Taurine demonstrates multiple cellular functions including a central role as a neurotransmitter, as a trophic factor in CNS development, in maintaining the structural integrity of the membrane, in regulating calcium transport and homeostasis, as an osmolyte, as a neuromodulator and as a neuroprotectant. The neurotransmitter properties of taurine are illustrated by its ability to elicit neuronal hyperpolarization, the presence of specific taurine synthesizing enzyme and receptors in the CNS and the presence of a taurine transporter system. Taurine exerts its neuroprotective functions against the glutamate induced excitotoxicity by reducing the glutamate-induced increase of intracellular calcium level, by shifting the ratio of Bcl-2 and Bad ratio in favor of cell survival and by reducing the ER stress. The presence of metabotropic taurine receptors which are negatively coupled to phospholipase C (PLC) signaling pathway through inhibitory G proteins is proposed, and the evidence supporting this notion is also presented.

In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.

1 The 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription-polymerase chain reaction (RT ± PCR). 2 The agonists 5-HT, 5-carboxamidotryptamine (5-CT, unselective for 5-HT 1 receptors) and sumatriptan (selective for 5-HT 1B/D receptors) all caused contraction and were equipotent (pEC 50 s: 7.0+0.2, 7.1+0.3 and 6.7+0.1, respectively) suggesting the presence of a 5-HT 1 receptor. 3 Ketanserin (5-HT 2A -selective antagonist, 0.1 mM) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (40.1 mM) whilst GR55562 (5-HT 1B/1D -selective antagonist, 1 mM) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pK B =7.7+0.2). SB-224289 (5-HT 1B -selective antagonist, 0.2 mM) inhibited sumatriptaninduced contractions (estimated pK B =8.4+0.1) whilst these were una ected by the 5-HT 1D -selective antagonist BRL15572 (0.5 mM) suggesting that the 5-HT 1B receptor mediates vasoconstriction in this vessel. 4 RT ± PCR con®rmed the presence of substantial amounts of mRNA for the 5-HT 2A and 5-HT 1B receptor subtypes in these arteries whilst only trace amounts of 5-HT 1D receptor message were evident. 5 These ®ndings suggest that a heterogeneous population of 5-HT 2A and 5-HT 1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT 1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-HT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT 1B receptor may provide a novel and potentially important therapeutic target.

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Redox-sensitive cysteine residues are present in the interaction domains of many protein complexes. There are examples in all of the major categories of transcription factors, including basic region, leucine zipper, helix-loop-helix, and zinc finger. Zinc finger structures require at least two zinc-coordinated cysteine sulfhydryl groups, and oxidation or alkylation of these can eliminate DNA-binding and transcriptional functions. We review here the evidence for oxidation of zinc finger cysteines, the pathways and reactive oxygen intermediates involved, and the functional and physiological consequences of these reactions. Despite skepticism that the strongly reducing intracellular environment would permit significant oxidation of cysteine residues within zinc finger transcription factors, there is compelling evidence that oxidation occurs both in vitro and in vivo. Early reports demonstrating reversible oxidation of zinc-coordinated cysteines with loss of binding function in vitro were shown to reflect accurately the changes in intact cells, and these in turn have been shown to correlate with physiological changes. In particular, the accumulation of oxidized Spl zinc fingers during aging, and estrogen receptors in tamoxifen-resistant breast cancers are dramatic examples of what may be a general sensitivity of zinc finger factors to changes in the redox state of the cell.

Reperfusion injury occurs when ischaemic tissue is reperfused. It involves the generation and release of reactive oxygen that activates numerous signalling pathways and initiates cell death. Exposure of isolated cardiac myocytes to chronic hypoxia followed by reoxygenation results in the early activation of c-Jun N-terminal kinase (JNK) and death by apoptosis of approx. 30% of the myocytes. Although JNK activation has been described in a number of models of ischaemia/reperfusion, the contribution of JNK activation to cell fate has not been established. Here we report that the activation of JNK by reoxygenation correlates with myocyte survival. Transfection of myocytes with JNK pathway interfering plasmid vectors or infection with adenoviral vectors support the hypothesis that JNK is protective. Transfection or infection with JNK inhibitory mutants increased the rates of apoptosis by almost 2-fold compared with control cultures grown aerobically or subjected to hypoxia and reoxygenation. Caspase 9 activity, measured by LEHD cleavage, increased > 3-fold during reoxygenation and this activity was enhanced significantly at all times in cultures infected with dominant negative JNK adenovirus. Hypoxia—reoxygenation mediated a biphasic (2.6- and 2.9-fold) activation of p38 mitogen-activated protein kinase, as well as a small increase of tumour necrosis factor α (TNFα) secretion, but treatments with the p38 MAPK-specific inhibitor SB203580 or saturating levels of a TNFα-1 blocking antibody provided only partial protection against apoptosis. The results suggest that JNK activation is protective and that the pathway is largely independent of p38 MAPK or secreted TNFα.

In the present era, investigators seek to find therapeutic interventions that are multifaceted in their mode of action. Such targets provide the most advantageous routes for addressing the multiplicity of pathophysiological avenues that lead to neuronal dysfunction and death observed in neurological disorders and neurodegenerative diseases. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions in the central nervous system. In this review, we describe the mode of action of taurine and its clinical application in the neurological diseases: Alzheimer's disease, Parkinson's disease and Huntington's disease.

Previously, we showed that taurine protects neurons against glutamate-induced excitotoxicity by inhibiting the glutamate-induced increase of [Ca2+](i). In this study, we report that taurine prevents glutamate-induced chromosomal condensation, indicating that taurine inhibits glutamate-induced apoptosis. We found that Bcl-2 was down-regulated while Bax was up-regulated by glutamate treatment, and these changes were prevented in the presence of taurine. We have also shown that taurine inhibits glutamate-induced activation of calpain. Furthermore, calpastatin, a specific calpain inhibitor, also prevented glutamate-induced cell death. Here we propose the mechanisms underlying glutamate-induced apoptosis and taurine's inhibition of glutamate-induced apoptosis to be as follows: glutamate stimulation induces [Ca2+](i) elevation, which in turn activates calpain; activation of calpain leads to a reduction of Bcl-2:Bax ratios; with decreased Bcl-2:Bax ratios Bax homodimers form, Bax homodimerization, and translocation to the mitochondria result in the release of cytochrome c; released cytochrome c in turn activates a downstream caspase cascade leading to apoptosis. The antiapoptotic function of taurine is due to its inhibition of glutamate-induced membrane depolarization.