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V Adam-Vizi

Publications and source records attributed to V Adam-Vizi.

At least 19 recordsLinked to original sources
PubMed2001

Analysis of high intracellular [Na+]-induced release of [3H]noradrenaline in rat hippocampal slices.

Our aim was to investigate the mechanisms involved in the high intracellular sodium-induced transmitter release in the CNS through the characterisation of the veratridine-evoked (40 microM) noradrenaline release from rat hippocampal slices. The response to veratridine was completely inhibited by tetrodotoxin (1 microM), indicating that the effect is due to the activation of sodium channels. Omission of Ca2+ from the superfusion fluid inhibited the veratridine-evoked release by 72%, showing that the majority of release results from external Ca2+-dependent exocytosis. The residual Ca2+-independent release was not blocked by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester (100 microM) suggesting that intracellular Ca2+ stores are not involved in this component of veratridine effect. The noradrenaline uptake blockers, desipramine (10 microM) and nisoxetine (10 microM), inhibited the external Ca2+-independent release by 50 and 46%, respectively, indicating that the release partly originates from the reversal of transporters (carrier-mediated release). In contrast to uptake blockers, lowering the temperature, another possibility to inhibit transporter function, completely inhibited the effect of veratridine in the absence of Ca2+. Further experiments revealed that low temperature (20 and 12 degrees C) reduces the veratridine-induced increase of intracellular sodium concentration ([Na+]i) in rat cortical synaptosomes (68 and 78% inhibition, respectively). The clinical relevance of our data is that during ischemia a massive release of transmitters occurs mainly due to the elevation of [Na+]i, which contributes to the development of ischemic brain injury. Our results show that low temperature may be a better therapeutic approach to the treatment of ischemia because it has a dual action on this process. Firstly, it inhibits the function of uptake transporters and hence reduces the carrier-mediated outflow of transmitters. Secondly, it inhibits the sodium influx and therefore prevents the unwanted elevation of [Na+]i. Our data also suggest that veratridine stimulation can be a suitable model for ischemic conditions.

Adrenergic Uptake Inhibitors↗
PubMed2001

Mitochondria deficient in complex I activity are depolarized by hydrogen peroxide in nerve terminals: relevance to Parkinson's disease.

Deficiency of complex I in the respiratory chain and oxidative stress induced by hydrogen peroxide occur simultaneously in dopaminergic neurones in Parkinson's disease. Here we demonstrate that the membrane potential of in situ mitochondria (Delta Psi m), as measured by the fluorescence change of JC-l (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbezimidazolyl-carbocyani ne iodide), collapses when isolated nerve terminals are exposed to hydrogen peroxide (H(2)O(2), 100 and 500 microM) in combination with the inhibition of complex I by rotenone (5 nM-1 microM). H(2)O(2) reduced the activity of complex I by 17%, and the effect of H(2)O(2) and rotenone on the enzyme was found to be additive. A decrease in Delta Psi m induced by H(2)O(2) was significant when the activity of complex I was reduced to a similar extent as found in Parkinson's disease (26%). The loss of Delta Psi m observed in the combined presence of complex I deficiency and H(2)O(2) indicates that when complex I is partially inhibited, mitochondria in nerve terminals become more vulnerable to H(2)O(2)-induced oxidative stress. This mechanism could be crucial in the development of bioenergetic failure in Parkinson's disease.

Animals↗
PubMed2001

Selective, high-resolution fluorescence imaging of mitochondrial Ca2+ concentration.

We have developed a digital image processing technique based on highpass filtering of microfluorimetric images for selective transmission of fine image details corresponding to mitochondria. This technique enabled the detection of the mitochondrial calcium signals with high selectivity, simultaneously with the cytosolic calcium signal. The validity of this technique was supported in primary cultures of rat brain capillary endothelial cells loaded with X-rhod-1 by the results that (i) inhibition of the mitochondrial Ca2+ uptake by discharging the mitochondrial membrane potential selectively abolished the transient of the highpass filtered signal evoked by ATP, and (ii) CGP-37157, a selective blocker of the mitochondrial Na+/Ca2+ exchanger, increased the peak amplitude of highpass filtered (mitochondrial) Ca2+ transients and caused a sustained plateau. The highpass filtering technique enabled the analysis of the mitochondrial Ca2+ transients in high temporal resolution. We found a uniform and monophasic rise of [Ca2+] in the mitochondrial population of the cell, following the cytosolic [Ca2+] with a delay at onset and peak. The introduced highpass filtering technique is a powerful tool in the high spatial and temporal resolution analysis of mitochondrial calcium transients, and it could be especially important in specimens where genetically targeted probes fail.

Adenosine Triphosphate↗
PubMed2000

Inhibition of Krebs cycle enzymes by hydrogen peroxide: A key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress.

In this study we addressed the function of the Krebs cycle to determine which enzyme(s) limits the availability of reduced nicotinamide adenine dinucleotide (NADH) for the respiratory chain under H(2)O(2)-induced oxidative stress, in intact isolated nerve terminals. The enzyme that was most vulnerable to inhibition by H(2)O(2) proved to be aconitase, being completely blocked at 50 microm H(2)O(2). alpha-Ketoglutarate dehydrogenase (alpha-KGDH) was also inhibited but only at higher H(2)O(2) concentrations (>/=100 microm), and only partial inactivation was achieved. The rotenone-induced increase in reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] fluorescence reflecting the amount of NADH available for the respiratory chain was also diminished by H(2)O(2), and the effect exerted at small concentrations (</=50 microm) of the oxidant was completely prevented by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU-insensitive decline by H(2)O(2) in the rotenone-induced NAD(P)H fluorescence correlated with inhibition of alpha-ketoglutarate dehydrogenase. Decrease in the glutamate content of nerve terminals was induced by H(2)O(2) at concentrations inhibiting aconitase. It is concluded that (1) aconitase is the most sensitive enzyme in the Krebs cycle to inhibition by H(2)O(2), (2) at small H(2)O(2) concentrations (</=50 microm) when aconitase is inactivated, glutamate fuels the Krebs cycle and NADH generation is unaltered, (3) at higher H(2)O(2) concentrations (>/=100 microm) inhibition of alpha-ketoglutarate dehydrogenase limits the amount of NADH available for the respiratory chain, and (4) increased consumption of NADPH makes a contribution to the H(2)O(2)-induced decrease in the amount of reduced pyridine nucleotides. These results emphasize the importance of alpha-KGDH in impaired mitochondrial function under oxidative stress, with implications for neurodegenerative diseases and cell damage induced by ischemia/reperfusion.

Aconitate Hydratase↗
PubMed2000

Exacerbated responses to oxidative stress by an Na(+) load in isolated nerve terminals: the role of ATP depletion and rise of [Ca(2+)](i).

We have explored the consequences of a [Na(+)](i) load and oxidative stress in isolated nerve terminals. The Na(+) load was achieved by veratridine (5-40 microM), which allows Na(+) entry via a voltage-operated Na(+) channel, and oxidative stress was induced by hydrogen peroxide (0.1-0.5 mM). Remarkably, neither the [Na(+)](i) load nor exposure to H(2)O(2) had any major effect on [Ca(2+)](i), mitochondrial membrane potential (Deltapsim), or ATP level. However, the combination of an Na(+) load and oxidative stress caused ATP depletion, a collapse of Deltapsim, and a progressive deregulation of [Ca(2+)](i) and [Na(+)](i) homeostasis. The decrease in the ATP level was unrelated to an increase in [Ca(2+)](i) and paralleled the rise in [Na(+)](i). The loss of Deltapsim was prevented in the absence of Ca(2+) but unaltered in the presence of cyclosporin A. We conclude that the increased ATP consumption by the Na,K-ATPase that results from a modest [Na(+)](i) load places an additional demand on mitochondria metabolically compromised by an oxidative stress, which are unable to produce a sufficient amount of ATP to fuel the ATP-driven ion pumps. This results in a deregulation of [Na(+)](i) and [Ca(2+)](i), and as a result of the latter, collapse of Deltapsim. The vicious cycle generated in the combined presence of Na(+) load and oxidative stress could be an important factor in the neuronal injury produced by ischemia or excitotoxicity, in which the oxidative insult is superimposed on a disturbed Na(+) homeostasis.

Adenosine Triphosphate↗
PubMed2000

Reversible depolarization of in situ mitochondria by oxidative stress parallels a decrease in NAD(P)H level in nerve terminals.

We have reported recently (Chinopoulos et al., 1999 J. Neurochem. 73, 220 228) that mitochondrial membrane potential (delta(psi)m) in isolated nerve terminals is markedly reduced by H2O2 in the absence of F0F1-ATPase working as a proton pump. Here we demonstrate that delta(psi)m reduced by H2O2 (0.5 mM) in the presence of oligomycin (10 mM), an inhibitor of the F0F1-ATPase, was able to recover by the addition of catalase (2000 U). Similarly, a decrease in the NAD(P)H level due to H2O2 can be reversed by catalase. In addition, H2O2 decreased the ATP level and the [ATP]:[ADP] ratio measured in the presence of oligomycin reflecting an inhibition of glycolysis by H2O2, but this effect was not reversible. The effect of H2O2 on delta(psi)m in the presence of the complex I inhibitor, rotenone, was also unaltered by addition of catalase. These results provide circumstantial evidence for a relationship between the decreased NAD(P)H level and the inability of mitochondria to maintain delta(psi)m during oxidative stress.

Animals↗
PubMed2000

Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.

Animals↗
PubMed2000

The pharmacology of nucleotide receptors on primary rat brain endothelial cells grown on a biological extracellular matrix: effects on intracellular calcium concentration.

1. Brain capillary endothelial cells express a variety of nucleotide receptors, but differences have been reported between culture models. This study reports examination of nucleotide receptors on primary cultured rat brain capillary endothelial cells (RBCEC) grown on a biological extracellular matrix (ECM) to produce a more differentiated phenotype. 2. Fura-2 fluorescence ratio imaging was used to monitor intracellular free calcium concentration [Ca(2+)](i). ATP, UTP, and 2-methylthioATP (2-MeSATP) increased [Ca(2+)](i) to similar levels, while 2-MeSADP, ADP and adenosine gave smaller responses. 3. Removal of extracellular calcium caused no significant change in the [Ca(2+)](i) response to 2-MeSATP, evidence that the response was mediated by a metabotropic (P2Y) receptor. 4. All cells tested responded to ATP, UTP, 2-MeSATP and ADP, while 63% responded to adenosine and 50% to 2-MeSADP. No cells responded to alpha, beta-methyleneATP. Cells grown on rat tail collagen instead of ECM gave smaller and less uniform [Ca(2+)](i) responses, suggesting that the differentiating effect of the ECM contributed to a more uniform receptor profile. 5. The [Ca(2+)](i) response to the P2Y(1)-selective agonist 2-MeSADP was abolished in the presence of the subtype-selective antagonist adenosine 3'-phosphate 5'-phosphosulphate (PAPS). 6. The P2Y(2) antagonist suramin completely blocked the response to ATP and inhibited the response to UTP by 66%. 7. The A(1) subtype-selective adenosine receptor agonist N(6)-Cyclopentyladenosine (CPA) gave a small but characteristic [Ca(2+)](i) response, while A(2A) and A(2B) subtype-selective agonists failed to generate [Ca(2+)](i) changes. 8. The results are consistent with the presence on RBCEC of a P2Y(2)-like receptor coupled to phospholipase C, and a P2Y(1)-like receptor mobilizing intracellular Ca(2+). The role of multiple nucleotide receptors in the function of the brain endothelium is discussed.

Adenosine Triphosphate↗
PubMed2000

Identification of thrombin receptors in rat brain capillary endothelial cells.

Both thrombin and plasmin induce contraction of brain endothelial cells, which may increase capillary permeability thereby leading to disruption of the blood-brain barrier. Identification of thrombin receptors, as well as the influence of plasmin on their activation, in capillary endothelial cells and astrocytes are therefore essential for understanding injury-related actions of thrombin in the brain. Using the reverse transcriptase-polymerase chain reaction method, the present study shows that primary cultures of rat brain capillary endothelial (RBCE) cells and astrocytes derived from rat brain express two different thrombin receptors. The first is proteolytically activated receptor (PAR)-1, the receptor responsible for the vast majority of the thrombin's cellular activation functions; the second is PAR-3, a receptor described to be essential for normal responsiveness to thrombin in mouse platelets. In addition to these thrombin receptors, the mRNA (messenger RNA) for PAR-2, a possible trypsin receptor, was also identified. Functional significance of thrombin receptors was indicated by changes in [Ca2+]i in response to thrombin, as measured by FURA-2 fluorescence in RBCE cells. Thrombin as low as 4 nmol/L induced an abrupt increase in [Ca2+]i whereas, upon addition of active site-blocked thrombin or plasmin, [Ca2+]i remained unchanged. The [Ca2+]i signal attributable to thrombin was smaller in a low Ca2+-containing medium, indicating that an influx of Ca2+ from the extracellular medium makes a contribution to the overall [Ca2+]i rise. The amplitude of the transient [Ca2+]i signal was dependent on the concentration of thrombin, and repeated application of the enzyme caused an essentially complete and long-term desensitization of the receptor. The PAR-1 agonist peptide SFLLRN also elicited a transient increase in [Ca2+]i. After activation by SFLLRN, cells showed a diminished response to thrombin, but the response was not absent, indicating that PAR-3 might contribute to the generation of the [Ca2+]i signal. Pretreatment of RBCE cells with 100 nmol/L plasmin completely prevented [Ca2+]i rise attributable to thrombin. These data show that RBCE cells and astrocytes express at least two receptors for thrombin, PAR-1 and PAR-3, and probably both receptors are involved in thrombin-induced [Ca2+]i signals. Plasmin itself does not elevate [Ca2+]i but prevents the activation of receptors by thrombin.

Animals↗
PubMed1999

Na+-Ca2+ exchange and its implications for calcium homeostasis in primary cultured rat brain microvascular endothelial cells.

1. The role of Na+-Ca2+ exchange in the regulation of the cytosolic free Ca2+ concentration ([Ca2+]i) was studied in primary cultured rat brain capillary endothelial cells. [Ca2+]i was measured by digital fluorescence imaging in cells loaded with fura-2. 2. ATP (100 microM) applied for a short period of time (6 s) caused a rise in [Ca2+]i from 127 +/- 3 (n = 290) to 797 +/- 25 nM, which then declined to the resting level, with a t time required for [Ca2+]i to decline to half of peak [Ca2+]i) of 5.4 +/- 0.09 s. This effect was independent of external Ca2+ and could be abolished by previously discharging the Ca2+ pool of the endoplasmic reticulum with thapsigargin (1 microM). 3. Application of thapsigargin (1 microM) or cyclopiazonic acid (10 microM) to inhibit the Ca2+-ATPase of the endoplasmic reticulum 6 s prior to ATP application did not influence the peak [Ca2+]i but greatly reduced the rate of decline of [Ca2+]i, with t values of 15 +/- 1.6 and 23 +/- 3 s, respectively. 4. In the absence of external Na+ (Na+ replaced by Li+ or N-methylglucamine) the basal [Ca2+]i was slightly elevated (152 +/- 6 nM) and the restoration of [Ca2+]i after the ATP stimulation was significantly slower (t , 7.3 +/- 0.46 s in Li+ medium, 8.12 +/- 0.4 s in N-methylglucamine medium). 5. The external Na+-dependent component of the [Ca2+]i sequestration was also demonstrated in cells stimulated by ATP subsequent to addition of cyclopiazonic acid; in a Na+-free medium [Ca2+]i remained at the peak level in 88 % of the cells after stimulation with ATP. 6. Addition of monensin (10 microM) in the presence of external Na+ increased the resting [Ca2+]i to 222 +/- 9 nM over approximately 1 min and subsequent removal of extracellular sodium resulted in a further increase in [Ca2+]i to a peak of 328 +/- 11 nM, which was entirely dependent on external Ca2+. 7. These findings indicate that a functional Na+-Ca2+ exchanger is present at the blood-brain barrier, which plays a significant role in shaping the stimulation-evoked [Ca2+]i signal and is able to work in reverse mode under pharmacological conditions.

Adenosine Triphosphate↗
PubMed1999

Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase.

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.

Animals↗
PubMed1998

The neuroprotective drug vinpocetine prevents veratridine-induced [Na+]i and [Ca2+]i rise in synaptosomes.

The effect of the neuroprotective drug, vinpocetine on the veratridine-evoked [Na+]i and [Ca2+]i rise in isolated nerve terminals was studied. Vinpocetine, in a pharmacologically relevant concentration range (0.4-10 microM)i reduced the increase of [Na+]i induced by veratridine (100 microM). The effect of the drug was concentration-dependent with 10 microM vinpocetine completely preventing the increase of [Na+]i. The [Ca2+]i rise in response to veratridine was also prevented by vinpocetine. In addition, the [Ca2+]i signal induced by depolarization with 20 mM K+ was reduced by vinpocetine (1-20 microM). This effect was not influenced by preincubation with 1 microM TTX and was also observed when Na+ was replaced by N-methyl glucamine in the medium. It is concluded that vinpocetine is capable of inhibiting voltage-dependent Na+ and Ca2+ channels, respectively, and these effects might contribute to the neuroprotection exerted by the drug.

Animals↗
PubMed1998

Improved growth of cultured brain microvascular endothelial cells on glass coated with a biological matrix.

An improved method for culturing primary rat brain capillary endothelial cells on glass has been developed, using a corneal extracellular matrix coat. Since the collagen-coated plastic attachment surface conventionally used for primary cultures of brain microvascular endothelium gives a high level of background fluorescence in microfluorimetric studies, an alternative attachment surface was tested involving no plastic element. Five substrata combinations were examined and a new combination of glass and corneal endothelial extracellular matrix coat was found to provide excellent cell adhesion, culture growth and purity. Other established substrata combinations tested for comparison, either involved plastic, or used glass with collagen or carbodiimide and collagen coating but the last two gave poor endothelial cell adhesion and growth. Our method using this new attachment surface combination results in stable and pure endothelial cultures, as verified by immunocytochemistry, which are suitable for fluorimetric investigations.

Animals↗
PubMed1998

Plasma membrane depolarization and disturbed Na+ homeostasis induced by the protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon in isolated nerve terminals.

The effect of the protonophore carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP) was studied on the intracellular [Na+], pH, and plasma membrane potential in isolated nerve terminals. FCCP induced a rise of [Na+]i at, and even below, the concentrations (0.025-1 microM) in which it is usually used in intact cells to eliminate Ca2+ uptake by mitochondria. The FCCP-induced increase of [Na+]i correlates with a fall in both the ATP level and the ATP/ADP ratio. In addition, a sudden rise of the intracellular proton concentration ([H+]i) from 83 +/- 0.4 to 124 +/- 0.7 nM was observed on the addition of FCCP (1 microM). Parallel with the rise in [H+]i, an abrupt depolarization was detected, followed by a slower decrease in the plasma membrane potential. Both the extent of the pHi change and the fast depolarization of the plasma membrane were proportional to the proton electrochemical gradient across the plasma membrane; when this gradient was increased, greater depolarization was detected. The slower decrease of the membrane potential after the fast initial depolarization was abolished when the medium contained no Na+. It is concluded that FCCP (1) gives rise to a depolarization by setting the plasma membrane potential close to the proton equilibrium potential and (2) enhances the intracellular [Na+] as a consequence of an insufficient ATP level and ATP/ADP ratio to fuel the Na+,K+/ATPase. Because both disturbed Na+ homeostasis and plasma membrane depolarization could profoundly interfere with Ca2+ homeostasis in the presence of protonophores, consideration given to these alterations may help to clarify the cellular Ca2+ sequestration processes.

Animals↗
PubMed1997

Enhanced depolarization-evoked calcium signal and reduced [ATP]/[ADP] ratio are unrelated events induced by oxidative stress in synaptosomes.

Oxidative insult elicited by hydrogen peroxide (H2O2) was previously shown to increase the basal intracellular Ca2+ concentration in synaptosomes. In the present study, the effect of H2O2 on the depolarization-evoked [Ca2+] signal was investigated. Pretreatment of synaptosomes with H2O2 (0.1-1 mM) augmented the [Ca2+] rise elicited by high K+ depolarization with essentially two alterations, the sudden sharp rise of [Ca2+]i due to K+ depolarization is enhanced and, instead of a decrease to a stable plateau, a slow, steady rise of [Ca2+]i follows the peak [Ca2+]i. H2O2 in the same concentration range lowered the ATP level and the [ATP]/[ADP] ratio. When carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) (1 microM) or rotenone (2 microM)/oligomycin (10 microM) was applied initially to block mitochondrial ATP production, the lowered [ATP]/[ADP] ratio was further reduced by subsequent addition of 0.5 mM H2O2. The decline of the [ATP]/[ADP] ratio was parallel with but could not explain the enhanced K+-evoked [Ca2+]i signal, indicated by experiments in which the [ATP]/[ADP] ratio was decreased by FCCP (0.1 microM) or rotenone (2 microM) to a similar value as by H2O2 without causing any alteration in the [Ca2+]i signal. These results indicate that H2O2-evoked oxidative stress, in its early phase, gives rise to a complex dysfunction in the Ca2+ homeostasis and, parallel with it, to an impaired energy status.

Adenosine Diphosphate↗
PubMed1996

Early events in free radical-mediated damage of isolated nerve terminals: effects of peroxides on membrane potential and intracellular Na+ and Ca2+ concentrations.

The effects of peroxides were investigated on the membrane potential, intracellular Na+ ([Na+]i) and intracellular Ca2+ ([Ca2+]i) concentrations, and basal glutamate release of synaptosomes. Both H2O2 and the organic cumene hydroperoxide produced a slow and continuous depolarization, parallel to an increase of [Na+]i over an incubation period of 15 min. A steady rise of the [Ca2+]i due to peroxides was also observed that was external Ca2+ dependent and detected only at an inwardly directed Ca2+ gradient of the plasma membrane. These changes did not correlate with lipid peroxidation, which was elicited by cumene hydroperoxide but not by H2O2. Resting release of glutamate remained unchanged during the first 15 min of incubation in the presence of peroxides. These alterations may indicate early dysfunctions in the sequence of events occurring in the nerve terminals in response to oxidative stress.

Animals↗