Mechanism of taurine as a neuroprotector

Taurine is one of the most abundant amino acids in mammals and several functions of taurine have been reported. One important function of taurine is its neuroprotection against the glutamate-induced neuronal damage. It was shown that the glutamate-induced neurotoxicity is caused by overexcitation of glutamate receptors and intracellular calcium, [Ca2+]i, elevation. In this dissertation, the mechanism underlying the action of taurine as a neuroprotector was investigated. It was found that taurine protected neurons against glutamate or Bay K 8644-induced neurotoxicity only at the concentration that inhibits the calcium influx induced by those two compounds. Furthermore, taurine couldn't protect neurons against sodium nitroprusside, a NO free radical donor, induced neurotoxicity. These results indicate that taurine exerts its neuroprotection by reducing the glutamate-induced [Ca2+]i elevation. Besides necrosis, apoptosis is another major way that glutamate induces neuronal cell death. The effect of taurine on the glutamate-induced apoptosis was investigated. It was found that taurine prevented the glutamate-induced DNA fragmentation, indicating taurine prevents the glutamate-induced apoptosis. We found that anti-apoptotic proteins (BCL-2 and BCL-X) were down-regulated by glutamate treatment and this down-regulation was prevented by taurine. No difference in pro-apoptotic proteins (BAX and BAD) was found. It was found that the down-regulation of BCL-2 and BCL-X was through calpain-mediated proteolysis, and taurine may exert its anti-apoptotic function by preventing the activation of calpain, which is due to the prevention of [Ca2+]i elevation. Furthermore, it was found that pre-treatment with taurine inhibited the glutamate-induced calcium influx through L-, P/Q-, N-type voltage-gated calcium channels and NMDA receptor. Surprisingly, taurine had no effect on calcium influx through the NMDA receptor when neurons were treated with NMDA in Mg 2+-free medium. The effect of taurine is unlikely through GABA A, or glycine receptors, since bicuculline and picrotoxin (GABA A receptor antagonists), and strychnine (glycine receptor antagonist), failed to block taurine's inhibitory effect on the glutamate-induced calcium influx. Since taurine was found to prevent the glutamate-induced membrane depolarization, we propose that taurine protects neurons against the glutamate excitotoxicity by preventing the glutamate-induced membrane depolarization, probably through the opening of chloride channels, therefore preventing the glutamate-induced calcium influx and the downstream events.