Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1990 Oct;53(10):847–853. doi: 10.1136/jnnp.53.10.847

Insulin protects cognitive function in experimental stroke.

A J Strong 1, J E Fairfield 1, E Monteiro 1, M Kirby 1, A R Hogg 1, M Snape 1, L Ross-Field 1
PMCID: PMC488244  PMID: 2266364

Abstract

There is evidence from in vitro systems that the extent of neuronal loss in acute central nervous system ischaemia can be reduced by manoeuvres which restrict availability of glucose to the ischaemic area. Experiments were designed to test whether hypoglycaemia induced with insulin is associated with improved behavioural outcome in a recovery model of stroke. Rats learned a maze task as a test of working memory, believed to be subserved by the hippocampus, and then had a period of cerebral ischaemia, followed by reperfusion. After an interval of 14 days they were tested on the same maze, where lesioned animals had very significant (p less than 0.0001) impairment of working memory, whereas lesioned and treated (2.0 u/kg-1 insulin, minimum single plasma glucose value: 3.1 mmol/l-1) animals were indistinguishable from control animals. It is concluded that a striking degree of protection can be obtained with levels of mild hypoglycaemia which may be acceptable and practicable for use in humans.

Full text

PDF
847

Images in this article

849Image
on p.849

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barnes C. A. Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat. Trends Neurosci. 1988 Apr;11(4):163–169. doi: 10.1016/0166-2236(88)90143-9. [DOI] [PubMed] [Google Scholar]
  2. Benveniste H., Drejer J., Schousboe A., Diemer N. H. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem. 1984 Nov;43(5):1369–1374. doi: 10.1111/j.1471-4159.1984.tb05396.x. [DOI] [PubMed] [Google Scholar]
  3. Berger L., Hakim A. M. Nimodipine prevents hyperglycemia-induced cerebral acidosis in middle cerebral artery occluded rats. J Cereb Blood Flow Metab. 1989 Feb;9(1):58–64. doi: 10.1038/jcbfm.1989.8. [DOI] [PubMed] [Google Scholar]
  4. Blaustein M. P. Calcium transport and buffering in neurons. Trends Neurosci. 1988 Oct;11(10):438–443. doi: 10.1016/0166-2236(88)90195-6. [DOI] [PubMed] [Google Scholar]
  5. Choi D. W. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 1988 Oct;11(10):465–469. doi: 10.1016/0166-2236(88)90200-7. [DOI] [PubMed] [Google Scholar]
  6. Collingridge G. L., Kehl S. J., McLennan H. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol. 1983 Jan;334:33–46. doi: 10.1113/jphysiol.1983.sp014478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Csiba L., Paschen W., Hossmann K. A. A topographic quantitative method for measuring brain tissue pH under physiological and pathophysiological conditions. Brain Res. 1983 Dec 19;289(1-2):334–337. doi: 10.1016/0006-8993(83)90037-9. [DOI] [PubMed] [Google Scholar]
  8. Cummings J. L., Tomiyasu U., Read S., Benson D. F. Amnesia with hippocampal lesions after cardiopulmonary arrest. Neurology. 1984 May;34(5):679–681. doi: 10.1212/wnl.34.5.679. [DOI] [PubMed] [Google Scholar]
  9. Davis H. P., Baranowski J. R., Pulsinelli W. A., Volpe B. T. Retention of reference memory following ischemic hippocampal damage. Physiol Behav. 1987;39(6):783–786. doi: 10.1016/0031-9384(87)90267-8. [DOI] [PubMed] [Google Scholar]
  10. Davis H. P., Tribuna J., Pulsinelli W. A., Volpe B. T. Reference and working memory of rats following hippocampal damage induced by transient forebrain ischemia. Physiol Behav. 1986;37(3):387–392. doi: 10.1016/0031-9384(86)90195-2. [DOI] [PubMed] [Google Scholar]
  11. Fukuoka S., Yeh H., Mandybur T. I., Tew J. M., Jr Effect of insulin on acute experimental cerebral ischemia in gerbils. Stroke. 1989 Mar;20(3):396–399. doi: 10.1161/01.str.20.3.396. [DOI] [PubMed] [Google Scholar]
  12. Ginsberg M. D., Prado R., Dietrich W. D., Busto R., Watson B. D. Hyperglycemia reduces the extent of cerebral infarction in rats. Stroke. 1987 May-Jun;18(3):570–574. doi: 10.1161/01.str.18.3.570. [DOI] [PubMed] [Google Scholar]
  13. Grotta J. C., Pettigrew L. C., Rosenbaum D., Reid C., Rhoades H., McCandless D. Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats. Stroke. 1988 Apr;19(4):447–454. doi: 10.1161/01.str.19.4.447. [DOI] [PubMed] [Google Scholar]
  14. Hakim A. M. Cerebral acidosis in focal ischemia: II. Nimodipine and verapamil normalize cerebral pH following middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1986 Dec;6(6):676–683. doi: 10.1038/jcbfm.1986.123. [DOI] [PubMed] [Google Scholar]
  15. Harris R. J., Symon L., Branston N. M., Bayhan M. Changes in extracellular calcium activity in cerebral ischaemia. J Cereb Blood Flow Metab. 1981;1(2):203–209. doi: 10.1038/jcbfm.1981.21. [DOI] [PubMed] [Google Scholar]
  16. Havrankova J., Roth J., Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978 Apr 27;272(5656):827–829. doi: 10.1038/272827a0. [DOI] [PubMed] [Google Scholar]
  17. Jorch G., Jorch N. Failure of autoregulation of cerebral blood flow in neonates studied by pulsed Doppler ultrasound of the internal carotid artery. Eur J Pediatr. 1987 Sep;146(5):468–472. doi: 10.1007/BF00441596. [DOI] [PubMed] [Google Scholar]
  18. Kalimo H., Rehncrona S., Söderfeldt B., Olsson Y., Siesjö B. K. Brain lactic acidosis and ischemic cell damage: 2. Histopathology. J Cereb Blood Flow Metab. 1981;1(3):313–327. doi: 10.1038/jcbfm.1981.35. [DOI] [PubMed] [Google Scholar]
  19. Kempski O., Staub F., Jansen M., Schödel F., Baethmann A. Glial swelling during extracellular acidosis in vitro. Stroke. 1988 Mar;19(3):385–392. doi: 10.1161/01.str.19.3.385. [DOI] [PubMed] [Google Scholar]
  20. Klip A., Ramlal T., Cragoe E. J., Jr Insulin-induced cytoplasmic alkalinization and glucose transport in muscle cells. Am J Physiol. 1986 May;250(5 Pt 1):C720–C728. doi: 10.1152/ajpcell.1986.250.5.C720. [DOI] [PubMed] [Google Scholar]
  21. Kågström E., Smith M. L., Siesjö B. K. Recirculation in the rat brain following incomplete ischemia. J Cereb Blood Flow Metab. 1983 Jun;3(2):183–192. doi: 10.1038/jcbfm.1983.25. [DOI] [PubMed] [Google Scholar]
  22. Lazarewicz J. W., Pluta R., Salinska E., Puka M. Beneficial effect of nimodipine on metabolic and functional disturbances in rabbit hippocampus following complete cerebral ischemia. Stroke. 1989 Jan;20(1):70–77. doi: 10.1161/01.str.20.1.70. [DOI] [PubMed] [Google Scholar]
  23. LeMay D. R., Gehua L., Zelenock G. B., D'Alecy L. G. Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke. 1988 Nov;19(11):1411–1419. doi: 10.1161/01.str.19.11.1411. [DOI] [PubMed] [Google Scholar]
  24. Myers R. E. A unitary theory of causation of anoxic and hypoxic brain pathology. Adv Neurol. 1979;26:195–213. [PubMed] [Google Scholar]
  25. Olton D. S. The radial arm maze as a tool in behavioral pharmacology. Physiol Behav. 1987;40(6):793–797. doi: 10.1016/0031-9384(87)90286-1. [DOI] [PubMed] [Google Scholar]
  26. Pickard J. D., Murray G. D., Illingworth R., Shaw M. D., Teasdale G. M., Foy P. M., Humphrey P. R., Lang D. A., Nelson R., Richards P. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989 Mar 11;298(6674):636–642. doi: 10.1136/bmj.298.6674.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Prado R., Ginsberg M. D., Dietrich W. D., Watson B. D., Busto R. Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cereb Blood Flow Metab. 1988 Apr;8(2):186–192. doi: 10.1038/jcbfm.1988.48. [DOI] [PubMed] [Google Scholar]
  28. Rehncrona S., Rosén I., Siesjö B. K. Brain lactic acidosis and ischemic cell damage: 1. Biochemistry and neurophysiology. J Cereb Blood Flow Metab. 1981;1(3):297–311. doi: 10.1038/jcbfm.1981.34. [DOI] [PubMed] [Google Scholar]
  29. Robertson C. S., Grossman R. G. Protection against spinal cord ischemia with insulin-induced hypoglycemia. J Neurosurg. 1987 Nov;67(5):739–744. doi: 10.3171/jns.1987.67.5.0739. [DOI] [PubMed] [Google Scholar]
  30. Siemkowicz E., Hansen A. J. Clinical restitution following cerebral ischemia in hypo-, normo- and hyperglycemic rats. Acta Neurol Scand. 1978 Jul;58(1):1–8. [PubMed] [Google Scholar]
  31. Simon R. P., Griffiths T., Evans M. C., Swan J. H., Meldrum B. S. Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metab. 1984 Sep;4(3):350–361. doi: 10.1038/jcbfm.1984.52. [DOI] [PubMed] [Google Scholar]
  32. Squire L. R., Zola-Morgan S. Memory: brain systems and behavior. Trends Neurosci. 1988 Apr;11(4):170–175. doi: 10.1016/0166-2236(88)90144-0. [DOI] [PubMed] [Google Scholar]
  33. Strong A. J., Miller S. A., West I. C. Protection of respiration of a crude mitochondrial preparation in cerebral ischaemia by control of blood glucose. J Neurol Neurosurg Psychiatry. 1985 May;48(5):450–454. doi: 10.1136/jnnp.48.5.450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sutherland G., Lesiuk H., Bose R., Sima A. A. Effect of mannitol, nimodipine, and indomethacin singly or in combination on cerebral ischemia in rats. Stroke. 1988 May;19(5):571–578. doi: 10.1161/01.str.19.5.571. [DOI] [PubMed] [Google Scholar]
  35. Suzuki R., Yamaguchi T., Li C. L., Klatzo I. The effects of 5-minute ischemia in Mongolian gerbils: II. Changes of spontaneous neuronal activity in cerebral cortex and CA1 sector of hippocampus. Acta Neuropathol. 1983;60(3-4):217–222. doi: 10.1007/BF00691869. [DOI] [PubMed] [Google Scholar]
  36. Swan J. H., Evans M. C., Meldrum B. S. Long-term development of selective neuronal loss and the mechanism of protection by 2-amino-7-phosphonoheptanoate in a rat model of incomplete forebrain ischaemia. J Cereb Blood Flow Metab. 1988 Feb;8(1):64–78. doi: 10.1038/jcbfm.1988.9. [DOI] [PubMed] [Google Scholar]
  37. Tamura A., Graham D. I., McCulloch J., Teasdale G. M. Focal cerebral ischaemia in the rat: 2. Regional cerebral blood flow determined by [14C]iodoantipyrine autoradiography following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1(1):61–69. doi: 10.1038/jcbfm.1981.7. [DOI] [PubMed] [Google Scholar]
  38. Voll C. L., Whishaw I. Q., Auer R. N. Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke. 1989 May;20(5):646–651. doi: 10.1161/01.str.20.5.646. [DOI] [PubMed] [Google Scholar]
  39. Volpe B. T., Hirst W. The characterization of an amnesic syndrome following hypoxic ischemic injury. Arch Neurol. 1983 Jul;40(7):436–440. doi: 10.1001/archneur.1983.04050070066017. [DOI] [PubMed] [Google Scholar]
  40. Wieloch T., Lindvall O., Blomqvist P., Gage F. H. Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path. Neurol Res. 1985 Mar;7(1):24–26. doi: 10.1080/01616412.1985.11739695. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES