Abstract
A high proportion of research relating to cerebral ischemia focuses on neuroprotection. The application of compounds normally present in the organism is popular, because they do not greatly influence the synaptic activity by receptor modulation, and can be administered without serious side effects. Oxaloacetate (OxAc) and acetyl-L-carnitine (ALC) are such favorable endogenous molecules. ALC can exert a protective effect by improving the energy state of the neurons under ischemic conditions. A promising neuroprotective strategy is glutamate scavenging, which can be achieved by the intravenous administration of OxAc. This study involved the possible protective effects of ALC and OxAc in different post-treatment protocols against long-term potentiation (LTP) impairment. Ischemia was induced in rats by 2-vessel occlusion, which led to a decreased LTP relative to the control group. High-dose (200 mg/kg) ALC or OxAc post-treatment resulted in a higher potentiation relative to the 2VO group, but it did not reach the control level, whereas low-dose ALC (100 mg/kg) in combination with OxAc completely restored the LTP function. Many previous studies have concluded that ALC can be protective only as pretreatment. The strategy described here reveals that ALC can also be neuroprotective when utilized as post-treatment against ischemia.
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References
Borum PR (1983) Carnitine. Ann Rev Nutr 3:233–259. doi:10.1146/annurev.nu.03.070183.001313
Castillo J, Davalos A, Naveiro J, Noya M (1996) Neuroexcitatory amino acids and their relation to infarct size and neurological deficit in ischemic stroke. Stroke J Cereb Circ 27:1060–1065
Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397
Fukuchi T, Katayama Y, Kamiya T, McKee A, Kashiwagi F, Terashi A (1998) The effect of duration of cerebral ischemia on brain pyruvate dehydrogenase activity, energy metabolites, and blood flow during reperfusion in gerbil brain. Brain Res 792:59–65
Gottlieb M, Wang Y, Teichberg VI (2003) Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem 87:119–126
Jalal FY, Bohlke M, Maher TJ (2010) Acetyl-L-carnitine reduces the infarct size and striatal glutamate outflow following focal cerebral ischemia in rats. Ann N Y Acad Sci 1199:95–104. doi:10.1111/j.1749-6632.2009.05351.x
Jones LL, McDonald DA, Borum PR (2010) Acylcarnitines: role in brain. Prog Lipid Res 49:61–75. doi:10.1016/j.plipres.2009.08.004
Kocsis K et al (2014) Acetyl-L-carnitine normalizes the impaired long-term potentiation and spine density in a rat model of global ischemia. Neuroscience 269:265–272. doi:10.1016/j.neuroscience.2014.03.055
Lozano R et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study. Lancet 380:2095–2128. doi:10.1016/S0140-6736(12)61728-0
Malaguarnera M et al (2011) Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol 46:750–759. doi:10.3109/00365521.2011.565067
Marosi M et al (2009) Oxaloacetate restores the long-term potentiation impaired in rat hippocampus CA1 region by 2-vessel occlusion. Eur J Pharmacol 604:51–57. doi:10.1016/j.ejphar.2008.12.022
Martin E, Rosenthal RE, Fiskum G (2005) Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress. J Neurosci Res 79:240–247. doi:10.1002/jnr.20293
O’Kane RL, Martinez-Lopez I, DeJoseph MR, Vina JR, Hawkins RA (1999) Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J Biol Chem 274:31891–31895
Picconi B et al (2006) Acetyl-L-carnitine protects striatal neurons against in vitro ischemia: the role of endogenous acetylcholine. Neuropharmacology 50:917–923. doi:10.1016/j.neuropharm.2006.01.002
Rani PJ, Panneerselvam C (2002) Effect of L-carnitine on brain lipid peroxidation and antioxidant enzymes in old rats The journals of gerontology Series A. Biol Sci Med Sci 57:B134–B137
Reed LJ (1981) Regulation of mammalian pyruvate dehydrogenase complex by a phosphorylation-dephosphorylation cycle. Curr Top Cell Regul 18:95–106
Shuaib A, Waqaar T, Wishart T, Kanthan R, Howlett W (1995) Acetyl-L-carnitine attenuates neuronal damage in gerbils with transient forebrain ischemia only when given before the insult. Neurochem Res 20:1021–1025
Sims NR (1995) Calcium, energy metabolism and the development of selective neuronal loss following short-term cerebral ischemia. Metab Brain Dis 10:191–217
Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A (2009) Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158:301–308. doi:10.1016/j.neuroscience.2008.02.075
Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G (2005) Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann N Y Acad Sci 1053:153–161. doi:10.1196/annals.1344.013
Zlotnik A, Gurevich B, Tkachov S, Maoz I, Shapira Y, Teichberg VI (2007) Brain neuroprotection by scavenging blood glutamate. Exp Neurol 203:213–220. doi:10.1016/j.expneurol.2006.08.021
Acknowledgments
This work was supported by grants from OTKA K105077, Hungarian Brain Research Program KTIA-13-NAP-A-III/9 and TÁMOP 4.2.2-A-11/KONV-2012-0052. This research was realized in the frames of TÁMOP 4.2.4 A/2-11-1-2012-0001 “National Excellence Program”—Elaborating and operating an inland student and researcher personal support system”. The project was subsidized by the European Union and co-financed by the European Social Fund.
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Kocsis, K., Knapp, L., Mészáros, J. et al. Acetyl-L-carnitine and oxaloacetate in post-treatment against LTP impairment in a rat ischemia model. An in vitro electrophysiological study. J Neural Transm 122, 867–872 (2015). https://doi.org/10.1007/s00702-014-1343-7
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DOI: https://doi.org/10.1007/s00702-014-1343-7