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Alpha Lipoic Acid Alleviates Oxidative Stress and Preserves Blood Brain Permeability in Rats with Subarachnoid Hemorrhage

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Abstract

The neuroprotective effect of alpha lipoic acid (ALA; 100 mg/kg, po), a dithiol antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) was assessed in Wistar albino rats. Neurological examination scores recorded at the 48th h of SAH induction were increased in SAH groups, which were accompanied with significant increases in the formation of reactive oxygen species, DNA fragmentation ratios, malondialdehyde levels and myeloperoxidase activity, while significant decreases in the brain glutathione content and Na+, K+-ATPase activity were observed. On the other hand, ALA treatment reversed all these biochemical indices as well as SAH-induced histopathological alterations. Increased brain edema, impaired blood-brain-barrier permeability and neurological scores were also improved by ALA treatment. The results demonstrate that ALA exerts neuroprotective effects via the enhancement of endogenous antioxidant enzyme activity, the inhibition of neutrophil accumulation and free radical generation, suggesting a therapeutic potential in reducing secondary injury after SAH in patients.

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References

  1. Koźniewska E, Michalık R, Rafałowska J et al (2006) Mechanisms of vascular dysfunction after subarachnoid hemorrhage. J Physiol Pharmacol 57(Suppl 11):145–160

    PubMed  Google Scholar 

  2. Takao A (1999) Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions. Crit Rev Neurosurg 9:303–318

    Article  Google Scholar 

  3. Broderick JP, Brott TG, Duldner JE et al (1994) Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 25:1342–1347

    CAS  PubMed  Google Scholar 

  4. Hütter BO, Kreitschmann-Andermahr I, Gilsbach JM (2001) Health-related quality of life after aneurysmal subarachnoid hemorrhage: impacts of bleeding severity, computerized tomography findings, surgery, vasospasm, and neurological grade. J Neurosurg 94:241–251

    Article  PubMed  Google Scholar 

  5. Peyrot F, Ducrocq C (2008) Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species. J Pineal Res 45:235–246

    Article  CAS  PubMed  Google Scholar 

  6. Nishizawa S, Yamamoto S, Yokoyama T et al (1997) Dysfunction of nitric oxide induces protein kinase C activation resulting in vasospasm after subarachnoid hemorrhage. Neurol Res 19:558–562

    CAS  PubMed  Google Scholar 

  7. Imperatore C, Germano A, d’Avella D et al (2000) Effects of the radical scavenger AVS on behavioral and BBB changes after experimental subarachnoid hemorrhage. Life Sci 66:779–790

    Article  CAS  PubMed  Google Scholar 

  8. Ostrowski RP, Tang J, Zhang JH (2006) Hyperbaric oxygen suppresses NADPH oxidase in a rat subarachnoid hemorrhage model. Stroke 37:1314–1318

    Article  CAS  PubMed  Google Scholar 

  9. Asano T, Takakura K, Sano K et al (1996) Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial. J Neurosurg 84:792–803

    Article  CAS  PubMed  Google Scholar 

  10. Haley EC Jr, Kassell NF, Apperson-Hansen C et al (1997) A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 86:467–474

    Article  CAS  PubMed  Google Scholar 

  11. Karaoglan A, Akdemir O, Barut S et al (2008) The effects of resveratrol on vasospasm after experimental subarachnoidal hemorrhage in rats. Surg Neurol 70:337–343

    Article  PubMed  Google Scholar 

  12. Aladag MA, Turkoz Y, Ozcan C et al (2006) Caffeic acid phenethyl ester (CAPE) attenuates cerebral vasospasm after experimental subarachnoidal haemorrhage by increasing brain nitric oxide levels. Int J Dev Neurosci 24:9–14

    Article  CAS  PubMed  Google Scholar 

  13. Green AR, Ashwood T (2005) Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord 4:109–118

    Article  CAS  PubMed  Google Scholar 

  14. Munakata A, Ohkuma H, Nakano T et al (2009) Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 64:423–428 (discussion 428-9)

    Article  PubMed  Google Scholar 

  15. Ersahin M, Toklu HZ, Cetinel S et al (2009) Melatonin reduces experimental subarachnoid hemorrhage-induced oxidative brain damage and neurological symptoms. J Pineal Res 46:324–332

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Moini H, Packer L, Saris NE (2002) Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 182:84–90

    Article  CAS  PubMed  Google Scholar 

  18. Packer L (1998) Alpha-lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev 30:245–275

    Article  CAS  PubMed  Google Scholar 

  19. Vincent AM, Stevens MJ, Backus C et al (2005) Cell culture modeling to test therapies against hyperglycemia-mediated oxidative stress and injury. Antioxid Redox Signal 7:1494–1506

    Article  CAS  PubMed  Google Scholar 

  20. Bharat S, Cochran BC, Hsu M et al (2002) Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson’s disease therapy. Neurotoxicology 23:479–486

    Article  CAS  PubMed  Google Scholar 

  21. Abdul HM, Butterfield DA (2007) Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-Lcarnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med 42:371–384

    Article  PubMed  CAS  Google Scholar 

  22. Toklu HZ, Hakan T, Biber N et al (2009) The protective effect of alpha lipoic acid against traumatic brain injury in rats. Free Radic Res 25:1–10

    Google Scholar 

  23. do Vale OC, Fonteles DS, Cabral FR et al (2003) A dual action of alpha-lipoic acid in the brain: an electrophysiological evaluation. Arq Neuropsiquiatr 61(3B):738–745

    PubMed  Google Scholar 

  24. Freitas RM (2009) The evaluation of effects of lipoic acid on the lipid peroxidation, nitrite formation and antioxidant enzymes in the hippocampus of rats after pilocarpine-induced seizures. Neurosci Lett 455:140–144

    Article  CAS  PubMed  Google Scholar 

  25. Jones RE, Moes N, Zwickey H et al (2008) Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning. Brain Behav Immun 22:538–543

    Article  CAS  PubMed  Google Scholar 

  26. Delgado TJ, Brismar J, Svendgaard NA (1985) Subarachnoid haemorrhage in the rat: angiography and fluorescence microscopy of the major cerebral arteries. Stroke 16:595–602

    CAS  PubMed  Google Scholar 

  27. Bederson JB, Pitts LH, Tsuji M et al (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurological examination. Stroke 17:472–476

    CAS  PubMed  Google Scholar 

  28. Haklar G, Yüksel M, Yalçın AS (1998) Chemiluminescence in the measurement of free radicals: theory and application on a tissue injury model. Marmara Med J 11:56–60

    Google Scholar 

  29. Wyllie H (1980) Glucocorticoid induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555–556

    Article  CAS  PubMed  Google Scholar 

  30. Burton K (1956) A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J 62:315–323

    CAS  PubMed  Google Scholar 

  31. Beuge JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 53:302–311

    Article  Google Scholar 

  32. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    CAS  PubMed  Google Scholar 

  33. Hillegas LM, Griswold DE, Brickson B et al (1990) Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods 24:285–295

    Article  Google Scholar 

  34. Reading HW, Isbir T (1980) The role of cation activated ATPase in transmitter release from the rat iris. Q J Exp Physiol 65:105–116

    CAS  Google Scholar 

  35. Fiske CH, Subbarow Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–400

    CAS  Google Scholar 

  36. Lowry OH, Rosenbrough NJ, Farr AL et al (1951) Protein measurements with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  37. Paravicini TM, Sobey CG (2003) Cerebral vascular effects of reactive oxygen species: recent evidence for a role of NADPH-oxidase. Clin Exp Pharmacol Physiol 30:855–859

    Article  CAS  PubMed  Google Scholar 

  38. Panigrahi M, Sadguna Y, Shivakumar BR et al (1996) Alpha-lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Brain Res 717:184–188

    Article  CAS  PubMed  Google Scholar 

  39. Lee WJ, Lee IK, Kim HS, Kim YM et al (2005) Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol 25:2488–2494

    Article  CAS  PubMed  Google Scholar 

  40. Sena CM, Nunes E, Louro T (2007) Effects of alpha-lipoic acid on endothelial function in aged diabetic and high-fat fed rats. Br J Pharmacol. doi:10.1038/sj.bjp.0707474 (e-pub ahead of print 1 October 2007)

    PubMed  Google Scholar 

  41. Smith AR, Hagen TM (2003) Vascular endothelial dysfunction in aging: loss of Akt-dependent endothelial nitric oxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid. Biochem Soc Trans 31:1447–1449

    Article  CAS  PubMed  Google Scholar 

  42. Sola S, Mir MQ, Cheema FA et al (2005) Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation 111:343–348

    Article  CAS  PubMed  Google Scholar 

  43. Maczurek A, Hager K, Kenklies M et al (2008) Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv Drug Deliv Rev 60:1463–1470

    Article  CAS  PubMed  Google Scholar 

  44. Ambrus A, Tretter L, Adam-Vizi V (2009) Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid. J Neurochem 109(Suppl 1):222–229

    Article  CAS  PubMed  Google Scholar 

  45. Germanó A, d’Avella D, Cicciarello R et al (1992) Blood-brain barrier permeability changes after experimental subarachnoid hemorrhage. Neurosurgery 30:882–886

    Article  PubMed  Google Scholar 

  46. Del Zoppo GJ, Hallenbeck JM (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb Res 98:73–81

    Article  CAS  PubMed  Google Scholar 

  47. Dóczi TP, Joó F, Adam G et al (1986) Blood-brain barrier damage during the acute stage of subarachnoid hemorrhage, as exemplified by a new animal model. Neurosurgery 18:733–739

    Article  PubMed  Google Scholar 

  48. Dóczi TP, Joó F, Balás I (1995) Atrial natriuretic peptide (ANP) attenuates brain oedema accompanying experimental subarachnoid haemorrhage. Acta Neurochir (Wien) 132:87–91

    Article  Google Scholar 

  49. Streck EL, Feier G, Búrigo M et al (2006) Effects of electroconvulsive seizures on Na(+), K(+)-ATPase activity in the rat hippocampus. Neurosci Lett 404:254–257

    Article  CAS  PubMed  Google Scholar 

  50. Grisar T (1984) Glial and neuronal Na+–K+ pump in epilepsy. Ann Neurol 16(Suppl):S128–S134

    Article  CAS  PubMed  Google Scholar 

  51. de Souza Wyse AT, Streck EL, Worm P et al (2000) Preconditioning prevents the inhibition of Na+, K+-ATPase activity after brain ischemia. Neurochem Res 25:971–975

    Article  PubMed  Google Scholar 

  52. Yang YB, Piao YJ (2003) Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin 24:703–710

    CAS  PubMed  Google Scholar 

  53. Stys PK (1998) Anoxic and ischemic injury of myelinated axons in CNS white matter: from mechanistic concepts to therapeutics. J Cereb Blood Flow Metab 18:2–25

    Article  CAS  PubMed  Google Scholar 

  54. Morini M, Roccatagliata L, Dell’Eva R et al (2004) Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol 148:146–153

    Article  CAS  PubMed  Google Scholar 

  55. Kolias AG, Sen J, Belli A (2009) Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches. J Neurosci Res 87:1–11

    Article  CAS  PubMed  Google Scholar 

  56. Ayer RE, Zhang JH (2008) Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl 104:33–41

    Article  CAS  PubMed  Google Scholar 

  57. Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890

    Article  CAS  PubMed  Google Scholar 

  58. Reiter RJ, Tan DX, Acuna-Castroviejo D et al (2000) Melatonin: mechanisms and actions as an antioxidant. Curr Top Biophys 24:171–183

    CAS  Google Scholar 

  59. Busse E, Zimmer G, Schopohl B et al (1992) Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung 42:829–831

    CAS  PubMed  Google Scholar 

  60. Han D, Tritschler HJ, Packer L (1995) Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line. Biochem Biophys Res 207:258–264

    Article  CAS  Google Scholar 

  61. Wedmore CV, Williams JT (1981) Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 289:646–650

    Article  CAS  PubMed  Google Scholar 

  62. Tonnesen MG, Worthen GS, Johnston RB (1988) Neutrophil emigration, activation, and tissue damage. In: Clark RAE, Hensen PM (eds) The molecular and cellular biology of wound repair. Plenum, New York, pp 149–184

    Google Scholar 

  63. Schoettle RJ, Kochanek PM, Magargee JM et al (1990) Early polymorphonuclear leukocyte accumulation correlates with the development of post-traumatic cerebral edema in rats. J Neurotrauma 7:207–217

    Article  CAS  PubMed  Google Scholar 

  64. Matsuo Y, Onodera H, Shiga Y et al (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat: effects of neutrophil depletion. Stroke 25:1469–1475

    CAS  PubMed  Google Scholar 

  65. Kolgazi M, Jahovic N, Yüksel M et al (2007) Alpha-lipoic acid modulates gut inflammation induced by trinitrobenzene sulfonic acid in rats. J Gastroenterol Hepatol 22:1859–1865

    Article  CAS  PubMed  Google Scholar 

  66. Sehirli O, Tatlidede E, Yüksel M et al (2008) Antioxidant effect of alpha-lipoic acid against ethanol-induced gastric mucosal erosion in rats. Pharmacology 81:173–180

    Article  CAS  PubMed  Google Scholar 

  67. Wilson JX, Gelb AW (2002) Free radicals, antioxidants, and neurologic injury: possible relationship to cerebral protection by anesthetics. J Neurosurg Anesthesiol 14:66–79

    Article  PubMed  Google Scholar 

  68. Dinçer Y, Telci A, Kayali R et al (2002) Effect of alpha-lipoic acid on lipid peroxidation and anti-oxidant enzyme activities in diabetic rats. Clin Exp Pharmacol Physiol 29:281–284

    Article  PubMed  Google Scholar 

  69. Vincent AM, McLean LL, Backus C et al (2005) Short-term hyperglycemia produces oxidative damage and apoptosis in neurons. FASEB J 19:638–640

    CAS  PubMed  Google Scholar 

  70. Matz PG, Copin J-C, Chan PH (2000) Cell death after exposure to subarachnoid hemolysate correlates inversely with expression of CuZn-superoxide dismutase. Stroke 31:2450–2458

    CAS  PubMed  Google Scholar 

  71. Matz PG, Fujimura M, Lewen A et al (2001) Increased cytochrome c-mediated DNA fragmentation and cell death in manganese-superoxide dismutase-deficient mice after exposure to subarachnoid hemolysate. Stroke 32:506–515

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey

    Mehmet Erşahin & M. Zafer Berkman

  2. Department of Pharmacology, School of Pharmacy, Marmara University, Tıbbiye Cad., 34668, Istanbul, Turkey

    Hale Z. Toklu & Göksel Şener

  3. Department of Histology & Embryology, School of Medicine, Marmara University, Istanbul, Turkey

    Şule Çetinel

  4. Vocational School of Health Related Professions, Marmara University, Istanbul, Turkey

    Meral Yüksel

  5. Department of Medical Biology, School of Medicine, Marmara University, Istanbul, Turkey

    Can Erzik

  6. Department of Physiology, School of Medicine, Marmara University, Istanbul, Turkey

    Berrak Ç. Yeğen

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  1. Mehmet Erşahin
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Erşahin, M., Toklu, H.Z., Çetinel, Ş. et al. Alpha Lipoic Acid Alleviates Oxidative Stress and Preserves Blood Brain Permeability in Rats with Subarachnoid Hemorrhage. Neurochem Res 35, 418–428 (2010). https://doi.org/10.1007/s11064-009-0072-z

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