Cytoprotective Effect of Acetyl-l-Carnitine Evidenced by Analysis of Gene Expression in the Rat Brain

Molecular Neurobiology - Tập 39 - Trang 101-106 - 2009
Giovanna Traina1, Giuseppe Federighi2, Marcello Brunelli2, Rossana Scuri2
1Department of Internal Medicine, University of Perugia, Perugia, Italy
2Department of Biology, Unit of General Physiology, University of Pisa, Pisa, Italy

Tóm tắt

Acetyl-l-carnitine (ALC), the acetyl ester of l-carnitine, is a naturally occurring substance that when administered at supraphysiological concentrations is neuroprotective. ALC plays an essential role in intermediary and mitochondrial metabolism. It has also neurotrophic and antioxidant actions. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various etiologies, and it is a molecule of considerable interest for its clinical application in various neural disorders, such as Alzheimer’s disease and painful neuropathies, although little is known regarding the effects of ALC on gene expression. Suppression subtractive hybridization methodology was used for the generation of subtracted complementary DNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after a chronic ALC treatment. In the present paper, we provide evidences for the up-regulation of the expression of prostaglandin D2 synthase, brain-specific Na+-dependent inorganic phosphate transporter, and cytochrome b oxidase, bc1 complex induced in the rat brain by ALC. On the contrary, ALC treatment down-regulates the expression of the gene of ferritin-H. Altogether, these results suggest that ALC might play a cytoprotective role against various brain stressors.

Tài liệu tham khảo

Bieber LL (1988) Carnitine. Annu Rev Biochem 57:261–283 Nalecz KA, Miecz D, Berezowski V, Cecchelli R (2004) Carnitine: transport and physiological functions in the brain. Mol Aspects Med 25:551–567 Shea TB (2007) Effects of dietary supplementation with N-acetyl cysteine, acetyl-l-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4. Neuromolecular Med 9(3):264–269 Virmani A, Binienda Z (2004) Role of carnitine esters in brain neuropathology. Mol Aspects Med 25:533–549 Bodis-Wollner I (1990) Physiological effects of acetyl levo carnitine in the central nervous system. Int J Clin Pharmacol Res 10:109–114 Kidd PM (1999) A review of nutrients and botanicals in the integrative management of cognitive dysfunctions. Altitude Med Rev 4:144–161 Calvani M, Arrigoni-Martelli E (1999) Attenuation by acetyl-l-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion. Int J Tissue React 21:1–6 Ori C, Freo U, Pizzolato G, Dam M (2002) Effects of acetyl-l-carnitine on regional cerebral glucose metabolism in awake rats. Brain Res 951:330–335 McDaniel MA, Maier SF, Einstein GO (2003) “Brain-specific” nutrients: a memory cure? Nutrition 19:957–975 Tanaka M, Nakamura F, Mizokawa S, Matsumura A, Matsumura K, Yasuyoshi W (2003) Role of acetyl-l-carnitine in the brain: revealed by bioradiography. Biochem Biophys Res Commun 306:1064–1069 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 Bertoni-Freddari C, Fattoretti P, Casoli T, Spagna C, Casell U (1994) Dynamic morphology of the synaptic junctional areas during aging: the effect of chronic acetyl-l-carnitine administration. Brain Res 656:359–366 Castorina M, Ferraris L (1994) Acetyl-l-carnitine affects aged brain receptorial system in rodents. Life Sci 54:1205–1214 Ando S, Tadenuma T, Tanaka Y, Fukui F, Kobayashi S, Ohashi Y, Kawabata TJ (2001) Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats. Neurosci Res 66:266–271 Calò LA, Pagnin E, Davis PA, Semplicioni A, Nicolai R, Calvani M, Pessina AC (2006) Antioxidant effect of l-carnitine and its short chain esters relevance for the protection from oxidative stress related cardiovascular damage. Int J Cardiol 107:54–60 Manfridi A, Forloni GL, Arrigoni-Martelli E, Mancia M (1992) Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-l-carnitine and NGF. Int J Dev Neurosci 10:321–329 Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS (2000) Biologic activity of mitochondrial metabolites on aging and age-related hearing loss. Am J Otol 21:161–167 White HL, Scates PW (1990) Acetyl l-carnitine as a precursor of acetylcholine. Neurochem Res 15:597–601 Barhwal K, Singh SB, Hota SK, Jayalakshmi K, Ilavazhagan G (2007) Acetyl-l-carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 570(1–3):97–107 Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED, Siebert PD (1996) Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci U S A 93(12):6025–6030 Traina G, Valleggi S, Bernardi R, Rizzo M, Calvani M, Nicolai R, Mosconi L, Durante M, Brunelli M (2004) Identification of differentially expressed genes induced in the rat brain by acetyl-l-carnitine as evidenced by suppression subtractive hybridisation. Mol Brain Res 132:57–63 Traina G, Bernardi R, Cataldo E, Macchi M, Durante M, Brunelli M (2008) In the rat brain acetil-l-carnitine treatment modulates the expression of gene involved in neuronal ceroid lipofuscinosis. Mol Neurobiol 38(2):146–152 Traina G, Federighi G, Brunelli M (2008) Up-regulation of kinesin light-chain 1 gene expression by acetyl-l carnitine: therapeutic possibility in Alzheimer’s disease. Neurochem Int 53:244–247 Traina G, Bernardi R, Rizzo M, Calvani M, Durante M, Brunelli M (2006) Acetyl-l-carnitine up-regulates expression of voltage-dependent anion channel in the rat brain. Neurochem Int 48:673–678 Jin HW, Flatters SJ, Xiao WH, Mulhern HL, Bennett GJ (2008) Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Exp Neurol 210:229–237 Sambrook J, Fristch EF, Maniatis T (1989) Extraction and purification of RNA, molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor laboratory Press, New York, pp 7.3–7.83 Calabrese V, Cornelius C, Mancuso C, Pennisi G, Calafato S, Bellia F, Bates TE, Giuffrida Stella AM, Schapira T, Dinkova Kostova AT, Rizzarelli E (2008) Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 33(12):2444–2471 Liang X, Liejun W, Tracey H, Katrin A (2005) Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 92(3):477–486 Lin TN, Cheung WM, Wu JS, Chen JJ, Lin H, Chen JJ, Liou JY, Shyue SK, Wu KK (2006) 15d-prostaglandin J2 protects brain from ischemia–reperfusion injury. Arterioscler Thromb Vasc Biol 26:481–487 Bellocchio EE, Reimer RJ, Fremeau RT Jr, Edwards RH (2000) Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289(5481):957–60 Glinn M, Ni B, Irwin RP, Kelley SW, Lin SZ, Paul SM (1998) Inorganic Pi increases neuronal survival in the acute early phase following excitotoxic/oxidative insults. J Neurochem 70(5):1850–1858 Raush WD, Hirada Y, Nagatsu T, Riederer P, Jellinger K (1988) Tyrosine hydroxylase activity in caudate nucleus from Parkinson’s disease: effect of iron and phosphorylating agents. J Neurochem 50:202–208 Wrigglesworth JM, Baum H (1988) Iron-dependent enzymes in the brain. In: Youdim MBH (ed) The brain iron: neurochemical and behavioral aspects. Taylor and Francis, Philadelphia, pp 25–66 Nappi AJ, Vass E (2000) Iron, metalloenzymes and cytotoxic reactions. Cell Mol Biol 46(3):637–647 Wu CG, Groenink M, Bosma A, Reitsma PH, vanDeventer SJH, Chamuleau RAFM (1997) Rat ferritin-H: cDNA cloning, differential expression and localization during hepatocarcinogenesis. Carcinogenesis 18:47–52 Connor JR, Menzies SL (1995) Cellular management of iron in the brain. J Neurol Sci 134:33–44 Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74(3):199–205 Petzold A, Eikelenboom J, Gveric D, Keir G, Chapman M, Lazeron RHC, Cuzner ML, Polman CH, Uitdehaag BMJ, Thompson EJ, Giovannoni G (2002) Marker for different glial cell responses in multiple sclerosis: clinical and pathological correlation. Brain 125:1462–1463 Worwood M (1980) Serum ferritin and iron deficiency anaemia in hospital patients. Lancet 1:375–376 Sanyal B, Polak PE, Szuchet S (1996) Differential expression of the heavy-chain ferritin gene in non-adhered and adhered oligodendrocytes. J Neurosci Res 46:187–197 Lal A, Atamna W, Killilea DW, Suh JH, Ames BN (2008) Lipoic acid and acetyl-carnitine reverse iron-induced oxidative stress in human fibroblasts. Redox Rep 13(1):2–10 Quereshi MY (1998) Stability of some hypothesized psychological determinants of fertility control. Psychol Rep 82(2):657–658