Neuroprotective effect of taurine against focal cerebral ischemia in rats possibly mediated by activation of both GABAA and glycine receptors
Introduction
Ischemic cerebral stroke is one of the leading causes of human death and disability across the world. If patients are able to survive the acute phase of cerebral infarction, they may encounter significant mental, physical, and economic stresses following neurological impairment. It is obvious that even a mild stroke could induce inevitable adverse consequences on each individual, their family and society due to the different extent of impairment of their daily life ability and vocational capacity. Up to now, treatment of ischemic cerebral stroke remains unsatisfactory (Cheng et al., 2004). In contrast to thrombolytics, neuroprotective agents, which have been proved promising in animal stroke experiments, have provided disappointing results in all clinical human trials (Jonas et al., 2001, Gladstone et al., 2002, Curry, 2003, Cheng et al., 2004). In fact, those neuroprotective agents in clinical trials of stroke intervention failed to produce beneficial results because their actions were too weak, or their application was too late as predicted from the animal models, i.e., “too little and too late” as pointed out by Jonas et al. (2001). However, the recent success of a trial of “FAST-MAG” therapy (Saver et al., 2004) fueled our interests in developing new neuroprotective therapies for cerebral stroke management.
Taurine, a β-amino acid, presents in high concentrations in the mammalian central nervous system (CNS) (Huxtable, 1989). It is believed to be involved in osmoregulation and cell volume adjustments (Huxtable, 1992, Hussy et al., 1997). Growing evidences suggest that taurine may function as a potent candidate of inhibitory neurotransmitter or modulator to regulate neuronal activity in many cerebral areas (Haas and Hosli, 1973, Huxtable, 1989, Hussy et al., 1997, Jiang et al., 2004). As an inhibitory amino acid in the CNS, taurine could activate glycine receptors (GlyRs) or γ-aminobutyric acid receptors (GABAR), showing the characteristics of a partial or full agonist of strychnine-sensitive GlyR and/or GABAAR (Haas and Hosli, 1973, Horikoshi et al., 1988, Hussy et al., 1997, Mori et al., 2002, Jiang et al., 2004). In adult individuals, activation of these two receptors will induce an inward Cl− movement and neuronal hyperpolarization, thus reducing neuronal excitability. Such activation can be used to antagonize cytotoxic effect of glutamate by counteracting neuronal depolarization and subsequent cascade of biochemical events that result in cell death during cerebral stroke (Green et al., 2000, Schwartz-Bloom and Sah, 2001).
Although controversy remains (Vaishnav and Lutsep, 2002, Lazar et al., 2003), several agents that could potentiate GABAergic synaptic neurotransmission have shown neuroprotective efficacy in acute cerebral ischemia (Green, 1998, Aerden et al., 2004). Moreover, in the recent two decades, taurine was proved protective on neurons which were exposed to many cell-damaging conditions (Kearns and Dawson, 2000, O'Byrne and Tipton, 2000, Saransaari and Oja, 2000, Louzada et al., 2004), including oxidants (such as hypochlorous acid and 1-methyl-4-phenylpyridinium), excitatory amino acids, hypoxia, and ischemic insults.
Whether the neuroprotective effect of taurine is mediated through GABAR or GlyR remains uncertain. Studies reported so far, however, investigated mostly the prophylactic effects of taurine treatment on many cell-damaging conditions, little information is available concerning its possible therapeutic efficacy in acute cerebral stroke. Hence, in the present study, we compared the neuroprotective efficacy of taurine treatments before and after a temporary occlusion of the middle cerebral artery (MCA) in rats and observed the blunting effects of GABAR and GlyR antagonists.
Section snippets
Animals and MCAO surgery
Male Sprague–Dawley rats (250–280 g body wt) were offered by the Experimental Animal Center of Nantong University, Nantong, China. All procedures used in this study were in accordance with our institutional guidelines, which comply with international rules and policies. Rats were anesthetized using 2 ml enflurane in an ether jar, and maintained with 10% chloral hydrate (400 mg kg−1, i.p.). The MCA was occluded with a 4-0 silicone-coated nylon suture by surgical operation in terms of report by
Comparison of the effects of taurine pretreatment and post-treatment
Neurology deficit score was measured at 3 h and 26 h after MCAO, and was inhibited at both time points when taurine was used (Fig. 1A). Meanwhile, cerebral infarct volume was also reduced in both pre- and post-treatment groups (Fig. 1B and C). Taurine pre-treated before MCAO operation significantly decreased the neurology deficit score and infarct volume, and post-treatment of taurine displayed similar effects, with taurine pretreatment superior to post-treatment in both indices (P < 0.05). In a
Discussion
Using TTC staining and MRI in the present study, we proved that post-treatment of taurine after temporal MCAO could decrease cerebral damage volume, though this effect was not as strong as that of taurine pretreatment. Meanwhile, taurine post-treatment reduced neurology score and brain water content. It is suggested that post-treatment of taurine could exert a neuroprotective effect on the brain subjected to ischemia/reperfusion. Moreover, according to the observation of the dose-dependent
Acknowledgements
This study was supported by grants from the Administration of Science and Technology of Nantong (Project No. S30018), and the Administration of Education of Jiangsu (Project No. 2005-76), Jiangsu Province, China.
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