Research report(−)-Epigallocatechin gallate protects against NO stress-induced neuronal damage after ischemia by acting as an anti-oxidant
Introduction
Nitric oxide (NO) is synthesized by the NO synthases, endothelial NO synthase (eNOS), neuronal NO synthase (nNOS), and inducible NO synthase (iNOS). NO originated from nNOS exerts a neurotoxic action, while NO from eNOS exhibits a vasodilative effect and is employed in the protective actions against neurotoxicity [13]. Recent studies suggest that the neurotoxic action of NO is also relevant to the pathogenesis of neurodegenerative diseases, such as Alzheimer disease [9], Parkinson disease [5], [6], and prion disease [4]. In addition, NO is thought to accelerate ischemic brain damage [3].
(−)-Epigallocatechin gallate (EGCG) is the major component of polyphenol in green tea. EGCG is shown to inhibit the growth and metastasis of malignant tumor [8], to protect against ischemic brain damage [10], and to decrease the risk of cardiovascular disease [12]. Little, however, is known about the mechanism underlying the protective action against ischemic brain damage. To understand this, we monitored real-time NO mobilizations in the intact rat hippocampus by using an NO sensitive microsensor and assayed cell viability with the dye, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The results of the present study suggest that EGCG reduces NO3−/NO2− conversion from NO, which is produced after ischemia, thereby protecting against ischemic neuronal damage.
Section snippets
Materials and methods
An ischemic model was made using adult Wistar rats by the method previously described [7]. Briefly, bilateral common carotid arteries and vertebral arteries, with the head being fixed with a stereotactic frame, were occluded for 10 min by ligation, and subsequently the occlusion was released. During experiments, rats were under general anesthesia with urethane (1.2 g/kg i.p.), with ventilation controlled with an artificial respirator and rectal temperature maintained at 37–38 °C with a heating
Results
For saline-injected rats, NO currents decreased during ischemia, but the ensuing reperfusion caused an increase in the currents, with a maximum of 2232±169 pA (∼268±20 μM) (Fig. 1A,B). Pre-treatment with EGCG (50 mg/kg i.p.) reduced the increase by 77% (524±113 pA, ∼63±14 μM) without affecting basal NO currents before or without ischemia (Fig. 1A,B), suggesting that EGCG inhibits NO synthesis or reduces NO3−/NO2− production from NO. Hippocampal blood flow transiently elevated after ischemia,
Discussion
NO radical or hydroxy radical from NO as well as other free radicals is well-recognized to perturb cells. We found earlier that brain ischemia causes a rise in NO (NO3−/NO2−) concentrations and that NO originated from nNOS, but not eNOS, exhibits a neurotoxic effect in the intact rat hippocampus [7]. In the present study, EGCG drastically attenuates a rise in hippocampal NO3−/NO2− concentrations after ischemia without affecting hippocampal blood flow. This raises the possibility that EGCG is
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