Research ReportFerulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia/reperfusion injury by inhibiting ICAM-1 mRNA expression in rats
Introduction
Inflammatory response and oxidative stress are known to exacerbate the damage caused by acute cerebral ischemia/reperfusion (I/R) injury (Shin et al., 2006). Cytokines elicit the synthesis of P-selectin, E-selectin and intercellular adhesion molecule-1 (ICAM-1), adhesion molecules that facilitate the adhesion of activated leukocytes to endothelial cells (ECs). Activated leukocytes then infiltrate the ECs, cross the vascular wall and migrate into the brain parenchyma (Soriano et al., 1999, Ding et al., 2003, Khan et al., 2007). Macrophage-1 antigen (Mac-1, CD11b/CD18), a heterodimeric protein consisting of α (CD11b) and β (CD18) subunits expressed on the surface of activated leukocytes, facilitates cell–endothelium interactions (Hickstein et al., 1993, Caimi et al., 2001, Arumugam et al., 2004). Mac-1 acts as an activation marker for microglia/macrophages (Berliner et al., 2000, Nakase et al., 2004, Ueno et al., 2006), which release a host of neurotoxic compounds, including reactive oxygen species (ROS), nitric oxide (NO), cytokines and lipid peroxidation products, that worsen secondary ischemic neuronal insults (Miyahara et al., 2003, Kao et al., 2006, Kapadia et al., 2006). Evidence suggests that necrosis and apoptosis are the main characteristics of neuronal death following acute cerebral I/R injury (Kao et al., 2006). ROS, which are robustly produced by activated microglia/macrophages, attack neuronal components including lipid, protein and DNA, causing nuclear DNA oxidation and lipid peroxidation (Won et al., 2001, Imai et al., 2003). Superoxide anions, primary oxygen free radicals produced by mitochondria, are rapidly converted in the cell to hydrogen peroxide, which is subsequently converted to the highly reactive hydroxyl radical (Klein and Ackerman, 2003). This radical then hydroxylates the C-8 position of guanine residues in G–C rich regions of DNA, leading to a G:C to T:A transversion mutation (Won et al., 2001, Sakurai et al., 2003). The well-recognized oxidative stress markers in DNA and lipids are 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE), respectively. Eight-OHdG is mainly produced in neurons after transient cerebral ischemia, and the accumulation of unrepaired oxidative DNA lesions in the nucleus can lead to either tumorigenesis or apoptosis (Hayashi et al., 1999, Nagayama et al., 2000, Sakurai et al., 2003). Four-HNE, a product toxic to neuronal perikarya, is released from polyunsaturated fatty side chains and contributes to the dysfunction of cell membrane transporters via lipid peroxidation, which then leads to apoptosis (McCracken et al., 2000, Gordon et al., 2005, Lee et al., 2005). Previous studies demonstrated that drugs designed to inhibit recruited leukocytes/microglia markedly curtailed inflammation and oxidative stress-related apoptosis, and consequently provided neuroprotection in cerebral I/R injury (Storini et al., 2005, Kao et al., 2006).
Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA), a component of Anglica sinensis (olivi) Didl. and Ligusticum chuoanxiong Hort., was shown to be a free radical scavenger and to have anti-inflammatory and antioxidation effects in a transient middle cerebral artery occlusion (MCAo) model (Wang et al., 2005). In our previous study, we found that FA (100 mg/kg) effectively inhibited ICAM-1 expression in the ischemic striatum and decreased the levels of superoxide anions in the ischemic brain parenchyma at 2 h of reperfusion after MCAo (submitted). The purpose of this study is to further investigate the neuroprotective effects of FA, and the possible mechanisms involved in the effects of FA against activated microglia/macrophages, oxidative stress and oxidative stress-related apoptosis in the penumbra and ischemic core areas during the cerebral I/R period.
Section snippets
Physiological parameters
Blood gas parameters (including pH, pO2 and pCO2) and blood sugar levels were measured at 10 min before and 90 min after cerebral ischemia. There were no significant differences in physiological parameters between the sham, control and FA groups (p > 0.05; Table 1).
Effects of FA on ICAM-1 and Mac-1 mRNA levels at 2 h of reperfusion
There were no significant differences in densitometry measurements of ICAM-1 mRNA in the ischemic area of the cortex between the sham, control and FA groups (p > 0.05; Fig. 1). In the ischemic striatum of the ipsilateral hemisphere, the
Discussion
There were no significant differences in the levels of blood gas (including pH, pO2 and pCO2) and blood sugar between the sham, control and FA groups measured at 10 min before and 90 min after cerebral ischemia, indicating that the ischemia process and FA treatment did not affect the physiological parameters and all the animals were studied under the same physiological condition.
Studies have shown that the expression of ICAM-1 mRNA remarkably increases in the ischemic area at 1–4 h of
General preparation
Adult male Sprague–Dawley rats weighing 300–350 g were employed in this study. Rats were fasted overnight with free access to water. All experimental procedures were performed under the guidelines approved by the Care and Use of Laboratory Animals Committee of the China Medical University.
Occlusion model
Ischemia was induced by intraluminal suture occlusion of the right middle cerebral artery (MCA) as previously described (Longa et al., 1989). Briefly, rats were anesthetized with chloral hydrate (400 mg/kg,
Acknowledgment
This study was supported by grants from the National Science Council (NSC 96-2320-B-039-017), Taiwan.
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