 2007). In addition, Tsukada et al. (2004) suggested that the cAMP signaling pathways mediated through 5-HT1A receptors as well as the dopamine receptors are involved in ischemic brain damage in monkeys. On the other hand, studies have proposed that activation of the cAMP pathway protects against ischemic brain damage (Tanaka, 2001). This is supported by the protective effect of rolipram and cilostazol, which increase intracellular cAMP levels by inhibiting phosphodiesterases (Block et al., 1997, Choi et al., 2002). Furthermore, pretreatment with a cell-permeable cAMP analogue, dibutyryl cAMP (db-cAMP) (Qiu et al., 2002), as well as phosphodiesterase inhibitors (Nikulina et al., 2004), promotes axonal regeneration in animal models of spinal cord lesions. However, direct administration of db-cAMP to the brain elicits seizures (Kuriyama and Kakita, 1980), which could lead to neural injury (Berg et al., 1993). In fact, Amadio et al. (2005) reported cell death induced by forskolin (a direct activator of adenylate cyclase), 3-isobutyl-1-methyl-xanthine (a phosphodiesterase inhibitor) and (4-chloro phenylthio)-cAMP (a cAMP analogue) in cultured cerebellar granule neurons. In these neurons, stimulation of purine receptors by an ATP analogue, ATPγS, enhanced both cAMP and ROS production (Amadio et al., 2005). In addition, direct administration of ATP to rat striatum was injurious (Ryu et al., 2002). Thus, it is likely that the cAMP signaling system has paradoxical functions in the brain.
It is known that intracellular production of cAMP is highly correlated with the efflux of cAMP to the extracellular space (Egawa et al., 1988, Rosenberg and Li, 1995), which can be monitored in the brain in vivo by microdialysis (Egawa et al., 1988, Hashimoto and Kuriyama, 1997, Klamer et al., 2005, Wade et al., 2004). In the present study, we found that the extracellular cAMP level was increased in the striatum of rats exposed to CO at 3000 ppm, but not 1000 ppm, as in the case of •OH production. It is likely that cAMP is a factor associated with the threshold of CO-induced •OH generation. Therefore, we explored the mechanism of increase in cAMP.
Section snippets
Animals
Male Sprague-Dawley rats, weighing 235–265 g, were purchased from Charles River Laboratories Japan (Kanagawa, Japan). Animals were acclimated with free access to food and water in a facility with controlled temperature (22–24 °C) on a 12-h/12-h light/dark cycle (lights on between 08:00 and 20:00 h), for at least one week before all of the experiments.
The experimental protocol of this work was approved by the Institutional Animal Care and Use Committee (IACUC) of Tokyo Medical University and all
Effect of CO and non-CO hypoxia on extracellular cAMP levels in rat striatum
Exposure to CO at 1000 ppm for 40 min had no effect on extracellular cAMP levels in the striatum. However, CO at 3000 ppm significantly increased it at 40 min (at the end of the exposure), 60 min and 80 min (20 min and 40 min after the exposure, respectively), although the last increase was less remarkable (Fig. 1). In the case of non-CO hypoxia caused by 5% O2, the increase in cAMP was significant at 20 min of exposure and reached a peak at 40 min of exposure (at the end of exposure) (Fig. 1). To
Discussion
In the present study, we demonstrated that extracellular cAMP levels were increased in the striatum of rats exposed to 3000 ppm of CO, which causes acute CO poisoning with over 70% COHb (Hara et al., 2002, Hara et al., 2011). This indicates that CO poisoning, as well as brain ischemia and hypoxia (Palmer, 1985), enhances cAMP production in the striatum. It is of interest that 1000 ppm CO did not exhibit this ability, with COHb reaching approximately 50% (Hara et al., 2002, Hara et al., 2011). In
Conflicts of interest
There are none.
Role of the funding source
This study was supported by a Grant-in-Aid for Scientific Research (C) (21590747) from the Ministry of Education, Science, Sports and Culture, Japan.
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