Neuroprotective Effects of Alpha-Lipoic Acid in Experimental Spinal Cord Injury in Rats

Abstract Background: Oxidative stress is a mediator of secondary injury to the spinal cord following trauma. Objective: To investigate the putative neuroprotective effect of α-lipoic acid (LA), a powerful antioxidant, in a rat model of spinal cord injury (SCI). Methods: Wistar albino rats were divided as control, vehicle-treated SCI, and LA-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10 was used. Injured animals were given either 50 mg/kg LA or saline at 30 minutes postinjury by intraperitoneal injection. At 7 days postinjury, neurologic examination was performed, and rats were decapitated. Spinal cord samples were taken for histologic examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and DNA fragmentation. Formation of reactive oxygen species in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. Results: SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in luminol CL and MDA levels, MPO activity, and DNA damage. Furthermore, LA treatment reversed all these biochemical parameters as well as SCI-induced histopathologic alterations. Conversely, impairment of the neurologic function caused by SCI remained unchanged. Conclusion: The present study suggests that LA reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation.

[1]  A. Khodadadi,et al.  Anti-Oxidative Effect of Lipoic Acid in Spinal Cord Ischemia/Reperfusion , 2010, Medical Principles and Practice.

[2]  M. Bracken.  Steroids for acute spinal cord injury. , 2012, The Cochrane database of systematic reviews.

[3]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[4]  J. Krieglstein,et al.  Neuroprotective effects of α-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia , 1996, Neuropharmacology.

[5]  L. Packer,et al.  Antioxidant activities of dihydrolipoic acid and its structural homologues. , 1993, Free radical research communications.

[6]  L. Gille,et al.  Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria. , 1995, Biochimica et biophysica acta.

[7]  R. Martins,et al.  Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. , 2008, Advanced drug delivery reviews.

[8]  G. Kurt,et al.  Neuroprotective effects of gabapentin on spinal cord ischemia-reperfusion injury in rabbits. , 2011, Journal of neurosurgery. Spine.

[9]  D E Griswold,et al.  Assessment of myeloperoxidase activity in whole rat kidney. , 1990, Journal of pharmacological methods.

[10]  Sébastien Tilleux,et al.  Neuroinflammation and regulation of glial glutamate uptake in neurological disorders , 2007, Journal of neuroscience research.

[11]  C. Bernards,et al.  Effect of postinjury intravenous or intrathecal methylprednisolone on spinal cord excitatory amino-acid release, nitric oxide generation, PGE2 synthesis, and myeloperoxidase content in a pig model of acute spinal cord injury , 2006, Spinal Cord.

[12]  L. Packer,et al.  Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. , 2002, Toxicology and applied pharmacology.

[13]  E. Şener,et al.  Alpha-lipoic acid protects against renal ischaemia-reperfusion injury in rats. , 2008, Clinical and experimental pharmacology & physiology.

[14]  H. Tritschler,et al.  Effects of α-lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids , 1998, Diabetologia.

[15]  T. Hakan,et al.  The protective effect of alpha lipoic acid against traumatic brain injury in rats , 2009, Free radical research.

[16]  S. Aust,et al.  Microsomal lipid peroxidation. , 1978, Methods in enzymology.

[17]  E. Melamed,et al.  Antioxidant Therapy in Acute Central Nervous System Injury: Current State , 2002, Pharmacological Reviews.

[18]  E. Hall,et al.  Neuroprotection and acute spinal cord injury: A reappraisal , 2011, NeuroRX.

[19]  M. Uchiba,et al.  Methylprednisolone reduces spinal cord injury in rats without affecting tumor necrosis factor-alpha production. , 2001, Journal of neurotrauma.

[20]  Y. Ng,et al.  Distinct roles of oxidative stress and antioxidants in the nucleus dorsalis and red nucleus following spinal cord hemisection , 2005, Brain Research.

[21]  T. Foster.  Efficacy and Safety of α-Lipoic Acid Supplementation in the Treatment of Symptomatic Diabetic Neuropathy , 2007, The Diabetes educator.

[22]  M. Fehlings,et al.  The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. , 2004, Journal of neurotrauma.

[23]  D. Bourdette,et al.  Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. , 2008, Endocrine, metabolic & immune disorders drug targets.

[24]  M. Baykaner,et al.  Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord ischemia–reperfusion injury in rabbits , 2010, Acta Neurochirurgica.

[25]  D. Bourdette,et al.  Lipoic acid stimulates cAMP production in T lymphocytes and NK cells. , 2007, Biochemical and biophysical research communications.

[26]  A Bast,et al.  The pharmacology of the antioxidant lipoic acid. , 1997, General pharmacology.

[27]  M. Fehlings,et al.  The relationships among the severity of spinal cord injury, motor and somatosensory evoked potentials and spinal cord blood flow. , 1989, Electroencephalography and clinical neurophysiology.

[28]  C H Tator,et al.  Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. , 1991, Journal of neurosurgery.

[29]  M. Mattson,et al.  Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury , 1997, Brain Research.

[30]  Colin L. Masters,et al.  Neurodegenerative diseases and oxidative stress , 2004, Nature Reviews Drug Discovery.

[31]  E. Kaptanoğlu,et al.  Magnesium sulfate treatment in experimental spinal cord injury: emphasis on vascular changes and early clinical results , 2003, Neurosurgical Review.

[32]  Alexander M Seifalian,et al.  The role of thiols in liver ischemia-reperfusion injury. , 2006, Current pharmaceutical design.

[33]  A. Faden,et al.  A potential role for excitotoxins in the pathophysiology of spinal cord injury , 1988, Annals of neurology.

[34]  Ş. Öter,et al.  The effect of alpha-lipoic acid in the prevention of peritoneal adhesions. , 2011, The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology.

[35]  J. Prehn,et al.  Dihydrolipoate Reduces Neuronal Injury after Cerebral Ischemia , 1992, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  L. Packer,et al.  Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. , 1992, Biochemical pharmacology.

[37]  R. M. Adibhatla,et al.  Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. , 2008, BMB reports.

[38]  Guoyao Wu,et al.  Glutathione metabolism and its implications for health. , 2004, The Journal of nutrition.

[39]  L. Packer,et al.  Neuroprotection by the metabolic antioxidant alpha-lipoic acid. , 1997, Free radical biology & medicine.

[40]  U. Topaloglu,et al.  Alpha-Lipoic Acid Protects against Hepatic Ischemia-Reperfusion Injury in Rats , 2007, Pharmacology.

[41]  B. Yeğen,et al.  Antioxidant Effect of Alpha-Lipoic Acid against Ethanol-Induced Gastric Mucosal Erosion in Rats , 2007, Pharmacology.

[42]  Özer Şehirli,et al.  α‐LIPOIC ACID PROTECTS AGAINST RENAL ISCHAEMIA–REPERFUSION INJURY IN RATS , 2008 .

[43]  K. Kiuchi,et al.  Effects of hyperbaric oxygen on GDNF expression and apoptosis in spinal cord injury , 2004, Neuroreport.

[44]  J. Phillis,et al.  The free radical scavenger, alpha-lipoic acid, protects against cerebral ischemia-reperfusion injury in gerbils. , 1995, Free radical research.

[45]  W. Lagrèze,et al.  The neuroprotective properties of gabapentin-lactam , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[46]  H. Tritschler,et al.  Lipoic Acid Improves Nerve Blood Flow, Reduces Oxidative Stress, and Improves Distal Nerve Conduction in Experimental Diabetic Neuropathy , 1995, Diabetes Care.

[47]  Alfred Reginald Allen,et al.  SURGERY OF EXPERIMENTAL LESION OF SPINAL CORD EQUIVALENT TO CRUSH INJURY OF FRACTURE DISLOCATION OF SPINAL COLUMN: A PRELIMINARY REPORT , 1911 .

[48]  H. Sürücü,et al.  Effect of mexiletine on lipid peroxidation and early ultrastructural findings in experimental spinal cord injury. , 1999, Journal of neurosurgery.

[49]  V. Ravindranath,et al.  α-Lipoic acid protects against reperfusion injury following cerebral ischemia in rats , 1996, Brain Research.

[50]  G. R. Davies,et al.  Mucosal reactive oxygen metabolite production in duodenal ulcer disease. , 1992, Gut.

[51]  Hong Zhu,et al.  Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid , 2009, Molecular and Cellular Biochemistry.

[52]  E. Kaptanoğlu,et al.  Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings , 2004, Neurosurgical Review.

[53]  Ç. Evliyaoğlu,et al.  Evaluation of protective effects of the alpha lipoic acid after spinal cord injury: an animal study. , 2010, Injury.

[54]  D. Bourdette,et al.  Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis , 2006, Journal of Neuroimmunology.

[55]  B. Gidal,et al.  Gabapentin dosing in the treatment of epilepsy. , 2003, Clinical therapeutics.

[56]  M. Yüksel,et al.  α‐Lipoic acid modulates gut inflammation induced by trinitrobenzene sulfonic acid in rats , 2007, Journal of gastroenterology and hepatology.

[57]  L. Packer,et al.  Redox regulation of cell functions by α‐lipoate: biochemical and molecular aspects , 1998 .

[58]  K. Burton.  [105] Determination of DNA concentration with diphenylamine , 1968 .

[59]  A. Bilska,et al.  Lipoic acid - the drug of the future? , 2005, Pharmacological reports : PR.

[60]  T. Isbir,et al.  Effects of naloxone on sodium- and potassium-activated and magnesium-dependent adenosine-5'-triphosphatase activity and lipid peroxidation and early ultrastructural findings after experimental spinal cord injury. , 1995, Neurosurgery.

[61]  I. Solaroglu,et al.  Recombinant human erythropoietin decreases myeloperoxidase and caspase-3 activity and improves early functional results after spinal cord injury in rats , 2007, Journal of Clinical Neuroscience.

[62]  L. Packer,et al.  Neuroprotection by the Metabolic Antioxidant α-Lipoic Acid , 1997 .

[63]  A. Konan,et al.  Comparison of the effects of melatonin and methylprednisolone in experimental spinal cord injury. , 2000, Journal of neurosurgery.

[64]  B. Yeğen,et al.  Alpha Lipoic Acid Alleviates Oxidative Stress and Preserves Blood Brain Permeability in Rats with Subarachnoid Hemorrhage , 2010, Neurochemical Research.

[65]  M. Yüksel,et al.  Chemiluminescence in the measurement of free radicals: Theory and application on a tissue injury model , 1998 .

[66]  H. Tritschler,et al.  Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve , 1999, Journal of the Neurological Sciences.

[67]  C. Sen,et al.  Protection against glutamate-induced cytotoxicity in C6 glial cells by thiol antioxidants. , 1997, American journal of physiology. Regulatory, integrative and comparative physiology.

[68]  G. Carlson,et al.  Current developments in spinal cord injury research. , 2002, The spine journal : official journal of the North American Spine Society.

[69]  C. Sen,et al.  Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization , 1997, BioFactors.

[70]  Karen Gale,et al.  Spinal cord contusion in the rat: Behavioral analysis of functional neurologic impairment , 1985, Experimental Neurology.

[71]  K. Manda,et al.  Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: Protective effect of α-lipoic acid , 2007, Behavioural Brain Research.

[72]  Denis Gris,et al.  The systemic inflammatory response after spinal cord injury damages lungs and kidneys , 2008, Experimental Neurology.

[73]  J. Weber,et al.  Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. , 2008, Current medicinal chemistry.

[74]  L. Packer,et al.  Redox regulation of cell functions by alpha-lipoate: biochemical and molecular aspects. , 1998, BioFactors.

[75]  A. Bast,et al.  The role of lipoic acid in the treatment of diabetic polyneuropathy. , 1997, Drug metabolism reviews.

[76]  Wei-jian Zhang,et al.  Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[77]  Wei-jian Zhang,et al.  α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway , 2007, Proceedings of the National Academy of Sciences.

[78]  E. Kaptanoğlu,et al.  Ultrastructural scoring of graded acute spinal cord injury in the rat. , 2002, Journal of neurosurgery.

[79]  M. Widlansky,et al.  Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. , 2004, Current medicinal chemistry.

[80]  F. Kaymaz,et al.  Neuroprotective effects of gabapentin in experimental spinal cord injury. , 2010, World neurosurgery.

[81]  L. Packer,et al.  Thioctic acid protects against ischemia-reperfusion injury in the isolated perfused Langendorff heart. , 1992, Free radical research communications.

[82]  E. Beutler,et al.  Improved method for the determination of blood glutathione. , 1963, The Journal of laboratory and clinical medicine.

[83]  Y. Olsson,et al.  Neuropathological changes and neurological function after spinal cord compression in the rat. , 1990, Journal of neurotrauma.