Skip to main content

Advertisement

SpringerLink
Log in

Effect of In Vivo l-Acetylcarnitine Administration on ATP-ases Enzyme Systems of Synaptic Plasma Membranes from Rat Cerebral Cortex

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The maximum rates (V max) of some enzymatic activities related to energy consumption (ATP-ases) were evaluated in two types of synaptic plasma membranes (SPM) isolated from cerebral cortex of rats subjected to in vivo treatment with l-acetylcarnitine at two different doses (30 and 60 mg kg−1 i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: acetylcholinesterase (AChE); Na+, K+, Mg2+-ATP-ase; ouabain insensitive Mg2+-ATP-ase; Na+, K+-ATP-ase; direct Mg2+-ATP-ase; Ca2+, Mg2+-ATP-ase; Low- and High-affinity Ca2+-ATP-ase. Sub-chronic treatment with l-acetylcarnitine increased Na+, K+-ATP-ase activity on SPM 2 and Ca2+, Mg2+-ATP-ase activity on both SPM fractions. These results suggest (1) that the sensitivity to drug treatment is different between the two populations of SPM, confirming the micro-heterogeneity of these sub-fractions, probably originating from different types of synapses, (2) the specificity of the molecular site of action of the drug on SPM and (3) its interference on ion homeostasis at synaptic level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Villa RF, Gorini A, Zanada F et al (1986) Action of l-acetylcarnitine on different cerebral mitochondrial populations from hippocampus. Arch Int Pharmacodyn Ther 279:195–211

    PubMed  CAS  Google Scholar 

  2. Villa RF, Gorini A (1991) Action of l-acetylcarnitine on different cerebral mitochondrial populations from hippocampus and striatum during aging. Neurochem Res 16:1125–1132

    Article  PubMed  CAS  Google Scholar 

  3. Gorini A, D’Angelo A, Villa RF (1998) Action of l-acetylcarnitine on different cerebral mitochondrial populations from cerebral cortex. Neurochem Res 23:1485–1491

    Article  PubMed  CAS  Google Scholar 

  4. Gorini A, D’Angelo A, Villa RF (1999) Energy metabolism of synaptosomal subpopulations from different neuronal systems of rat hippocampus: effect of l-acetylcarnitine administration in vivo. Neurochem Res 24:617–624

    Article  PubMed  CAS  Google Scholar 

  5. Battino M, Quiles JL, Huertas JR et al (2000) Cerebral cortex synaptic heavy mitochondria may represent the oldest synaptic mitochondrial population: biochemical heterogeneity and effect of l-acetylcarnitine. J Bioenerg Biomembr 32:163–173

    Article  PubMed  CAS  Google Scholar 

  6. Inano A, Sai Y, Nikaido H et al (2003) Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2. Biopharm Drug Dispos 24:357–365

    Article  PubMed  CAS  Google Scholar 

  7. Nalecz KA, Miecz D, Berezowski V et al (2004) Carnitine: transport and physiological functions in the brain. Mol Aspects Med 25:551–567

    Article  PubMed  CAS  Google Scholar 

  8. Miecz D, Januszewicz E, Czeredys M et al (2008) Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood-brain barrier. J Neurochem 104:113–123

    PubMed  CAS  Google Scholar 

  9. Burlina AP, Sershen H, Debler EA et al (1989) Uptake of acetyl-L-carnitine in the brain. Neurochem Res 14:489–493

    Article  PubMed  CAS  Google Scholar 

  10. Turpeenoja L, Villa RF, Magri MG et al (1988) Changes of mitochondrial membrane proteins in rat cerebellum during aging. Neurochem Res 13:859–865

    Article  PubMed  CAS  Google Scholar 

  11. Aureli T, Miccheli A, Ricciolini R et al (1990) Aging brain: effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy. Brain Res 526:108–112

    Article  PubMed  CAS  Google Scholar 

  12. Gorini A, Ghigini B, Villa RF (1996) Acetylcholinesterase activity of synaptic plasma membranes during ageing: effect of l-acetylcarnitine. Dementia 7:147–154

    PubMed  CAS  Google Scholar 

  13. Paradies G, Ruggero FM, Gadaleta MN et al (1992) The effect of aging and acetyl-L-carnitine on the activity of the phosphate carrier and on the phospholipid composition in rat heart mitochondria. Biochim Biophys Acta 1103:324–326

    Article  PubMed  CAS  Google Scholar 

  14. Hagen TM, Ingersoll RT, Wehr CM et al (1998) Acetyl-l-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci USA 95:9562–9566

    Article  PubMed  CAS  Google Scholar 

  15. Carta A, Calvani M, Bravi D et al (1993) Acetyl-L-carnitine and Alzheimer’s disease: pharmacological considerations beyond the cholinergic sphere. Ann NY Acad Sci 695:324–326

    Article  PubMed  CAS  Google Scholar 

  16. Jones LL, McDonald DA, Borum PR (2010) Acylcarnitines: role in brain. Prog Lipid Res 49:61–75

    Article  PubMed  CAS  Google Scholar 

  17. Kobayashi S, Iwamoto M, Kon K et al (2010) Acetyl-L-carnitine improves aged brain function. Geriatr Gerontol Int 10:S99–S106

    Google Scholar 

  18. Toth E, Harsing LG Jr, Sershen H et al (1993) Effect of acetyl-L-carnitine on extracellular amino acid levels in vivo in rat brain regions. Neurochem Res 18:573–578

    Article  PubMed  CAS  Google Scholar 

  19. Gherlandini C, Galeotti N, Calvani M et al (2002) Acetyl-l-carnitine induces muscarinic antinocieption in mice and rats. Neuropharmacology 43:1180–1187

    Article  Google Scholar 

  20. Pettegrew JW, Levine J, McClure RJ (2000) Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry 5:616–632

    Article  PubMed  CAS  Google Scholar 

  21. Arienti G, Ramacci MT, Maccari F et al (1992) Acetyl-L-carnitine influences the fluidity of brain microsomes and of liposomes made of rat brain microsomal lipid extracts. Neurochem Res 17:671–675

    Article  PubMed  CAS  Google Scholar 

  22. Corbucci GG, Melis A, Piga M et al (1992) Influence of acetyl-carnitine on some mitochondrial enzymic activities in the human cerebral tissue in conditions of acute hypoxia. Int J Tiss Reac 14:183–194

    CAS  Google Scholar 

  23. Blokland A, Bothmer J, Honig W et al (1993) Behavioural and biochemical effects of acute central metabolic inhibition: effects of acetyl-L-carnitine. Eur J Pharmacol 235:275–281

    Article  PubMed  CAS  Google Scholar 

  24. Barhwal K, Singh SB, Hota SK et al (2007) Acetyl-L-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 570:97–107

    Article  PubMed  CAS  Google Scholar 

  25. Barhwal K, Hota SK, Prasad D et al (2008) Hypoxia-induced deactivation of NGF-mediated ERK1/2 signaling in hippocampal cells: neuroprotection by acetyl-L-carnitine. J Neurosci Res 86:2705–2721

    Article  PubMed  CAS  Google Scholar 

  26. Rosadini G, Marenco S, Nobili F et al (1990) Acute effects of acetyl-L-carnitine on regional cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol Res 10:123–128

    PubMed  CAS  Google Scholar 

  27. Shuaib A, Waqaar T, Wishart T et al (1995) Acetyl-L-carnitine attenuates neuronal damage in gerbils with transient forebrain ischemia only when given before the insult. Neurochem Res 9:1021–1025

    Article  Google Scholar 

  28. Zanelli SA, Solenski NJ, Rosenthal RE et al (2005) Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann NY Acad Sci 1053:153–161

    Article  PubMed  CAS  Google Scholar 

  29. Jalal FY, Böhlke M, Maher TJ (2010) Acetyl-L-carnitine reduces the infarct size and striatal glutamate outflow following focal cerebral ischemia in rats. Ann NY Acad Sci 1199:95–104

    Article  PubMed  CAS  Google Scholar 

  30. Onofrj M, Fulgente T, Melchionda D et al (1995) l-acetylcarnitine as a new therapeutic approach for peripheral neuropathies with pain. Int J Clin Pharmacol Res 15:9–15

    PubMed  CAS  Google Scholar 

  31. Taglialatela G, Navarra D, Cruciani R et al (1994) Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. Exp Gerontol 29:55–66

    Article  PubMed  CAS  Google Scholar 

  32. Kentroti S, Ramacci MT, Vernadakis A (1992) Acetyl-L-carnitine has a neuromodulatory influence on neuronal phenotypes during early embryogenesis in the chick embryo. Dev Brain Res 70:259–266

    Article  CAS  Google Scholar 

  33. Lin SC, Way EL (1982) Calcium-activated ATPases in presynaptic nerve endings. J Neurochem 39:1641–1651

    Article  PubMed  CAS  Google Scholar 

  34. Benzi G, Gorini A, Ghigini B et al (1994) Modifications by hypoxia and drug treatment of cerebral ATPase plasticity. Neurochem Res 19:517–524

    Article  PubMed  CAS  Google Scholar 

  35. Ellman GL, Courtney KD, Andres V et al (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–96

    Article  PubMed  CAS  Google Scholar 

  36. Smith L (1955) Spectrophotometric assay of cytochrome c oxidase. In: Glick D (ed) Methods of biochemical analysis. Wiley Interscience, New York, pp 427–434

    Chapter  Google Scholar 

  37. Wharton DC, Tzagoloff A (1977) Cytochrome oxidase from beef heart mitochondria. In: Estabrook RW, Pulman ME (eds) Methods in enzymology. Academic Press, New York, pp 245–250

    Google Scholar 

  38. Bergmeyer HU, Bernt E (1974) Lactate dehydrogenase: UV-assay with pyruvate and NADH. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Academic Press, New York, pp 574–579

    Google Scholar 

  39. Shallom JM, Katyare SS (1985) Altered synaptosomal ATPase activity in rat brain following prolonged in vivo treatment with nicotine. Biochem Pharmacol 34:3445–3449

    Article  PubMed  CAS  Google Scholar 

  40. Palayoor ST, Seyfried TN, Bernard DJ (1986) Calcium ATPase activities in synaptic plasma membranes of seizure-prone mice. J Neurochem 46:1370–1375

    Article  PubMed  CAS  Google Scholar 

  41. Le Bel D, Poirier GG, Beaudolin AR (1978) A convenient method for the ATPase assay. Anal Biochem 85:86–89

    Article  CAS  Google Scholar 

  42. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  43. Villa RF, Turpeenoja L, Benzi G et al (1988) Action of l-acetylcarnitine on age-dependent modifications of mitochondrial membrane protein from rat cerebellum. Neurochem Res 13:909–916

    Article  PubMed  CAS  Google Scholar 

  44. Villa RF, Gorini A, Hoyer S (2002) ATPases of synaptic plasma membranes from hippocampus after ischemia and recovery during ageing. Neurochem Res 27:861–870

    Article  PubMed  CAS  Google Scholar 

  45. Gorini A, Rancati A, D’Angelo A et al (2000) Effect of in vivo administration of Naloxone on ATP-ase’s enzyme systems of synaptic plasma membranes from rat cerebral cortex. Neurochem Res 25:867–873

    Article  PubMed  CAS  Google Scholar 

  46. Gorini A, Villa RF (2001) Effect of in vivo treatment of Clonidine on ATP-ase’s enzyme systems of synaptic plasma membranes from rat cerebral cortex. Neurochem Res 26:819–825

    Article  Google Scholar 

  47. Cotman CW, Matthews DA (1971) Synaptic plasma membranes from rat brain synaptosomes: isolation and partial characterization. Biochim Biophys Acta 249:380–394

    Article  PubMed  CAS  Google Scholar 

  48. Gurd JW, Jones LR, Mahler HR et al (1974) Isolation and partial characterization of rat brain synaptic plasma membranes. J Neurochem 22:281–290

    Article  PubMed  CAS  Google Scholar 

  49. Gorini A, Canosi U, Devecchi E et al (2002) ATPases enzyme activities during aging in different types of somatic and synaptic plasma membranes from rat frontal cerebral cortex. Prog Neuropsychopharmacol Biol Psychiatry 26:81–90

    Article  PubMed  CAS  Google Scholar 

  50. Lin SC, Way EL (1982) A high affinity Ca2+-ATPase in enriched nerve-ending plasma membranes. Brain Res 235:387–392

    Article  PubMed  CAS  Google Scholar 

  51. Michaelis EK, Michaelis ML, Chang HH et al (1983) High affinity Ca2+-stimulated Mg2+-dependent ATPase in rat brain synaptosomes, synaptic membranes, and microsomes. J Biol Chem 258:6101–6108

    PubMed  CAS  Google Scholar 

  52. Berridge MJ (2004) Calcium signal transduction and cellular control mechanisms. Biochim Biophys Acta 1742:3–7

    Article  PubMed  CAS  Google Scholar 

  53. Ross DH, Cardenas HL (1983) Calmodulin stimulation of Ca2+-dependent ATP hydrolysis and ATP-dependent transport in synaptic membranes. J Neurochem 41:161–171

    Article  PubMed  CAS  Google Scholar 

  54. Douglas WW (1968) Stimulus-secretion coupling: the concept and clues from chromaffin and other cells. Br J Pharmacol 34:451–474

    PubMed  CAS  Google Scholar 

  55. Powis DA, Wattus GD (1981) The stimulatory effect of calcium on Na, K-ATPase of nervous tissue. FEBS Lett 126:285–288

    Article  PubMed  CAS  Google Scholar 

  56. Lin SC, Way EL (1984) Characterization of calcium-activated and magnesium-activated ATPases of brain nerve endings. J Neurochem 42:1697–1706

    Article  PubMed  CAS  Google Scholar 

  57. Gandhi CR, Ross DH (1988) Characterization of a high-affinity Mg2+-independent Ca2+-ATPase from rat brain synaptosomal membranes. J Neurochem 50:248–256

    Article  PubMed  CAS  Google Scholar 

  58. Villa RF, Gorini A, Hoyer S (2006) Differentiated effect of aging of Krebs’ cycle, electron transfer complexes and glutamate metabolism of non-synaptic and intra-synaptic mitochondria from cerebral cortex. J Neural Transm 113:1659–1670

    Article  PubMed  CAS  Google Scholar 

  59. Villa RF, Gorini A, Hoyer S (2009) Effect of ageing and ischemia on enzymatic activities linked to Krebs’ cycle, electron transfer chain, glutamate and amino acids metabolism of free and intra-synaptic mitochondria of cerebral cortex. Neurochem Res 34:2102–2116

    Article  PubMed  CAS  Google Scholar 

  60. Rosca MG, Lemieux H, Hoppel CL (2009) Mitochondria in the elderly: is acetylcarnitine a rejuvenator? Adv Drug Deliv Rev 61:1332–1342

    Article  PubMed  CAS  Google Scholar 

  61. Long J, Gao F, Tong L et al (2009) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res 34:755–763

    Article  PubMed  CAS  Google Scholar 

  62. Packer L, Witt EH, Tritschler HJ (1995) Alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med 19:227–250

    Article  PubMed  CAS  Google Scholar 

  63. Battino M, Fato R, Parenti-Castelli G et al (1990) Coenzyme Q can control the efficiency of oxidative phosphorylation. Int J Tissue React 12:137–144

    PubMed  CAS  Google Scholar 

  64. Lenaz G, Battino M, Castelluccio C et al (1990) Studies on the role of ubiquinone in the control of the mitochondrial respiratory chain. Free Rad Res Commun 8:317–327

    Article  CAS  Google Scholar 

  65. Rauchová H, Battino M, Fato R et al (1992) Coenzyme Q-pool function in glycerol-3-phosphate oxidation in hamster brown adipose tissue mitochondria. J Bioenerg Biomembr 24:235–241

    Article  PubMed  Google Scholar 

  66. Ragusa N, Turpeenoja L, Magri G et al (1989) Age-dependent modifications of mitochondrial proteins in cerebral cortex and striatum of rat brain. Neurochem Res 14:415–418

    Article  PubMed  CAS  Google Scholar 

  67. Mata M, Fink DJ, Gairner H et al (1980) Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem 34:213–215

    Article  PubMed  CAS  Google Scholar 

  68. Mishra OP, Delivoria-Papadopoulos M, Cahillane G et al (1990) Lipid peroxidation as the mechanism of modification of the affinity of the Na+, K+-ATPase active sites for ATP, K+, Na+, and strophanthidin in vitro. Neurochem Res 14:845–851

    Article  Google Scholar 

  69. Chakraborty H, Sen P, Sur A et al (2003) Age-related oxidative inactivation of Na+, K+-ATPase in rat brain crude synaptosomes. Exp Gerontol 38:705–710

    Article  PubMed  CAS  Google Scholar 

  70. Viani P, Cervato G, Fiorilli A et al (1991) Age-related differences in synaptosomal peroxidative damage and membrane properties. J Neurochem 56:253–258

    Article  PubMed  CAS  Google Scholar 

  71. Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184

    Article  PubMed  CAS  Google Scholar 

  72. Carta A, Calvani M (1991) Acetyl-L-carnitine: a drug able to slow the progress of Alzheimer’s disease? Ann NY Acad Sci 640:228–232

    PubMed  CAS  Google Scholar 

  73. Beauregard G, Roufogalis BD (1977) The role of tightly bound phospholipid in the activity of erythrocyte acetylcholinesterase. Biochem Biophys Res Commun 77:211–219

    Article  PubMed  CAS  Google Scholar 

  74. Rieger F, Vigny M (1976) Solubilization and physicochemical characterization of rat brain acetylcholinesterase: development and maturation of its molecular forms. J Neurochem 27:121–129

    Article  PubMed  CAS  Google Scholar 

  75. Nemat-Gorgani M, Meisami E (1979) Use of Arrhenius plots of Na-K ATPase and acetylcholinesterase as a tool for studying changes in lipid-protein interactions in neuronal membranes during brain development. J Neurochem 32:1027–1032

    Article  PubMed  CAS  Google Scholar 

  76. Toll L, Howard BD (1978) Role of Mg2+-ATPase and a pH gradient in the storage of catecholamines in synaptic vesicles. Biochemistry 17:2517–2523

    Article  PubMed  CAS  Google Scholar 

  77. Nagy A, Shuster TA, Rosemberg MD (1983) Adenosine triphosphatase activity at the external surface of chicken brain synaptosomes. J Neurochem 40:226–234

    Article  PubMed  CAS  Google Scholar 

  78. Fyske EM, Fonnum F (1991) Transport of gamma-aminobutyrate and L-glutamate into synaptic vesicles. Effect of different inhibitors on the vesicular uptake of neurotransmitters and on the Mg2+-ATPase. Biochem J 276:363–367

    Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Italian Ministry of University and Technological and Scientific Research (M.U.R.S.T.) and partially by Sigma-Tau, Rome.

Author information

Authors and Affiliations

  1. Department of Forensic Medicine and Pharmacological-Toxicological Sciences, Division of Pharmacological and Toxicological Sciences, Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, University of Pavia, Via Ferrata, 9, 27100, Pavia, Italy

    Roberto Federico Villa, Federica Ferrari & Antonella Gorini

Authors
  1. Roberto Federico Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonella Gorini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Federico Villa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Villa, R.F., Ferrari, F. & Gorini, A. Effect of In Vivo l-Acetylcarnitine Administration on ATP-ases Enzyme Systems of Synaptic Plasma Membranes from Rat Cerebral Cortex. Neurochem Res 36, 1372–1382 (2011). https://doi.org/10.1007/s11064-011-0462-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0462-x

Keywords

Search

Navigation