Susana Garcia de Arriba

Paul-Flechsig-Institut für Hirnforschung, Leipzig, Saxony, Germany

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Publications (16)49.18 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Advanced glycation end products (AGEs) are found in various intraneuronal protein deposits such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease. Among the many reactive carbonyl compounds and AGE precursors, methylglyoxal is most likely to contribute to intracellular AGE formation, since it is extremely reactive and constantly produced by degradation of triosephosphates. Furthermore, methylglyoxal levels increase under pathophysiological conditions, for example, when trisosephosphate levels are elevated, the expression or activity of glyoxalase I is decreased, as is the case when the concentration of reduced glutathione, the rate-determining co-factor of glyoxalase I, is low. However, the effects of methylglyoxal on mitochondrial function and energy levels have not been studied in detail. In this study, we show that methylglyoxal increases the formation of intracellular reactive oxygen species and lactate in SH-SY5Y neuroblastoma cells. Methylglyoxal also decreases mitochondrial membrane potential and intracellular ATP levels, suggesting that carbonyl stress-induced loss of mitochondrial integrity could contribute to the cytotoxicity of methylglyoxal. The methylglyoxal-induced effects such as ATP depletion and mitochondrial dysfunction can be prevented by pre-incubation of the cells with the carbonyl scavengers aminoguanidine and tenilsetam. In a clinical context, these compounds could not only offer a promising therapeutic strategy to reduce intracellular AGE-accumulation, but also to decrease the dicarbonyl-induced impairment of energy production in aging and neurodegeneration.
    Neurobiology of aging 08/2007; 28(7):1044-50. · 5.94 Impact Factor
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    ABSTRACT: The biochemical pathways involved in neuronal cell death in Parkinson's disease are not completely characterized. Mitochondrial dysfunction, specifically alteration of the mitochondrial complex I, is the primary target of the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) induced apoptosis in neurons. In the present study, we examine the role of caspase-dependent and -independent routes in MPP+-induced apoptosis in rat cerebellar granule neurons (CGNs). We show a distinct increase in the expression of the cell cycle proteins cyclin D, cyclin E, cdk2, cdk4 and the transcription factor E2F-1 following a MPP+ treatment of CGNs. Flavopiridol (FLAV), a broad inhibitor of cyclin-dependent kinases (CDKs), attenuated the neurotoxic effects of MPP+ and significantly attenuates apoptosis mediated by MPP+ 200 microM. Likewise, the antioxidant vitamin E (vit E) increases neuronal cell viability and attenuates apoptosis induced by MPP+. Moreover, the expression levels of cyclin D and E2F-1 induced by this parkinsonian neurotoxin were also attenuated by vit E. Since, the broad-spectrum caspase inhibitor zVAD-fmk did not attenuate MPP+-induced apoptosis in CGNs, our data provide a caspase-independent mechanism mediated by neuronal reentry in the cell cycle and increased expression of the pro-apoptotic transcription factor E2F-1. Our results also suggest a potential role of oxidative stress in neuronal reentry in the cell cycle mediated by MPP+. Finally, our data further support the therapeutic potential of flavopiridol, for the treatment of Parkinson's disease.
    Neuroscience 05/2007; 146(1):350-65. · 3.12 Impact Factor
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    ABSTRACT: In the present study, human NT2 neurons obtained from embryonic teratocarcinoma (NT2) cells were established as human in-vitro model to investigate the mechanisms associated with hypoxia/ischemia-induced neuronal injury. NT2 neurons express functional NMDA receptors that are of particular significance for hypoxia/ischemia-related neuronal damage. In patch-clamp recordings under normoxic conditions, NMDA (plus 10 microM glycine)-induced inward currents (EC(50)=43.7 microM) were distinctly antagonized by memantine, a blocker of the receptor channel, but only slightly by 5,7-dichlorokynurenic acid (DCKA), a glycine(B) binding site antagonist. Immunohistochemistry demonstrated that the NT2 neurons are mostly GABAergic; they predominantly express the NMDA receptor subunits NR2B and NR2C, and lower levels of NR1 and, particularly, of NR2A. Upon glucose and oxygen deprivation for 3h the loss of cell viability measured directly after 3h was higher than after application of either hypoxia or aglycemia as assessed by propidium iodide flow cytometry. Ischemic conditions significantly reduced the NMDA responses associated with a decrease in EC(50) and decreased mitochondrial membrane potential as detected by JC-1 flow cytometry. Memantine (50 microM) and CGS19755 (a competitive NMDA receptor antagonist; 10 microM) reduced ischemia-induced cell death, in contrast to DCKA (10 microM). In conclusion, in the present human in-vitro model for studying the molecular mechanisms associated with ischemic injury, neuroprotection could be achieved with NMDA receptor antagonists but not with a glycine(B) binding site antagonist. Accordingly, glycine antagonists might not represent an optimal therapeutic strategy for preventing ischemic neuronal damage in contrast to NMDA receptor antagonists like memantine.
    Neurochemistry International 11/2006; 49(5):466-74. · 2.66 Impact Factor
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    ABSTRACT: Methylglyoxal (MG) is a reactive alpha-ketoaldehyde physiologically generated as a by-product of glycolysis. MG that is able to form protein adducts resulting in advanced glycation end products accumulates under conditions associated with neurodegeneration such as impaired glucose metabolism or oxidative stress. In the present study, short-term exposure of human neuroblastoma SH-SY5Y cells to MG was associated with an early depolarization of the plasma membrane, glutamate release, and formation of reactive oxygen species. In addition, long-term exposure (24 h) of SH-SY5Y cells to MG caused a decrease in cell viability, intracellular ATP, and rhodamine 123 (Rh-123) fluorescence. ATP depletion and the decrease in Rh-123 fluorescence were prevented by carbonyl scavengers, the nitric oxide synthase inhibitor L-NAME, and N-methyl-d-aspartate (NMDA) receptor antagonists. Furthermore, the MG-induced glutamate release and the loss in cell viability were prevented by NMDA receptor antagonists. Therefore, MG renders cells more vulnerable to excitotoxicity. In conclusion, carbonyl scavengers as well as NMDA receptor antagonists may represent effective therapeutic tools to reduce the risk of pathophysiological changes associated with carbonyl stress in neurodegenerative diseases.
    Free Radical Biology and Medicine 04/2006; 40(5):779-90. · 5.27 Impact Factor
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    ABSTRACT: Exposure of cultured cortical neurons to elevated extracellular K(+) concentrations (25 mM) induces membrane depolarization and an increase in action-potential firing. Long-term high K(+) treatment was associated with an increased neuronal cell death. In surviving neurons, multiple changes occurred in the proportion of individual NMDA receptor subunit 1 (NR1) splice variant mRNA expression, whereas the overall expression of NR1, NR2A and NR2B transcripts remained unaffected. The high K(+)-induced changes in NR1 splice variant expression were virtually abolished upon a concurrent administration of tetrodotoxin (TTX; 3 microM). In voltage-clamp recordings performed on neurons resistant to high K(+) treatment, inward currents induced by NMDA (1-1,000 microM) were reduced. In K(+)-resistant cells, the activity of calpain but not of caspase-3 was diminished compared with controls kept in regular medium. NR function as well as calpain activity was not affected in cultures concomitantly treated with high K(+) and either TTX or a NR antagonist (CGS19755 (selfotel) or memantine). In conclusion, the present data indicate adaptive changes in NR1 splice variant expression and a decrease in NR function upon a sustained increase in neurotransmission. Accordingly, alternative splicing could be an endogenous mechanism to counteract cellular damage due to overactivation of excitatory NRs and may be associated with an impairment of necrotic mechanisms.
    British Journal of Pharmacology 04/2006; 147(6):622-33. · 5.07 Impact Factor
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    ABSTRACT: The cytoskeleton is critical to neuronal functioning and survival. Cytoskeletal alterations are involved in several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We studied the possible pathways involved in colchicine-induced apoptosis in cerebellar granule neurons (CGNs). Although colchicine evoked an increase in caspase-3, caspase-6 and caspase-9 activation, selective caspase inhibitors did not attenuate apoptosis. Inhibitors of other cysteine proteases such as PD150606 (a calpain-specific inhibitor), Z-Phe-Ala fluoromethyl ketone (a cathepsins-inhibitors) and N(alpha)-p-tosyl-l-lysine chloromethyl ketone (serine-proteases inhibitor) also had no effect on cell death/apoptosis induced by colchicine. However, BAPTA-AM 10 microM (intracellular calcium chelator) prevented apoptosis mediated by cytoskeletal alteration. These data indicate that calcium modulates colchicine-induced apoptosis in CGNs. PARP-1 inhibitors did not prevent apoptosis mediated by colchicine. Finally, colchicine-induced apoptosis in CGNs was attenuated by kenpaullone, a cdk5 inhibitor. Kenpaullone and indirubin also prevented cdk5/p25 activation mediated by colchicine. These findings indicate that cytoskeletal alteration can compromise cdk5 activation, regulating p25 formation and suggest that cdk5 inhibitors attenuate apoptosis mediated by cytoskeletal alteration. The present data indicate the potential therapeutic value of drugs that prevent the formation of p25 for the treatment of neurodegenerative disorders.
    Biochemical Pharmacology 09/2005; 70(3):470-80. · 4.58 Impact Factor
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    ABSTRACT: The pharmacological treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) currently represents a major medical challenge. The mechanisms involved in the apoptotic neuronal cell death, associated with such disorders, are still not clear, but recent data suggest that cyclindependent kinases (CDKs) play a prominent role (Liu et al., 2003). Canonical CDKs such as CDK2 and CDK4/CDK6 are enzymes associated with cyclin regulatory subunits that control cell cycle progression. The evidence that neurons in postmortem brain tissue from patients with neurodegenerative diseases express CDKs, supports to the hypothesis that re-entry into the cell cycle could be an apoptotic pathway involved in the neurodegenerative process. Several authors suggest that the transcription factor E2F-1 function as a link between the cell cycle and apoptosis in neurons. Additionally the expression of CDK5 has been demonstrated in postmortem brain tissue from patients with neurodegenerative diseases. CDK5 is an atypical CDK, that does not require association with a cyclin and is not implicated in the cell cycle progression. Instead, it is associated with the neuronal co-activators p35 and p39, and is required for neuronal development, axonal outgrowth, learning and memory. Recent evidence also points to a leading role for CDK5/p25 in apoptosis and neurodegeneration. CDK inhibitors such as flavopiridol and roscovitine are being developed and tested in clinical trials as novel antineoplasic agents. Thus, due to the implication of CDKs in neuronal apoptosis, a new application of these drugs in the treatment of neurodegenerative diseases is suggested.
    Current Medicinal Chemistry - Central Nervous System Agents 05/2005; 5(2):101-109.
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    ABSTRACT: Although numerous studies have demonstrated a neuroprotective and anti-apoptotic role of lithium in neuronal cell cultures, the precise mechanism by which this occurs, remains to be elucidated. In this study, we evaluated the lithium-mediated neuroprotection against colchicine-induced apoptosis in cultured cerebellar granule neurons. Previously, it has been demonstrated that colchicine mediates apoptosis in cerebellar granule neurons through cytoskeletal alteration and activation of an intrinsic pro-apoptotic pathway. Recently we also demonstrated a potential role of cyclin-dependent kinase 5 (cdk5) in this pathway. Here we report that colchicine induces dephosphorylation in Ser-9 and phosphorylation in Tyr-216, and thus activation, of glycogen synthase kinase-3beta in cerebellar granule neurons, and that this modification is inhibited by the presence of 5 mM lithium. However, the selective glycogen synthase kinase-3beta inhibitors SB-415286 and SB-216763 were unable to prevent colchicine-induced apoptosis in these cells, suggesting that the anti-apoptotic activity of lithium is not mediated by glycogen synthase kinase-3beta under these conditions. On the other hand, 5 mM lithium prevented the colchicine-induced increase in cdk5 expression and breakdown of cdk5/p35 to cdk5/p25. In addition, we show that up-regulation of cdk5/p25 is unrelated to inhibition of the activity of myocyte enhancer factor 2, a pro-survival transcription factor. These data suggest a previously undescribed neuroprotective mechanism of lithium associated with the modulation of cdk5/p35 or cdk5/p25 expression.
    Neuroscience 02/2005; 134(3):1001-11. · 3.12 Impact Factor
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    ABSTRACT: Advanced glycation end products (AGEs) have been identified in age-related intracellular protein deposits of Alzheimer's disease (amyloid plaques and neurofibrillary tangles) and Parkinson disease (Lewy bodies), suggesting that these protein deposits have been exposed to AGE precursors such as the reactive dicarbonyl compound methylglyoxal. In ageing tissue and under diabetic pseudohypoxia, intracellular methylglyoxal levels rise through an impairment of triosephosphate utilization. Furthermore, methylglyoxal detoxification is impaired when reduced glutathione levels are low, conditions, which have all been described in Alzheimer's disease. However, there is less known about the toxicity of methylglyoxal, particularly about therapeutic strategies to scavenge such dicarbonyl compounds and attenuate their toxicity. In our study, extracellularly applied methylglyoxal was shown to be toxic to human neuroblastoma cells in a dose-dependent manner above concentrations of 150 microM with a LD50 of approximately 1.25 mM. Pre-incubation of methylglyoxal with a variety of carbonyl scavengers such as aminoguanidine or tenilsetam and the thiol antioxidant lipoic acid significantly reduced its toxicity. In summary, carbonyl scavengers might offer a promising therapeutic strategy to reduce the neurotoxicity of reactive carbonyl compounds, providing a potential benefit for patients with age-related neurodegenerative diseases.
    Neurotoxicity Research 02/2005; 7(1-2):95-101. · 2.87 Impact Factor
  • B Kuhla, C Loske, S Garcia De Arriba, R Schinzel, J Huber, G Münch
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    ABSTRACT: Beta-amyloid peptide (Abeta) and "Advanced glycation endproducts" (AGEs) are components of the senile plaques in Alzheimer's disease patients. It has been proposed that both AGEs and Abeta exert many of their effects, which include the upregulation of pro-inflammatory cytokines, through RAGE ("receptor for advanced glycation endproducts"). To investigate whether Abeta and AGEs cause similar or identical effects on cell survival and energy metabolism, we have compared the effects of a model-AGE and Abeta on cell viability, ATP level, glucose consumption and lactate production in the neuroblastoma cell line SH-SY5Y. The results show that AGEs and Abeta increase glucose consumption and decrease ATP levels in a dose dependent manner. Furthermore, both compounds decrease mitochondrial activity measured by the MTT assay. However, only AGEs decrease the number of cells and significantly increase lactate production. These data indicate that both AGEs and Abeta can cause differential disturbances in neuronal metabolism, which may contribute to the pathophysiological findings in Alzheimer's disease. However, their signalling pathways are apparently quite distinct, a fact which should stimulate a more detailed investigation in this field, e.g. for the purpose of a rational design of potential "neuroprotective" RAGE antagonists.
    Journal of Neural Transmission 04/2004; 111(3):427-39. · 3.05 Impact Factor
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    ABSTRACT: Advanced glycation endproducts (AGEs) accumulate on long-lived proteins, including beta-amyloid plaques in Alzheimer's disease, and are suggested to contribute to neuronal dysfunction and cell death. We have investigated the effects of a model AGE upon glucose metabolism and energy production in a neuroblastoma cell line. AGEs decrease cellular ATP levels and increase glucose consumption and lactate production. All of the AGE-induced metabolic changes can be attenuated by antioxidants such as (R+)-alpha-lipoic acid and 17beta-estradiol. These antioxidants may become useful drugs against (AGE-mediated) effects in neurodegeneration through their positive effects on cellular energy metabolism.
    Journal of Cerebral Blood Flow & Metabolism 12/2003; 23(11):1307-13. · 5.40 Impact Factor
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    ABSTRACT: The present study was aimed at characterizing alterations of the nucleotide content and morphological state of rat corticoencephalic cell cultures subjected to metabolic damage and treatment with modulators of mitochondrial ATP-dependent potassium channels (mitoK(ATP)). In a first series of experiments, in vitro ischemic changes of the contents of purine and pyrimidine nucleoside diphosphates and triphosphates were measured by high performance liquid chromatography (HPLC) and the corresponding histological alterations were determined by celestine blue/acid fuchsin staining. As an ischemic stimulus, incubation with a glucose-free medium saturated with argon was used. Ischemia decreased the levels of adenosine, guanine and uridine triphosphate (ATP, GTP, UTP) and increased the levels of the respective dinucleotides ADP and UDP, whereas the GDP content was not changed. Both 5-hydroxydecanoate (5-HD) and diazoxide failed to alter the contents of nucleoside diphosphates and triphosphates, when applied under normoxic conditions. 5-HD (30 microM) prevented the ischemia-induced changes of nucleotide and nucleoside levels. Diazoxide (300 microM), either alone or in combination with 5-hydroxydecanoate (30 microM) was ineffective. Pyruvate (5 mM) partially reversed the effects of ischemia or ischemia plus 2-deoxyglucose (20mM) in the incubation medium. Diazoxide (300 microM) and 5-HD (30 microM) had no effect in the presence of pyruvate (5mM) and 2-deoxyglucose (20mM). Staining the cells with celestine blue/acid fuchsin in order to classify them as intact, reversibly or profoundly injured, revealed a protective effect of 5-HD. When compared with 5-HD, diazoxide, pyruvate and 2-deoxyglucose had similar but less pronounced effects. In conclusion, these results suggest a protective role of 5-hydroxydecanoate on early corticoencephalic nucleotide and cell viability alterations during ischemia.
    Neurochemistry International 12/2003; 43(6):563-71. · 2.66 Impact Factor
  • S Garcia de Arriba, H Franke, M Pissarek, K Nieber, P Illes
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    ABSTRACT: Morphological changes induced by 30 min of hypoxia (incubation in medium saturated with 95% N2-5% CO2 instead of the normal 95% O2-5% CO2) were investigated in neurons (layers II/III of the parietal cortex) of rat neocortical brain slices. The cells were identified as intact, reversibly or irreversibly injured. As expected, hypoxia decreased the number of intact cells and increased the number of irreversibly injured cells. Pretreatment of slices with diazoxide (300 microM), an agonist of ATP-dependent potassium (KATP) channels completely prevented the morphological damage induced by hypoxia, whereas tolbutamide (300 microM), an antagonist of KATP channels, was ineffective when given alone. However, tolbutamide (300 microM) co-applied with diazoxide (300 microM), partly reversed the neuroprotective effect of this agonist during hypoxia. In conclusion, KATP channels appear to be present on neocortical neurons and their opening counteracts hypoxia-induced cell injury.
    Neuroscience Letters 10/1999; 273(1):13-6. · 2.03 Impact Factor
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    ABSTRACT: Morphological changes induced by 30 min of hypoxia (incubation in medium saturated with 95% N2–5% CO2 instead of the normal 95% O2–5% CO2) were investigated in neurons (layers II/III of the parietal cortex) of rat neocortical brain slices. The cells were identified as intact, reversibly or irreversibly injured. As expected, hypoxia decreased the number of intact cells and increased the number of irreversibly injured cells. Pretreatment of slices with diazoxide (300 μM), an agonist of ATP-dependent potassium (KATP) channels completely prevented the morphological damage induced by hypoxia, whereas tolbutamide (300 μM), an antagonist of KATP channels, was ineffective when given alone. However, tolbutamide (300 μM) co-applied with diazoxide (300 μM), partly reversed the neuroprotective effect of this agonist during hypoxia. In conclusion, KATP channels appear to be present on neocortical neurons and their opening counteracts hypoxia-induced cell injury.
    Neuroscience Letters. 01/1999;
  • M Pissarek, S Garcia de Arriba, M Schäfer, D Sieler, K Nieber, P Illes
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    ABSTRACT: In a first series of experiments, intracellular recordings were made from pyramidal cells in layers II-III of the rat primary somatosensory cortex. Superfusion of the brain slice preparations with hypoxic medium (replacement of 95%O2-5%CO2 with 95%N2-5%CO2) for up to 30 min led to a time-dependent depolarization (HD) without a major change in input resistance. Short periods of hypoxia (5 min) induced reproducible depolarizations which were concentration-dependently depressed by an agonist of ATP-dependent potassium (K(ATP)) channels, diazoxide (3-300 microM). The effect of 30 but not 300 microM diazoxide was reversed by washout. Tolbutamide (300 microM), an antagonist of K(ATP) channels, did not alter the HD when given alone. It did, however, abolish the inhibitory effect of diazoxide (30 microM) on the HD. Neither diazoxide (3-300 microM) nor tolbutamide (300 microM) influenced the membrane potential or the apparent input resistance of the neocortical pyramidal cells. Current-voltage (I-V) curves constructed at a membrane potential of -90 mV by injecting both de- and hyperpolarizing current pulses were not altered by diazoxide (30 microM) or tolbutamide (300 microM). Moreover, normoxic and hypoxic I-V curves did not cross each other, excluding a reversal of the HD at any membrane potential between -130 and -50 mV. The hypoxia-induced change of the I-V relation was the same both in the absence and presence of tolbutamide (300 microM). In a second series of experiments, nucleoside di- and triphosphates separated with anion exchange HPLC were measured in the neocortical slices. After 5 min of hypoxia, levels of nucleoside triphosphates declined by 29% (GTP), 34% (ATP), 44% (UTP) and 58% (CTP). By contrast, the levels of nucleoside diphosphates either did not change (UDP) or increased by 13% (GDP) and 40% (ADP). In slices subjected to 30 min of hypoxia the triphosphate levels continued to decrease, while the levels of GDP and ADP returned to control values. The tri- to diphosphate ratios progressively declined for ATP/ADP and GTP/GDP, but not for UTP/UDP when the duration of hypoxia was increased from 5 to 30 min. Hence, the rapid fall in the ratios of nucleoside tri- to diphosphates without the induction of a potassium current failed to indicate an allosteric regulation of a plasmalemmal K(ATP) channel by purine and pyrimidine nucleotides. Diazoxide had no effect on neocortical pyramidal neurons and was effective only in combination with a hypoxic stimulus; it is suggested that both plasmalemmal and mitochondrial K(ATP) channels are involved under these conditions. The hypoxic depolarization may be due to blockade of K+,Na+-ATPase by limitation of energy supplying substrate.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/1998; 358(4):430-9. · 2.15 Impact Factor
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    ABSTRACT: The present study evaluates the effect of the naturally occurring dipeptide carnosine on primary cell cultures established from patients with glioblastoma multiforme. Surgically removed tumors were used to establish primary cell cultures that were incubated for 96h with medium supplemented with carnosine at concentrations of 20, 40 and 50mM. Following incubation, dehydrogenase activity, cellular adenosine triphosphate concentration (ATP), caspase activity, lactate dehydrogenase (LDH) release and the rate of DNA synthesis were determined. After 96h of carnosine treatment a significant reduction in cellular ATP and dehydrogenase activity was detected already at a concentration of 20mM carnosine. Carnosine (50mM) reduced ATP concentration to 42.7±13.5% (n=6) and dehydrogenase activity to 41.0±19.3% (n=6) compared to untreated cells. Additional experiments revealed no sign of enhanced apoptosis or necrosis in the presence of carnosine. However, a quantitative bromo-desoxy-uridine-based proliferation assay demonstrated a clear effect of carnosine on DNA synthesis reducing its rate down to 50% (2cultures) and 10% (4cultures). Therefore, it can be concluded that carnosine is obviously able to inhibit proliferation of cells derived from glioblastoma. Since it is a naturally occurring substance that appears to be non-toxic to normal tissue and is able to penetrate the blood–brain barrier it may be a candidate for a therapeutic agent that may reduce proliferation of neoplastic cells even invivo and especially in cases of glioblastoma multiforme.
    International Journal of Peptide Research and Therapeutics 14(2):127-135. · 1.28 Impact Factor

Publication Stats

265 Citations
49.18 Total Impact Points


  • 2006
    • Paul-Flechsig-Institut für Hirnforschung
      Leipzig, Saxony, Germany
  • 1998–2006
    • University of Leipzig
      • • Rudolf-Boehm-Institut für Pharmakologie und Toxikologie
      • • Institut für Pharmakologie, Pharmazie und Toxikologie
      Leipzig, Saxony, Germany
  • 2005
    • James Cook University
      • Comparative Genomics Centre
      Townsville, Queensland, Australia