Melatonin and pinoline prevent aluminium-induced lipid peroxidation in rat synaptosomes

J. Trace Elem. Med. BioL VoL 17 (I) 39-44 (2003) http://www.urbanfischer.de/journals/jtracee[m

© 2003 by Urban & Fischer Ver[ag

Melatonin and pinoline prevent aluminium-induced lipid peroxidation in rat synaptosomes Sergio MiltOn-Piano 1, Joaquin 3. Garcia 1,2,*, Enrique Martinez-BaLLarin 1, RusseL J. Reiter 2, Santiago Ortega-Guti6rrez 1, Rosa Maria L~zaro1, and Jesos Fernando Escanero1 Department of Pharrnaco[ogyand Physiology, University of Zaragoza,Spain 2 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, USA

Received November 2001 • Accepted May 2002

Abstract The serum concentrations of aluminum, a metal potentially involved in the pathogenesis of Alzheimer's disease, increase with age. Also, intense and prolonged exposure to aluminum may result in dementia. Melatonin and pinoline are two well known antioxidants that efficiently reduce lipid peroxidation due to oxidative stress. Herein, we investigated the effects of melatonin and pinoline in preventing aluminum promotion of lipid peroxidation when the metal was combined with FeCI3 and ascorbic acid in rat synaptosoma[ membranes. Lipid peroxidaLion was estimated by quantifying ma[ondia[dehyde (MDA) and 4-hydroxya[kenal (4-HDA) concentrations in the membrane suspension. Under the experimental conditions used herein, the addition of aluminum (0.0001 to 1 mmol/L) enhanced MDA + 4-HDA formation in the synaptosomes. Melatonin and pino[ine reduced, in a concentration-dependent manner, lipid peroxidation due to aluminum, FeCl3 and ascorbic acid in the synaptosoma[ membranes. These results suggest that the indoleamine me[atonin and the ~-carbo[ine pinoline may potentially act as neuroprotectant agents in the therapy of those diseases with elevated aluminum concentrations in the tissues. Key words: Melatonin, pinoline, aluminum, iron, lipid peroxidation, synaptosome

Introduction The nervous system is highly sensitive to oxidative damage resulting from free radicals because neurons have an elevated metabolic rate and also because the brain has poorly developed antioxidant defense mechanisms (I). When free radicals react with the phosphoLipids of a bioLogical membrane, they initiate a devastating chain reaction, identified as Lipid peroxidation, that Leads to Loss or suppression of numerous membrane-dependent cellular functions and even to the ceil death (2). ALuminum is a very abundant metal in the Earth's crust. Therefore Living organisms are continuously exposed to

*Correspondence to: Jos~ 3oaquin Garcia Garcia, Departamento de FarmacoLogia y Fisio[ogia, Facultad de Medicina, Universidad de Zaragoza, Domingo MiraLs/n, 50009 Zaragoza, Spain, Phone: 34-976-761000, Ext.4386, Fax: 34-976-761745, E-mail: [email protected]

non-toxic Low a(uminum concentrations. However, an excessive and prolonged aluminum exposure, e.g. for those patients with chronic renal failure undergoing Longterm hemodiaLysis that use solutions with aluminum or who receive antacids containing aluminum, is directly related to dementia and other neurological disorders (I, 3). The uremic patients on hemodiaLysis exhibit high aluminum and ma[ondiaLdehyde (MDA) concentrations in their sera when compared to healthy people (4). BLood aluminum Levels increase with age (5, 6) and moreover high aluminum concentrations and Lipid peroxidation processes are reportedly involved in the pathogenesis of ALzheimer's disease (7, 8). N-acety[-5-methoxytryptamine or melatonin is the major product of the pineal gland in vertebrates. MeLatonin concentrations in blood and the pineal gland show a daily rhythm with highest concentrations during nighttime and Low Levels during daytime (9). Intensive research 0946-672X/03/17/01-039 $ 15.00/0

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over the last four decades has shown meLatonin to be involved in the modulation of a variety of endocrine, neural and immune functions and, additionally, the indo[eamine possesses a variety of antioxidant actions

(lO, 11).

6-methoxy-l,2,3,4-tetrahydro-13-carboline or pinoline is a tricyc[ic ~-carboLine isolated from the pineal gland and other tissues as we[[ (12, 13). Some ~-carbo[ines, including pino[ine, may be formed by condensation between indo[eamines and aldehydes via the Pictet-Speng[er reaction (14). ALthough its physioLogicaL role is stiLL unknown, pinoLine has been shown to increase serotonin LeveLs in the brain and to be a neuromodu[ator of the 3Himipramine recognition site (15). Like me[atonin, pino[ine also has antioxidant activity. In recent years it has been shown that both moLecuLes, me[atonin and pino[ine, reduce Lipid peroxidation in aLL bioLogicaL membranes induced by free radicals. The purpose of this study was to examine the potential of melatonin and pinoline in preventing aLuminum-enhanced Lipid peroxidation due to iron in rat brain synaptosomes. The study was considered important because increasing age is associated with a marked reduction in meLatonin LeveLs in aLL animaLs including humans (16) and the drop in me[atonin has been speculated to be in part related to the neuronal Lossin the aged (17).

Material and methods ChemicaLs ALCL3, FeC[3, ascorbic acid, metatonin and pinotine were purchased from Sigma (Madrid, Spain). The Bioxytech LP0-586 kit for Lipid peroxidation was obtained from Caymen Chemical (Ann Arbor, MI, USA). Other chemicals used were of the highest quality available. MeLatonin was diluted in absolute ethanol and incubation buffer. EthanoL was 2% (v/v) in the final mixture. ALCL3, Feet3, ascorbic acid and pinotine were diluted in the incubation buffer. ALL solutions were prepared fresh just prior to use. Animals and membrane isolation Sprague-Daw[ey rats weighing 225-250 g were purchased from Harlan Iberica (BarceLona, Spain), and received standard chow and water ud Ubitum. After being accLimated for two weeks, the animals were sacrificed by decapitation. The brains were quickly removed, washed in saline solution (0.9% NaC[) and homogenized 1/10 w/v in 0.32 moL/L sucrose. The resulting suspension was centrifuged at 1,000 g for 10 rain at 4 °C to remove cell debris and nuclei. The supernatant was centrifuged at 20,000 g for 20 rain at 4 °C. The pellet obtained was resuspended in cold water and centrifuged at 8,000 g for 20 rain at 4 °C. The supernatant, which contained the membranes, was recentrifuged at 48,000 g for 20 rain at 4 °C. The resulting pellet was washed 2 times and the final pellet was suspended 1/2 v/v in 20 mmoL/L Tris-HCL buffer (pH = 7.4), and frozen at -30 °C until assay. ,]. Trace E[em. Med. Biol.

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Peroxidation of synaptosomes A[iquots of synaptosoma[ membranes (0.5 mg protein/mL) suspended in 20 mmoL/L Tris-HC[ buffer (pH = 7.4) were incubated in a water bath with shaking at 37 °C for 60 rain with 0.1 mmoL/L FeCL3, 0.1 mmoL/L ascorbic acid and ALC[3 (0.0001, 0.001, 0.01, 0.1, 0.5, 1 retool/L). In a subsequent phase of the experiment, melatonin (0.1, 1, 5 mmoL/L) or pinoLine (0.001, 0.01, 0.1 mmo[/L) were added at the same time than FeCL3, ascorbic acid and ALCL3. MeLatonin and pinoLine concentrations were chosen in accordance with their antioxidative activity in reducing Lipid peroxidation as described elsewhere (18). In all experiments Lipid peroxidation was stopped by placing the membrane solution into ice-cold water for 10 rain. Measurements of MDA and 4-hydroxyatkena[ (4-HDA) LeveLsand protein concentrations MDA and 4-HDA Levels were used as an index of the oxidative breakdown of Lipid in the synaptosma[ preparations (19). These products were determined using the Bioxytech kit. In this assay, MDA and 4-HDA react with N-methy[-2phenyLindoLe, yielding a stable chromophore with a peak of maximum absorbance at 586 nm. Results are expressed as MDA + 4-HDA nmoL/mg of synaptosoma[ protein. The protein concentrations in the incubation media were determined using the method of Bradford (20), bovine serum albumin served as standard. Statistical analysis Results are expressed as means _+standard error (SE). Student's t-tests were used for comparison of the means. Values were accepted as being statistically significant different if the p value was <0.05.

Results Incubation of the synaptosoma[ membranes with FeCL3 and ascorbic acid raised MDA + 4-HDA concentrations, indicating the oxidation of membrane [ipids. The addition of ALCL 3 to the incubation mixture further increased levels of MDA + 4-HDA such that the values where significantly elevated over those induced by FeCI3 and ascorbic acid only. The promotion of Lipid peroxidation was proportional to the concentration of aluminum added to the medium. Fig. 1 illustrates these results. Fig. 2 shows the effect of the addition of meLatonin (0.1, 1 or 5 mmoL/L) to synaptosomes exposed to FeCL3, ascorbic acid and ALC[3. The co-incubation of the synaptosomes with metatonin reduced the Levels of the products of Lipid peroxidation which were induced by aluminum. Additionally, at concentrations of 1 and 5 mmoL/L me[atonin, MDA + 4-HDA Levels were Lower than those measured in membranes incubated with FeEl3 and ascorbic acid in the absence of ALCL 3. PinoLine was similarly protective of aluminum-induced Lipid degradation in synaptosomes when pinoLine (0.001, 0.01, 0.1 mmoL/L) was added in the incubation medium; the increase in lipid peroxidation products due to aluminum was clearly reduced (Fig. 3). PinoLine at 0.1 mmoL/L

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Discussion Studies using a wide variety of bioLogicaLmembranes have reported that aLuminum in vitro promotes iron-initiated Lipid peroxidation, this effect being dependent on the concentration of aLuminum in the incubation medium (21-25). Since ferrous ions are present at physioLogicaLLy high conditions in the brain (26), the present observations are in agreement with in vivo studies where the generation of increased thiobarbituric acid reactive substances in the brain of mice fed using a diet containing high LeveLsof aLuminum was observed (27). The present resuLts using synaptosoma[ membranes support the observations of aLuminum as a iron-Lipid peroxidation enhancer. Two previous reports showed that meLatonin efficientLy reduces aluminum and 13-amytoid-induced Lipid peroxidaLion in pLatelet membranes (23, 28). The present experiments extend these results to brain synaptosomaL membranes. MeLatonin is weLL-documented as an antioxidant in numerous toxicoLogicaL modeLs of induced oxidative damage (10, 11). One molecuLe of metatonin is known to neutralize two hydroxyL radicaLs (29). In addition, me[atonin scavenges hydrogen peroxide (30), which is formed in the brain and is the precursor of hydroxyL radicaLs formed via the Fenton reaction (1). Besides these direct interactions with oxygen-derived reactants, meLatonin stimulates enzymes impLicated in the physioLogicaL antioxidant defense system, e.g. superoxide dismutase and g[utathione peroxidase (31, 32). FinaLLy,the products derived of the interaction of metatonin with free radicaLs also possess antioxidant activity; thus, these derivatives

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Fig. 2. Protective effect of metatonin on aLuminum promotion in Lipid peroxidation induced by iron and ascorbic acid in rat synaptosomes. A) 0.1 mmo[/L meLatonin, B) ] mmoL/L meLatonin, C) 5 mmo[/L meLatonin. VaLues are means _+ standard errors (n = 6-8). * p < 0.05 versus synaptosomes with iron and ascorbic acid. 3. Trace Hem. Med. Biol. 17/i (2003)

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Fig. 3. Effect of pinoEine on MDA+4-HDA formation induced by aluminum, FeC[3 and ascorbic acid in rat brain synaptosomes. A) 0.001 mmo[/L pino[ine, B) 0.01 mmo[/L pino[ine,C) 0.1 mmo[/L pino[ine. Valuesare means_+standard errors (n = 7-8). * p < 0.05 versus control (0.1 mmol/L FeC[3 and 0.I mmo[/L ascorbic acid). J. Trace Elem. Med. Biol. 17/1 (2003)

are believed to augment the direct protective actions of melatonin against free radicals (33). Although it is clear that the addition of aluminum to the incubation medium increased significantly the MDA + 4-HDA levels in the synaptosoma[ membranes, the mechanisms responsible for the aluminum's prooxidant activity remain unclear. Aluminum is a redox inert metal that possesses a fixed valency of 3. Thus, aluminum does not directly initiate radical reactions. One possible explanation for the enhanced lipid peroxidation due to aluminum is related to its ability to bind to the membranes, which may disturb the order as well as other dynamic parameters of the bilayer (34, 35). The consequential phospholipid rearrangement may aid in the propagation of lipid peroxidation (1). Since numerous cell functions require the bilayer integrity as well as an optimal level of lipid and protein fluidity, these alterations in the dynamics of the membrane may explain, at least partially, aluminum neurotoxidty. Banks and Kastin (36) reported that aluminum modifies membrane function at the level of the blood-brain barrier; aluminum increases the rate of transmembrane diffusion and influences saturable transport systems, which allow toxins and drugs, which do not normally cross the blood-brain barrier, easy access to the brain tissue. We previously reported that melatonin prevents membrane rigidity of hepatic microsomes induced by FeC%,ADP and NADPH (37-39). This membrane stabilizing action of melatonin relates to its ability to prevent lipid peroxidation and possibly its specific position in the membrane (40). Since metatonin stabilizes biological membranes against lipid peroxidation while aluminum produces alterations in membrane fluidity and promotes lipid peroxidation due to iron, melatonin may have an advantage over other antioxidants such as flavonoids, which only scavenge free radicals without a direct effect on membrane fluidity (25). Some antioxidants prevent the prooxidant activity of aluminum becausethey are metal chelators, e.g. deferoxamine (21) and ethylenediaminetetraacetic acid (24). Limson et al. (41) recently showed, using adsorptive voltammetry, that melatonin and other indoleamines which are metatonin precursors,i.e. tryptophan and serotonin, may form complexes with aluminum. Because of these findings this group suggested a new therapeutic use of melatonin as a metal detoxifying molecule; they proposed that melatonin, because of this action, may be a very beneficial molecule in ALzheimefs disease as weR as in other diseaseswhere high aluminum concentrations have been identified. In the current study we also show for the first time that pinoline, a ~-carboline formed from melatonin as well as from other indoleamines, affords protection against the promotional effect of aluminum on lipid peroxidation. Pinoline is a powerful antioxidant molecule that reduces nitric oxide-induced lipid peroxidation in retinal homogenates (42) and protects DNA against oxidative damage induced by chromium (43). Moreover, we have shown that pinoline, like melatonin, stabilizes microsoma[ membranes against the rigidity due to lipid peroxidation, an effect that is enhanced when melatonin is also added to the incubation medium (39). In these in vitro studies,

Me[atonin and pinoEineprevent a[uminium-induced Lipidperoxidationin rat synaptosomes 43 pino[ine was more effective than meLatonin in preventing membrane rigidity. WhiLe both me[atonin and pino[ine may be potential useful as therapeutic agents to reduce Lipid peroxidation in vivo, there are differences between the two moLecuLes in terms of their reLative toxicities. ALthough pino[ine seems to have Low toxicity, high intravenous doses (112 mg/kg) do cause LethaLity in 50% of mice (44). To date, however, no serious toxicity is reported for meLatonin; for exampLe it has not been possible to define a dose that wiLL kit[ an animaL, so no LDso has been found. SecondLy, although pinoLine stabilizes membranes against Lipid peroxidation, high pinoLine concentrations (>0.3 mmoL/L) perturb moLecuLar motion in membranes in the absence of oxidative stress. This is indicated by its ability to alter polarization parameters, which reflect membrane rigidity as observed using fluorescence spectroscopy methods. No similar side effect is observed for meLatonin. Even 3 mmoE/L meLatonin concentrations maintain membranes at an optima[ Level of fluidity (37). FinaLLy,the efficiency of pinoLine has not been tested in vivo. By contrast, meLatonin has been successfuLLyevaluated in numerous in vivo expeFimenta[ models of oxidative stress (11, 45, 46). The current findings show that me[atonin and pino[ine afford protection against the increase in the peroxidation of synaptosoma[ Lipid induced by aluminum in brain homogenates. Since aluminum has been implicated in the etiology of A[zheimefs disease (47), the results reinforce a potential use of me[atonin in this pathology. In support of this possibility, Pappo[[a et aL. (48) demonstrated that me[atonin greatly reduced ceLLuLardeath in murine neurobLastoma (N2a) ceLLsco-incubated with amyLoid-13 peptide. ALso, the amyLoid-~ peptide induced Lipid degradation in membranes from pLateLetswas totaLLy prevented by meLatonin (28). In summary, this study shows that the indo[eamine meLatonin and the ~-carbo[ine pino[ine in vitro efficiently reduce the increase in iron-mediated Lipid peroxidation due to aluminum. Based on these studies and considering the previous results relative to the antioxidant activity of meLatonin, the therapeutic use of me[atonin in diseases which involve aluminum toxicity should be considered.

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