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. 2006 Jun 7;11(2):113–140. doi: 10.1111/j.1527-3458.2005.tb00265.x

KTX 0101: A Potential Metabolic Approach to Cytoprotection in Major Surgery and Neurological Disorders

Sharon L Smith 1,✉, David J Heal 1, Keith F Martin 2
PMCID: PMC6741747  PMID: 16007235

ABSTRACT

KTX 0101 is the sodium salt of the physiological ketone, D‐β‐hydroxybutyrate (βOHB). This neuroprotectant, which has recently successfully completed clinical Phase IA evaluation, is being developed as an intravenous infusion fluid to prevent the cognitive deficits caused by ischemic foci in the brain during cardiopulmonary bypass (CPB) surgery. KTX 0101 maintains cellular viability under conditions of physiological stress by acting as a “superfuel” for efficient ATP production in the brain and peripheral tissues. Unlike glucose, this ketone does not require phosphorylation before entering the TCA cycle, thereby sparing vital ATP stores. Although no reliable models of CPB‐induced ischemia exist, KTX 0101 is powerfully cytoprotectant under the more severe ischemic conditions of global and focal cerebral ischemia, cardiac ischemia and lung hemorrhage. Neuroprotection has been demonstrated by reductions in infarct volume, edema, markers of apoptosis and functional impairment. One significant difference between KTX 0101 and other potential neuroprotectants in development is that βOHB is a component of human metabolic physiology which exploits the body's own neuroprotective mechanisms. KTX 0101 also protects hippocampal organotypic cultures against early and delayed cell death in an in vitro model of status epilepticus, indicating that acute KTX 0101 intervention in this condition could help prevent the development of epileptiform foci, a key mechanism in the etiology of intractable epilepsy. In models of chronic neurodegenerative disorders, KTX 0101 protects neurons against damage caused by dopaminergic neurotoxins and by the fragment of β‐amyloid, Aβ1–42, implying possible therapeutic applications for ketogenic strategies in treating Parkinson's and Alzheimer's diseases. Major obstacles to the use of KTX 0101 for long term therapy in chronic disorders, e.g., Parkinson's and Alzheimer's diseases, are the sodium loading problem and the need to administer it in relatively large amounts because of its rapid mitochondrial metabolism. These issues are being addressed by designing and synthesizing orally bioavailable multimers of βOHB with improved pharmacokinetics.

Keywords: Alzheimer's disease, Cardiopulmonary bypass, Cytoprotection, Epilepsy, Excitotoxicity, Ischemia, Ketones, KTX 0101, Neuroprotection, Parkinson's disease, Sodium D‐β‐hydroxybutyrate, Status epilepticus, Stroke

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REFERENCES

  • 1. Aitken SP, Brown WM. Treatment of epilepsy: Existing therapies and future developments. Front Biosci 2000;5:E124–E152. [DOI] [PubMed] [Google Scholar]
  • 2. Alam HB, Austin B, Koustova E, Rhee P. Resuscitation‐induced pulmonary apoptosis and intracellular adhesion molecule‐1 expression in rats are attenuated by the use of ketone ringer's solution. J Am Coll Surg 2001;193:255–263. [DOI] [PubMed] [Google Scholar]
  • 3. Al‐Mudallal AS, LaManna JC, Lust WD, Harik SI. Diet‐induced ketosis does not cause cerebral acidosis. Epilepsia 1996;37:258–61. [DOI] [PubMed] [Google Scholar]
  • 4. Arrowsmith JE, Harrison MJ, Newman SP, Stygall J, Timberlake N, Pugsley WB. Neuroprotection of the brain during cardiopulmonary bypass: A randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke 1998;29:2357–2362. [DOI] [PubMed] [Google Scholar]
  • 5. Babb TL, Kupfer WR, Pretorius JK, Crandall PH, Levesque MF. Synaptic reorganisation by mossy fibers in human epileptic fascia‐dentata. Neuroscience 1991;42:351–363. [DOI] [PubMed] [Google Scholar]
  • 6. Ben‐Ari Y. Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. [DOI] [PubMed] [Google Scholar]
  • 7. Bernasconi N, Bernasconi A, Caramanos Z, et al. Entorhinal cortex atrophy in epilepsy patients exhibiting normal hippocampal volumes. Neurology 2001;56:1335–1339. [DOI] [PubMed] [Google Scholar]
  • 8. Bough KJ, Eagles DA. A ketogenic diet increases the resistance to pentylenetetrazole‐induced seizures in the rat. Epilepsia 1999;40:138–143. [DOI] [PubMed] [Google Scholar]
  • 9. Bough KJ, Valiyil R, Han FT, Eagles DA. Seizure resistance is dependent upon age and calorie restriction in rats fed a ketogenic diet. Epilepsy Res 1999;35:21–28. [DOI] [PubMed] [Google Scholar]
  • 10. Bowen DM, Davison AN. The failing brain. J Chronic Dis 1983;36:3–13. [DOI] [PubMed] [Google Scholar]
  • 11. Brookmeyer R, Corrada MM, Curriero FC, Kawas C. Survival following a diagnosis of Alzheimer disease. Arch Neurol 2002;59:1764–1767. [DOI] [PubMed] [Google Scholar]
  • 12. Cahill GF, Aoki TT. Alternate fuel utilization in brain In: Passonneau JV, Hawkins RA, Lust WD, Welsh FA, Eds. Cerebral Metabolism and Neural Function. Baltimore : Williams and Wilkins, 1980. ;234–242. [Google Scholar]
  • 13. Cahill, GF , Veech, RL. Ketoacids? Good medicine Trans Am Clin Climatol Assoc 2003;114:149–161; discussion: 162–163. [PMC free article] [PubMed] [Google Scholar]
  • 14. Cheung N, Pascoe CJ, Giardina SF, John CA, Beart, PM. Micromolar L‐glutamate induces extensive apoptosis in an apoptotic‐necrotic continuum of insult dependent, excitotoxic injury in cultured cortical neurones. Neuropharmacology 1998;37:1419–1429. [DOI] [PubMed] [Google Scholar]
  • 15. Cohen G. Oxidative stress, mitochondrial respiration, and PD. Ann NY Acad Sci 2000;899:112–120. [DOI] [PubMed] [Google Scholar]
  • 16. Coyle JT, Price DL, DeLong MR. Alzheimer's disease: A disorder of cortical cholinergic innervation. Science 1983;219:1184–1190. [DOI] [PubMed] [Google Scholar]
  • 17. Dardzinski BJ, Smith SL, Towfighi J, Williams GD, Vannucci RC, Smith MB. Increased plasma beta‐hydroxybutyrate, preserved cerebral energy metabolism and amelioration of brain damage during neonatal hypoxia ischaemia with dexamethasone pretreatmeant. Pediatric Res 2000;48:248–225. [DOI] [PubMed] [Google Scholar]
  • 18. Davies P. The neurochemistry of Alzheimer's disease and senile dementia. Med Res Rev 1983;3:221–236. [DOI] [PubMed] [Google Scholar]
  • 19. DeVivo DC, Leckie MP, Ferrendelli JS, McDougal DB Chronic ketosis and cerebral metabolism. Ann Neurol 1978;3:331–337. [DOI] [PubMed] [Google Scholar]
  • 20. Diegeler A, Hirsch R, Schneider F, et al. Neuromonitoring and neurocognitive outcome in off‐pump versus conventional coronary bypass operation. Ann Thorac Surg 2000;69:1162–1166. [DOI] [PubMed] [Google Scholar]
  • 21. Dodson WE, Prensky AL, DeVivo DC, Goldring S, Dodge PR. Management of seizure disorders: Selected aspects. Part I. J Pediatry 1976;89:527–40. [DOI] [PubMed] [Google Scholar]
  • 22. Dodson WE, Prensky AL, DeVivo DC, Goldring S, Dodge PR. Management of seizure disorders: Selected aspects. Part II. J Pediatry 1976;89:695–703. [DOI] [PubMed] [Google Scholar]
  • 23. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. J Am Med Assoc 1989;262:2551–2556. [PubMed] [Google Scholar]
  • 24. Fery F, Balasse EO. Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis. Diabetes 1985;34:326–332. [DOI] [PubMed] [Google Scholar]
  • 25. Freeman JM, Vining EPG, Pyzik PL, Gilbert DL. Beta‐hydroxybutyrate levels in blood correlate with seizure control in children on the ketogenic diet. Epilepsia 1998;39:167–171. 9577996 [Google Scholar]
  • 26. Fujikawa DG, Shinmei SS, Cai BY. Kainic acid‐induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: Implications for programmed cell death mechanisms. Neuroscience 2000;98:41–53. [DOI] [PubMed] [Google Scholar]
  • 27. Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 1994;269:13623–13628. [PubMed] [Google Scholar]
  • 28. Gilman S. Cerebral disorders after open heart surgery. N Engl J Med 1965;272:489–498. [DOI] [PubMed] [Google Scholar]
  • 29. Graham DI, Gentleman SM, Nicoll JA, et al. Altered beta‐APP metabolism after head injury and its relationship to the aetiology of Alzheimer's disease. Acta Neurochir 1996;66:96–102. [DOI] [PubMed] [Google Scholar]
  • 30. Grocott J, Phillips‐Bute B, Newman M. Lidocaine does not prevent cognitive dysfunction after cardiac surgery. Anesth Analg 2004;98:SCA1–134. 15085850 [Google Scholar]
  • 31. Hall SEH, Wastney ME, Bolton TM, Braaten JT, Berman M. Ketone body kinetics in humans: The effects of insulin‐dependent diabetes, obesity and starvation. J Lipid Res 1984;25:1184–1194. [PubMed] [Google Scholar]
  • 32. Hardy JA, Higgins GA. Alzheimer's disease: The amyloid cascade hypothesis. Science 1992;256:184–185. [DOI] [PubMed] [Google Scholar]
  • 33. Heal DJ, Jagger L, Martin KF. KTX 0101 protects hippocampal neurones in an in vitro model of status epilepticus. 34th Annual Meeting of the Society for Neuroscience, San Diego , 2004; Abstract No. 2635. [Google Scholar]
  • 34. Hetherington HP, Pan JW, Spencer DD. 1H and 31P spectroscopy and bioenergetics in the lateralization of seizures in temporal lobe epilepsy. J Magn Reson Imaging 2002;16:477–483. [DOI] [PubMed] [Google Scholar]
  • 35. Ide T, Steinke J, Cahill, GF Metabolic interactions of glucose, lactate and β‐hydroxybutyrate in rat brain slices. Am J Physiol 1969;217:784–791. [DOI] [PubMed] [Google Scholar]
  • 36. Ilic TV, Jovanovic M, Jovicic A, Tomovic M. Oxidative stress indicators are elevated in de novo PD patients. Funct Neurol 1999;14:141–147. [PubMed] [Google Scholar]
  • 37. Imamura K, Takeshima T, Kashiwaya Y, Fukuhara Y, Nakaso K, Veech RL, Nakashima K. D‐β‐hydroxybutyrate (DBHB) protects SH‐SY5Y dopaminergic neuroblastoma cells in the rotenone and MPP+ models of Parkinson' disease. 34th Annual Meeting of the Society for Neuroscience, San Diego , 2004;Abstract No. 1013.15. [Google Scholar]
  • 38. Jagger L, Cheetham SC, Heal DJ, Mason R. Validation of an in vitro model of status epilepticus Br J Pharmacol 2005; In press. [Google Scholar]
  • 39. Jagger L, Parker TL, Starkey S and Mason RM. Kainic acid‐induced epileptiform activity and neuronal cell death in hippocampal organotypic slices. Br J Pharmacol 2002;135:103P. 11786485 [Google Scholar]
  • 40. Janigro D. Blood‐brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res 1999;37:223–32. [DOI] [PubMed] [Google Scholar]
  • 41. Jenner P. Oxidative stress in PD. Ann Neurol 2003;53:S26–S36; discussion: S36–S38. [DOI] [PubMed] [Google Scholar]
  • 42. Kalaria RN, Bhatti SU, Lust WD, Perry G. The amyloid precursor protein in ischemic brain injury and chronic hypoperfusion. Ann NY Acad Sci 1993;695:190–193. [DOI] [PubMed] [Google Scholar]
  • 43. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D‐β‐Hydroxybutyrate protects neurons in models of Alzheimer's and PD. Proc Natl Acad Sci USA 2000;97:5440–5444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Kondratyev A, Gale K. Temporal and spatial patterns of DNA fragmentation following focally or systemically‐evoked status epilepticus in rats. Neurosci Lett 2001;310:13–16. [DOI] [PubMed] [Google Scholar]
  • 45. Kong RS, Butterworth J, Aveling W, et al. Clinical trial of the neuroprotectant clomethiazole in coronary artery bypass graft surgery: A randomized controlled trial. Anesthesiology 2002;97:585–591. [DOI] [PubMed] [Google Scholar]
  • 46. Koustova E, Rhee P, Hancock T, et al. Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation. Surgery 2003;134:267–274. [DOI] [PubMed] [Google Scholar]
  • 47. Kunikowska G, Jenner P. Alterations in m‐RNA expression for Cu, Zn‐superoxide dismutase and glutathione peroxidase in the basal ganglia of MPTP‐treated marmosets and patients with PD. Brain Res 2003;968:206–218. [DOI] [PubMed] [Google Scholar]
  • 48. Kuusisto J, Koivisto K, Mykkanen L, et al. Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: Cross sectional population based study. Br Med J 1997;315:1045–1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Laffel L. Ketone bodies: A review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:412–426. [DOI] [PubMed] [Google Scholar]
  • 50. Li H, Dryhurst G. Oxidative metabolites of 5‐S‐cysteinyldopamine inhibit the pyruvate dehydrogenase complex. J Neural Transm 2001;108:1363–1374. [DOI] [PubMed] [Google Scholar]
  • 51. Li PA, He QP, Csiszar K, Siesjo BK. Does long‐term glucose infusion reduce brain damage after transient cerebral ischemia Brain Res 2001;912:203–205. [DOI] [PubMed] [Google Scholar]
  • 52. Lin L, Georgievska B, Mattsson A, Isacson O. Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proc Natl Acad Sci USA 1999;96:12108–12113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Llinas R, Barbut D, Caplan LR. Neurologic complications of cardiac surgery. Prog Cardiovasc Dis 2000;43:101–112. [DOI] [PubMed] [Google Scholar]
  • 54. Longa EZ, Weinstein PR, Carlson SC, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 1989;20:84–91. [DOI] [PubMed] [Google Scholar]
  • 55. Lowenstein DH. Status epilepticus: An overview of the clinical problem. Epilepsia 1999;40:S3–S8. [DOI] [PubMed] [Google Scholar]
  • 56. Mark DB, Newman MF. Protecting the brain in coronary artery bypass graft surgery. J Am Med Assoc 2002;287:1448–1450. [DOI] [PubMed] [Google Scholar]
  • 57. Massieu L, Haces ML, Montiel T, Hernandez‐Fonseca K. Acetoacetate protects hippocampal neurons against glutamate‐mediated neuronal damage during glycolysis inhibition. Neuroscience 2003;120:365–378. [DOI] [PubMed] [Google Scholar]
  • 58. Masuda R, Monahan JW, Fukuhara Y, et al. Neuroprotective effect of D‐β‐hydroxybutyrate against hypoxia in serum free hippocampal primary culture. J Neurosci Res 2005;In press. [DOI] [PubMed] [Google Scholar]
  • 59. Nakamura S, Koshimura K, Kato T, et al. Neurotransmitters in dementia. Clin Ther 1984;7:18–34. [PubMed] [Google Scholar]
  • 60. Nicklas WJ, Yougster SK, Kindt MV, Heikkila RE. MPTP, MPP+ and mitochondrial function. Life Sci 1987;40:721–729. [DOI] [PubMed] [Google Scholar]
  • 61. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Brain metabolism during fasting. J Clin Invest 1967;46:1589–1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Owen OE, Reichard GA Jr, Patel MS, Boden G. Energy metabolism in feasting and fasting. Adv Exp Med Biol 1979;111:169–188. [DOI] [PubMed] [Google Scholar]
  • 63. Pan JW, Bebin EM, Chu WJ, Hetherington HP. Ketosis and epilepsy: 31P spectroscopic imaging at 4.1 T. Epilepsia 1999;40:703–7. [DOI] [PubMed] [Google Scholar]
  • 64. Peterman MG. The ketogenic diet in the treatment of epilepsy. A preliminary report. Am J Dis Child 1924;28:28–33. [Google Scholar]
  • 65. Pollard H, Charriaut‐Marlangue C, Cantagrel S, et al. Kainate‐induced apoptotic cell death in hippocampal neurons. Neuroscience 1994;63:7–18. [DOI] [PubMed] [Google Scholar]
  • 66. Sato KY, Kashiwaya CA, Keon N, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 1995;9:651–658. [DOI] [PubMed] [Google Scholar]
  • 67. Schwartz RH, Eaton J, Bower BD, Aynsley‐Green A. Ketogenic diets in the treatment of epilepsy. Short‐term clinical effects. Dev Med Child Neurol 1989;31:145–151. [DOI] [PubMed] [Google Scholar]
  • 68. Selkoe DJ. Alzheimer's disease: Genotypes, phenotypes, and treatments. Science 1997;275:630–631. [DOI] [PubMed] [Google Scholar]
  • 69. Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta‐protein. J Alzheimer's Dis 2001;3:75–80. [DOI] [PubMed] [Google Scholar]
  • 70. Sims NR, Bowen DM, Smith CC, et al. Glucose metabolism and acetylcholine synthesis in relation to neuronal activity in Alzheimer's disease. Lancet 1980;1:333–336. [DOI] [PubMed] [Google Scholar]
  • 71. Simuni T, Stern MB. Does levodopa accelerate PD. Drugs Aging 1999;14:399–408. [DOI] [PubMed] [Google Scholar]
  • 72. Sutula T, Cascino G, Cavazos J, Parada I, Ramirez L. Mossy fiber synaptic reorganization in the epileptic human temporal lobe. Ann Neurol 1989;26:321–330. [DOI] [PubMed] [Google Scholar]
  • 73. Suzuki M, Suzuki M, Kitamura Y, et al. Beta‐hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia. Jpn J Pharmacol 2002;89:36–43. [DOI] [PubMed] [Google Scholar]
  • 74. Suzuki M, Suzuki M, Sato K, et al. Effect of β‐hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol 2001;87:143–150. [DOI] [PubMed] [Google Scholar]
  • 75. Swink TD, Vining EP, Freeman JM. The ketogenic diet. Adv Pediatry 1997;44:297–329. [PubMed] [Google Scholar]
  • 76. Tamura A, Graham DI, McCulloch J, Teasdale G. Focal cerebral ischemia in the rat. I. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1981;1:53–60. [DOI] [PubMed] [Google Scholar]
  • 77. Tieu K, Perier C, Caspersen C, et al. D‐β‐Hydroxybutyrate rescues mitochondrial respiration and mitigates features of PD. J Clin Invest 2003;112:892–901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. VanItallie TB, Nonas C, Di Rocco, A , Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson disease with diet‐induced hyperketonemia: A feasibility study. Neurology 2005;64:728–730. [DOI] [PubMed] [Google Scholar]
  • 79. VanItallie TB, Nufert TH. Ketones: Metabolism's ugly duckling. Nutrition Rev 2003;61:327–341. [DOI] [PubMed] [Google Scholar]
  • 80. Veech RL. The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: Ketosis, ketogenic diet, redox states, insulin resistance, and mitochondria metabolism. Prost Leuk Essential Fatty Acids 2004;70:309–319. [DOI] [PubMed] [Google Scholar]
  • 81. Vining EPG. Clinical efficacy of the ketogenic diet. Epilepsy Res 1999;37:181–190. [DOI] [PubMed] [Google Scholar]
  • 82. Volicer L, McKee A, Hewitt S. Dementia. Neurol Clin 2001;19:867–885. [DOI] [PubMed] [Google Scholar]
  • 83. Wang D, Wu X, Li J, Xiao F, Liu X, Meng M. The effect of lidocaine on early postoperative cognitive dysfunction after coronary artery bypass surgery. Anesth Analg 2002;95:1134–1141. [DOI] [PubMed] [Google Scholar]
  • 84. Wastney ME, Hall SEH, Berman M. Ketone body kinetics in humans: A mathematical model. J Lipid Res 1984;25:160–174. [PubMed] [Google Scholar]
  • 85. Wilder RM. The effect of ketonemia on the course of epilepsy. Mayo Clin Bull 1921;2:307–308. [Google Scholar]
  • 86. Wolfson C, Wolfson DB, Asgharian M, et al. Clinical Progression of Dementia Study Group. A reevaluation of the duration of survival after the onset of dementia. N Engl J Med 2001;344:1111–1116. [DOI] [PubMed] [Google Scholar]
  • 87. Woodyatt RT. Objects and method of diet adjustment in diabetics. Arch Intern Med 1921;28:125–141. [Google Scholar]
  • 88. Young RS. Controversies in treatment of neonatal seizures. Pediatry Neurol 1993;9:331–332. [DOI] [PubMed] [Google Scholar]
  • 89. Zinker BA, Britz K, Brooks GA. Effects of a 36‐hour fast on human endurance and substrate utilization. J Appl Physiol 1990;69:1849–1855. [DOI] [PubMed] [Google Scholar]
  • 90. Zou Z, Sasaguri S, Rajesh KG, Suzuki R. dl‐3‐Hydroxybutyrate administration prevents myocardial damage after coronary artery occlusion in rat hearts. Am J Physiol Heart Circ Physiol 2002;283:H1968–H1974. [DOI] [PubMed] [Google Scholar]

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