Herminia Pasantes-Morales

Taurine and hypotaurine inhibit light-induced lipid peroxidation and protect rod outer segment structure

Exposure of isolated frog rod outer segments to light (5000 lux) induces membrane disorganization and swelling. An increase of about 50% on lipid peroxidation, measured by the extent of malonaldehyde formation, accompanied the light-induced damage. Taurine and hypotaurine (25 mM) prevented the increase in lipid peroxidation, and provided an entire protection of rod outer segment structure.

Contribution of organic and inorganic osmolytes to volume regulation in rat brain cells in culture

In this work we examined the time course and the amount released, by hyposmolarity, for the most abundant free amino acids (FAA) in rat brain cortex astrocytes and neurons in culture. The aim was to evaluate their contribution to the process of cell volume regulation. Taurine, glutamate, andd-aspartate in the two types of cells, β-alanine in astrocytes and GABA in neurons were promptly released by hyposmolarity, reaching a maximum within 1–2 min. after an osmolarity change. A substantial amount of the intracellular pool of these amino acids was mobilized in response to hyposmolarity. The amount released in media with osmolarity reduced from 300 mOsm to 150 mOsm or 210 mOsm, represented 50%–65% and 13%–31%, respectively, of the total amino acid content in cells. In both astrocytes and neurons, the efflux of glutamine and alanine was higher under isosmotic conditions and increased only marginally during hyposmotic conditions.86Rb+, used as tracer for K+, was released from astrocytes, 30% and 11%, respectively, in hyposmotic media of 150 mOsm or 210 mOsm but was not transported in neurons. From these results it was calculated that FAA contribute 54% and inorganic ions 46% to the process of volume regulation in astrocytes exposed to a 150 mOsm hyposmotic medium. This contribution was 55% for FAA and 45% for K+ and Cl− in cells exposed to 210 mOsm hyposmotic solutions. These results indicate that the contribution of FAA to the process of cell volume regulation is higher in astrocytes than in other cell types including renal and blood cells.

Amino Acid Osmolytes in Regulatory Volume Decrease and Isovolumetric Regulation in Brain Cells: Contribution and Mechanisms

Brain adaptation to hyposmolarity is accomplished by loss of both electrolytes and organic osmolytes, including amino acids, polyalcohols and methylamines. In brain in vivo, the organic osmolytes account for about 35% of the total solute loss. This review focus on the role of amino acids in cell volume regulation, in conditions of sudden hyposmosis, when cells respond by active regulatory volume decrease (RVD) or after gradual exposure to hyposmotic solutions, a condition where cell volume remains unchanged, named isovolumetric regulation (IVR). The amino acid efflux pathway during RVD is passive and is similar in many respects to the volume-activated anion pathway. The molecular identity of this pathway is still unknown, but the anion exchanger and the phospholemman are good candidates in certain cells. The activation trigger of the osmosensitive amino acid pathway is unclear, but intracellular ionic strength seems to be critically involved. Tyrosine protein kinases markedly influence amino acid efflux during RVD and may play an important role in the transduction signaling cascades for osmosensitive amino acid fluxes. During IVR, amino acids, particularly taurine are promptly released with an efflux threshold markedly lower than that of K+, emphasizing their contribution (possibly as well as of other organic osmolytes) vs inorganic ions, in the osmolarity range corresponding to physiopathological conditions. Amino acid efflux also occurs in response to isosmotic swelling as that associated with ischemia or trauma. Characterization of the pathway involved in this type of swelling is hampered by the fact that most osmolyte amino acids are also neuroactive amino acids and may be released in response to stimuli concurrent with swelling, such as depolarization or intracellular Ca++ elevation.

Volume regulation in brain cells: Cellular and molecular mechanisms

The dis e volume of each cell type is continuously challenged by the osmotic gradient imposed by the presence of nondiffusible ions within the cell . This long term regulation of cell volume requires the concerted action of a number of active transport systems to keep a balance with the leak fluxes . Details of the underlying control mechanisms and the connections between the different transport pathways are still unclear . It is also largely unknown how the cell measures its own volume and adjusts its volume set-point. Yet, the steady-state maintenance of cell volume is critical for survival and normal cell functioning (Macknight, 1988) . Besides the requirement of a stable cell volume to keep constant the concentration of intracellular solutes, many of which are part of complex signaling events, cell volume is now proposed to directly participate as a messenger for metabolic control, as signal for growth and proliferation and as trigger for mechanisms initiating insertion of membrane proteins, channels, receptors and transporters . In brain, cell swelling may represent an important component of the hyperexcitability cascade, because reduction of the extracellular space due to astrocyte swelling caused by neuronal firing promotes neuronal excitation through field effects (Saly and Andrew, 1993) . It has been recently reported that preventing shrinkage of the extracellular space by decreasing glial swelling with furosemide dissociates the neuronal synchronization involved in epileptiform activity (Hochman et al., 1995) .

Role of taurine in osmoregulation in brain cells: Mechanisms and functional implications

SummaryAll cells including neurons and glial cells are able to keep their volume within a very limited range. The volume regulatory mechanism involves changes in the concentration of osmolytes of which taurine appears to be of particular importance in brain cells. Swelling in brain cells may occur as a result of depolarization or small fluctuations in osmolarity. In isolated brain cells these conditions will always lead to a release of taurine, the time course of which is superimposable on that of the volume regulatory decrease which follows the initial cell swelling. The mechanism responsible for taurine release associated with swelling has not been fully elucidated but a large body of evidence seems to exclude participation of the taurme high affinity carrier. Using a number of inhibitors of anion exchangers it has been demonstrated that both volume regulation and taurine release in brain cells are inhibited by these drugs, implicating an anion channel in the process. It has be controversial issue as to whether or not taurine release is Ca++ dependent. Recent evidence appears to suggest that the release process is not associated with Ca++ or Ca++ channels. It is, however, quite possible that the swelling process may involve the Ca++ calmodulin system or other second messengers. Taurine also contributes to volume regulation after shrinkage of brain cells, in this case by increasing its intracellular concentration. This change is accomplished byan upregulation of the Na+/taurine cotransporter, together with reduced passive fluxes and increased endogenous synthesis.

Taurine: An Osmolyte in Mammalian Tissues

One of the distinctive features of taurine is its presence at high levels in most animal tissues5,3. Although differences exist among cells and species, taurine is consistently found in mM concentrations. It is noteworthy that excitable tissues including brain, striatal muscle and heart contain large, inert, and intracellular taurine pools3,9. The most prominent example in this respect is the retina. In all species so far examined, retinal taurine levels exceed 20 mM and in some species its concentration is as high as 60 mM39. In addition to these high levels, taurine in excitable tissues has a very slow turnover rate. In rat organs, values for taurine turnover rate fit into three main groups: those with a relatively fast rate calculated in less than 1 day and include liver, kidney and pancreas; a second group, with a medium rate of about 2–3 days comprises lung, spleen, intestine, testes, bone marrow and the third group, with the slowest rate of more than 3 days and up to 7 days, is represented by brain, heart and muscle30;.

Brain volume regulation: osmolytes and aquaporin perspectives

Cerebral water control is critical to maintain neuronal excitability, and to prevent injuries derived from brain swelling or shrinkage. The influence of aquaporins (AQPs) in the balance of water distribution between intracranial compartments is getting much experimental support. The importance of AQPs in fluid clearance during vasogenic brain edema seems well established but their role in cytotoxic swelling and in brain cell shrinkage is not known in detail. The main AQPs function as water channels anticipates their influence on cell volume changes as well as on the mechanisms of volume recovery, which include notably the osmolyte translocation across the cell membrane. Osmolyte fluxes permit the reestablishment of an osmotic balance and volume recovery in anisosmotic-elicited cell volume changes, but are also causal factors per se of brain cell swelling or shrinkage in pathological situations. This review aims to inform on the so far described functional interactions between AQPs and osmolyte fluxes and their volume-sensitive pathways. It also points to the coincidence of AQPs and activation of osmolyte fluxes in physiological and pathological conditions and to the importance of finding possible functional links between these two events, thus enlarging the possibilities via AQP manipulations, to prevent the adverse consequences of cell volume changes in brain.

Signaling Events during Swelling and Regulatory Volume Decrease

Brain cell swelling compromises neuronal function and survival by the risk of generation of ischemia episodes as compression of small vessels occurs due to the limits to expansion imposed by the rigid skull. External osmolarity reductions or intracellular accumulation of osmotically active solutes result in cell swelling which can be counteracted by extrusion of osmolytes through specific efflux pathways. Characterization of these pathways has received considerable attention, and there is now interest in the understanding of the intracellular signaling events involved in their activation and regulation. Calcium and calmodulin, phosphoinositides and cAMP may act as second messengers, carrying the information about a cell volume change into signaling enzymes. Small GTPases, protein tyrosine kinases and phospholipases, also appear to be part of the signaling cascades ultimately modulating the osmolyte efflux pathways. This review focus on i) the influence of hyposmotic and isosmotic swelling on these signaling events and molecules and ii) the effects of manipulating their function on the osmolyte fluxes, particularly K+, CI− and amino acids, and on the consequent efficiency of cell volume adjustment.

Treatment with Taurine, Diltiazem, and Vitamin E Retards the Progressive Visual Field Reduction in Retinitis Pigmentosa: A 3-Year Follow-Up Study

The purpose of this study to assess the effect of the formula taurine/diltiazem/vitamin E on the progression of visual field loss in retinitis pigmentosa. A double blind, placebo controlled study in 62 patients: visual field threshold values were obtained in a Humphrey Field Analyzer from center (30°) and periphery (30–60°), every 4 months during 3-year follow-up. Data were analyzed by univariate regression, with slopes obtained from the best fit lines. Based on slope values, three groups of patients were identified as those showing negative, positive, or zero slope: ≥-1 to ≤ + 1. In controls (32 patients), at central area, the distribution in negative, zero, or positive slope was, respectively, 16 (50%),11 (35%), and 5 (15%). In the treated group (30 patients) this distribution was 6 (20%) negative, 17 (53%) zero, and 7 (23%) positive slope. In periphery, 16 control patients were distributed as 11 (69%) negative, 4 (25%) zero, and 1 (6%) positive slope. In the treated group (17 patients), the distribution was opposite: 1 (6%) negative, 7 (41%) zero, and 9 (53%) positive slope. Nineteen patients receiving treatment up to 6 years showed similar distribution by slope values. Eight out of 9 patients switched from placebo (2 years) to treatment (2–3 years), showed improving changes in their slope values. A beneficial effect of the treatment decreasing the rate of visual field loss was observed, likely through a protective action from free radical reactions in affected photoreceptors.

Mechanisms Counteracting Swelling in Brain Cells During Hyponatremia

Water gain in the brain consequent to hyponatremia is counteracted by mechanisms that initially include a compensatory displacement of liquid from the interstitial space to cerebrospinal fluid and systemic circulation and subsequently an active reduction in cell water accomplished by extrusion of intracellular osmolytes to reach osmotic equilibrium. Potassium (K+), chloride (Cl-), amino acids, polyalcohols, and methylamines all contribute to volume regulation, with a major contribution of ions at the early phase and of organic osmolytes at the late phase of the regulatory process. Experimental models in vitro show that osmolyte fluxes occur via leak pathways for organic osmolytes and separate channels for Cl- and K+. Osmotransduction signaling cascades for Cl- and taurine efflux pathways involve tyrosine kinases and phosphoinositide kinases, while Ca2+ and serine-threonine kinases modulate K+ pathways. In-depth knowledge of the cellular and molecular adaptive mechanisms of brain cells during hyponatremia contributes to a better understanding of the associated complications, including the risks of inappropriate correction of the hyponatremic condition.