Skip to main content
SpringerLink
Log in

Blood flow and metabolism in heterotopic cerebellar grafts during hypoglycemia

  • Regular Papers
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Summary

Hypoglycemia-induced disturbances of brain metabolism and neuronal injury exhibit a distinct predilection for forebrain structures, in particular the caudate-putamen, hippocampus and cerebral cortex, whereas the cerebellum is remarkably resistant. In an attempt to assess the biological basis of this differential regional vulnerability, we have used a neural transplantation technique to compare hemodynamic and metabolic changes in cerebellum during servere hypoglycemia with those in heterotopic cerebellar grafts. To this end, the cerebellar anlage of fetal rat brain (day 15 of gestation) was stereotactically transplanted into the vulnerable caudate-putamen. Following a differentiation period of 8 weeks the grafts had developed into an organotypic population of mature cells with laminar histoarchitecture. Host animals were then subjected to insulin-induced hypoglycemia. After 15 min of isoelectric EEG, blood flow was increased throughout the brain but residual glucose consumption was significantly higher in cerebellum (0.29 μmol/g per min) and cerebellar grafts (0.22 μmol/g per min) as a result of increased glucose extraction. Hypoglycemia caused a depletion of ATP in all brain structures except cerebellum where normal levels were maintained. Correlation of local ATP content and glucose utilization revealed a threshold-like decline of ATP at a glucose utilization rate of 0.27 μmol/g per min. ATP, in consequence, was normal in cerebellum but partially depleted in cerebellar grafts. It is concluded that the resistance of cerebellum to hypoglycemia is due to its capacity for higher glucose extraction at low blood glucose levels, and that this unique intrinsic property is preserved after heterotopic transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Abdul-Rahman A, Siesjö BK (1980) Local cerebral glucose consumption during insulin-induced hypoglycemia and in the recovery period folowing glucose administration. Acta Physiol Scand 110:149–159

    Google Scholar 

  2. Abdul-Rahman A, Agardh C-D, Siesjö BK (1980) Local cerebral blood flow in the rat during servere hypoglycemia, and in the recovery period following glucose injection. Acta Physiol Scand 109:307–314

    Google Scholar 

  3. Abdul-Rahman A, Dahlgren N, Ingvar M, Rehncrona N, Siesjö BK (1979) Local versus regional blood flow in the rat at high (hypoxia) and low (phenobarbital anesthesia) flow rates. Acta Physiol Scand 106:53–60

    Google Scholar 

  4. Agardh C-D, Kalimo H, Olsson Y, Siesjö BK (1980) Hypoglycemic brain injury. I. Metabolic and light microscopic findings in rat cerebral cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. Acta Neuropathol (Berl) 50:31–41

    Google Scholar 

  5. Agardh C-D, Kalimo H, Olsson Y, Siesjö BK (1981) Hypoglycemic brain injury: metabolic and structural findings in rat cerebellar cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. J Cereb Blood Flow Metab 1:71–84

    Google Scholar 

  6. Anagnostopoulos J, Knoth R, Duffner T, Klein PJ, Volk B (1987) Vascularization of fetal cerebellar tissue transplanted into the striatum of adult rats. In: Cervós-Navarro J, Ferszt R (eds) Stroke and microcirculation. Raven Press, New York, pp 171–176

    Google Scholar 

  7. Auer RN (1986) Progress review: hypoglyemic brain damage. Stroke 17:699–708

    Google Scholar 

  8. Auer RN, Wieloch T, Olsson Y, Siesjö BK (1984) The distribution of hypoglycemic brain damage. Acta Neuropathol (Berl) 64:177–191

    Google Scholar 

  9. Auer R, Kalimo H, Olsson Y, Wieloch T (1985) The dentate gyrus in hypoglycemia: pathology implicating excitotoxin-mediated neuronal necrosis. Acta Neuropathol (Berl) 67:279–288

    Google Scholar 

  10. Ausprunk DH, Knighton DR, Folkman J (1975) Vascularization of normal and neoplastic tissues transplanted to the chick chorioallantois. Role of host and preexisting graft blood vessels. Am J Pathol 79:597–618

    Google Scholar 

  11. Beck DW, Vinters HV, Hart MN, Cancilla PA (1984) Glial cells influence polarity of the blood-brain barrier. J Neuropathol Exp Neurol 43:219–224

    Google Scholar 

  12. Betz AL, Iannotti F (1983) Simultaneous determination of regional cerebral blood flow and blood-brain glucose transport kinetics in the gerbil. J Cereb Blood Flow Metab 3:193–199

    Google Scholar 

  13. Björklund A, Stenevi U (1984) Intracerebral neural transplants: neuronal replacement and reconstruction of damaged circuitries. Ann Rev Neurosci 7:297–803

    Google Scholar 

  14. Bodian D (1936) A new method for staining nerve fibers and nerve endings in mounted paraffin sections. Anat Rec 65:89–97

    Google Scholar 

  15. Braun LD, Miller LP, Pardridge WM, Oldendorf WH (1985) Kinetics of regional blood-brain glucose transport and cerebral blood flow determined with the carotid injection technique in conscious rats. J Neurochem 44:911–915

    Google Scholar 

  16. Broadwell RD, Charlton HM, Balin BJ, Salcman M (1987) Angioarchitecture of the CNS, pituitary gland, and intracerebral grafts revealed with peroxidase cytochemistry. J Comp Neurol 260:47–62

    Google Scholar 

  17. Bryan RM, Keefer KA, MacNeill C (1986) Regional cerebral glucose utilization during insulin-induced hypoglycemia in unanesthetized rats. J Neurochem 44:1904–1910

    Google Scholar 

  18. Butcher SP, Jacobson I, Sandberg M, Hagberg H, Hamberger A (1987) 2-Amino-5-phosphonovalerate attenuates the severe hypoglycemia-induced loss of perforant pathevoked field potentials in the rat hippocampus. Neurosci Lett 76:296–300

    Google Scholar 

  19. Butcher SP, Sandberg M, Hagberg H, Hamberger A (1987) Cellular origins of endogenous amino acids released into the extracellular fluid of the rat striatum during severe insulin-induced hypoglycemia. J Neurochem 48:722–728

    Google Scholar 

  20. Chapman AG, Westerberg E, Siesjö BK (1981) The metabolism of purine and pyrimidine nucleotides in rat cortex during insulin-induced hypoglycemia. J Neurochem 36:179–189

    Google Scholar 

  21. Chapman AG, Engelsen B, Meldrum BS (1987) 2-Amino-7-phosphoheptanoic acid inhibits insulin-induced convulsions and striatal aspartate accumulation in rats with frontal cortical ablation. J Neurochem 49:121–127

    Google Scholar 

  22. Collins RC (1986) Selective vulnerability of brain: new insights form the excitatory synapse. Metab Brain Dis 4:231–233

    Google Scholar 

  23. Craigie EH (1920) On the relative vascularity of various parts of the central nervous system of the albino rat. J Comp Neurol 31:429–464

    Google Scholar 

  24. Crane PD, Pardridge WM, Braun LD, Nyerges AM, Oldendorf WH (1981) The interaction of transport and metabolism on brain glucose utilization: a reevaluation of the lumped constant. J Neurochem 36:1601–1604

    Google Scholar 

  25. Cremer JE, Cunningham VJ, Pardridge WM, Braun LD, Oldendorf WH (1979) Kinetics of blood-brain barrier transpor of pyruvate, lactate and glucose in suckling, weanling and adult rats. J Neurochem 33:439–445

    Google Scholar 

  26. Cremer JE, Cunningham VJ, Seville MP (1983) Relationships between extraction and metabolism of glucose, blood flow, and tissue blood volume in regions of rat brain. J Cereb Blood Flow Metab 3:291–302

    Google Scholar 

  27. Dahlgren N, Ingvar M, Yokoyama H, Siesjö BK (1981) Influence of nitrous oxide on local blood flow in awake, minimally restrained rats. J Cereb Blood Flow Metab 1:211–218

    Google Scholar 

  28. Das GD, Hallas BH, Das KG (1979) Transplantation of neural tissues in the brains of laboratory mammals: technical details and comments. Experienta 35:143–153

    Google Scholar 

  29. De Bault LE, Cancilla PA (1980) γ-Glutamyl transpeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science 207:653–655

    Google Scholar 

  30. Dick APK, Harik SI (1986) Distribution of the glucose transporter in the mammalian brain. J Neurochem 46:1406–1411

    Google Scholar 

  31. Dick APK, Harik SI, Klip A, Walker DM (1984) Identification and characterization of the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. Proc Natl Acad Sci USA 81:7233–7237

    Google Scholar 

  32. Engelsen B, Westerberg E, Fonnum F, Wieloch T (1986) Effect of insulin-induced hypoglycemia on the concentrations of glutamate and related amino acids and energy metabolites in the intact and decorticalted rat neostriatum. J Neurochem 47:1634–1641

    Google Scholar 

  33. Freed WJ, de Medinaceli L, Wyatt RJ (1985) Promoting functional plasticity in the damaged nervous system. Science 227:1544–1552

    Google Scholar 

  34. Frotscher M, Zimmer J (1987) GABAergic nonpyramidal neurons in intracerebral transplants of the rat hippocampus and fascia dentata: a combined light and electron microscopic study. J Comp Neurol 259:266–276

    Google Scholar 

  35. Gage FH, Dunnett SB, Brundin P, Isaacson O, Björklund A (1983) Intracerebral grafting of embryonic neural cells into the adult host brain: An overview of the cell suspension method and its application. Dev Neurosci 6:137–151

    Google Scholar 

  36. Gjedde A (1983) Modulation of substrate transport to the brain. Acta Neurol Scand 67:3–25

    Google Scholar 

  37. Gjedde A (1987) Does deoxyglucose uptake in the brain reflect energy metabolism? Biochem Pharmacol 36:1853–1861

    Google Scholar 

  38. Gjedde A, Diemer NH (1985) Double tracer study of the fine regional blood-brain glucose transfer in the rat by computerassisted autoradiography. J Cereb Blood Flow Metabol 5:282–289

    Google Scholar 

  39. Gjedde A, Rasmussen M (1980) Pentobarbital anesthesia reduces blood-brain glucose transfer in the rat. J Neurochem 35:1381–1387

    Google Scholar 

  40. Hargreaves RJ, Planas AM, Cremer JE, Cunningham VJ (1986) Studies on the relationship between cerebral glucose transport and phosphorylation using 2-deoxyglucose. J Cereb Blood Flow Metab 6:708–716

    Google Scholar 

  41. Ingvar M, Siesjö BK (1982) Effect of nitrous oxide on local cerebral glucose utilization in rats. J Cereb Blood Flow Metab 2:481–486

    Google Scholar 

  42. Janzer RC, Raff MC (1987) Astrocytes induce blood-brain properties in endothelial cells. Nature 325:253–257

    Google Scholar 

  43. Kalimo H, Olsson Y (1980) Effect of severe hypoglycemia on the human brain. Acta Neurol Scand 62:345–356

    Google Scholar 

  44. Kiessling M, Weigel K, Gartzen D, Kleihues P (1982) Regional heterogenity ofl-(3-3H)tyramine incorporation into rat brain proteins during severe hypoglycemia. J Cereb Blood Flow Metab 2:249–253

    Google Scholar 

  45. Kiessling M, Xie Y, Kleihues P (1984) Regionally selective inhibition of cerebral protein synthesis in the rat during hypoglycemia and recovery. J Neurochem 43:1507–1514

    Google Scholar 

  46. Kleihues P, Kiessling M, Thilmann R, Xie Y, Uozumi A, Volk B (1986) Resistance to hypoglycemia of cerebellar transplants in the rat forebrain. Acta Neuropathol (Berl) 72:23–28

    Google Scholar 

  47. Kobayashi H, Magnoni MS, Goroni S, Izumi F, Wada A, Trabucchi M (1985) Neuronal control of brain microvessel function. Experientia 41:427–434

    Google Scholar 

  48. Kogure K, Alonso OF (1978) A pictorial representation of endogenous brain ATP by a bioluminescent method. Brain Res 154:273–284

    Google Scholar 

  49. LaManna JC, Harik SI (1985) Regional comparison of brain glucose influx. Brain Res 326:299–305

    Google Scholar 

  50. Lee HB, Blaufox MD (1985) Blood volume in the rat. J Nucl Med 25:72–76

    Google Scholar 

  51. Lewis LD, Ljundggren B, Ratcheson RA, Siesjö BK (1974) Changes in carbohydrate substrates, amino acids and ammonia in the brain during insulin-induced hypoglycemia. J Neurochem 23:659–671

    Google Scholar 

  52. Lindvall O, Auer RN, Siesjö BK (1986) Selective lesions of mesostriatal dopamine neurons ameliorate hypoglycemic damage in the caudate-putamen. Exp Brain Res 18:382–386

    Google Scholar 

  53. Michenfelder JD (1974) The interdependancy of cerebral functional and metabolic effects folowing massive doses of thiopental in the dog. Anesthesiology 41:231–236

    Google Scholar 

  54. Norberg K, Siesjö BK (1976) Oxidative metabolism of the cerbral cortex of the rat in severe insulin-induced hypoglycemia. J Neurochem 26:345–352

    Google Scholar 

  55. Pardridge WM, Crane PD, Mietus LJ, Oldendorf WH (1982) Nomogram for 2-deoxyglucose lumped constant for rat brain cortex. J Cereb Blood Flow Metab 2:197–202

    Google Scholar 

  56. Paschen W, Niebuhr I, Hossmann K-A (1981) A bioluminescence method for the demonstration of regional glucose distribution in brain slices. J Neurochem 36:513–517

    Google Scholar 

  57. Paschen W, Hossmann K-A, van den Kerckhoff W (1983) Regional assessment of energy-producing metabolism following prolonged complete ischemia of cat brain. J Cereb Blood Flow Metab 3:321–329

    Google Scholar 

  58. Paschen W, Mies G, Kloiber O, Hossmann K-A (1985) Regional quantitative determination of brain glucose in tissue sections: a bioluminescent approach. J Cereb Blood Flow Metab 5:456–468

    Google Scholar 

  59. Paschen W, Siejö BK, Ingvar M, Hossmann K-A (1986) Regional differences in brain glucose content in graded hypoglycemia. Neurochem Pathol 5:131–142

    Google Scholar 

  60. Ratcheson RA, Blank AC, Ferendelli JA (1981) Regionally selective metabolic effects of hypoglycemia in brain. J Neurochem 36:1952–1958

    Google Scholar 

  61. Rothman S, Olney JW (1985) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19:105–111

    Google Scholar 

  62. Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo[14C]antipyrine. Am J Physiol 243:H59-H66

    Google Scholar 

  63. Sandberg M, Butcher SP, Hagberg H (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem 47:178–184

    Google Scholar 

  64. Schmidt RH, Ingvar M, Lindvall O, Stenevi U, Björklund A (1981) Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and 2-[14C]deoxy-d-glucose autoradiography. J Neurochem 38:737–748

    Google Scholar 

  65. Siesjö BK (1978) Brain energy metabolism. Wiley, New York, pp 101–131

    Google Scholar 

  66. Siesjö BK (1981) Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1:155–185

    Google Scholar 

  67. Siesjö BK, Agardh C-D (1983) Hypoglycemia. In: Lajtha A (ed) Metabolism in the nervous system. Handbook of Neurochemistry, 2nd edn, vol. 3. Plenum Press, New York London, pp 353–379

    Google Scholar 

  68. Simon RP, Schmidley JW, Meldrum BS, Swan JH, Chapman AG (1986) Excitotoxic mechanisms in hypoglycemic hippocampal injury. Neuropathol Appl Neurobiol 12:567–576

    Google Scholar 

  69. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakudara O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

    Google Scholar 

  70. Stewart PA, Wiley MJ (1981) Developing nervous tissue induces formation of blood-barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev Biol 84:183–192

    Google Scholar 

  71. Svendgaard N-A, Björklund A, Hardebo J-E, Stenevi U (1975) Axonal degeneration associated with a defective blood-brain barrier in cerebral implants. Nature 255:334–336

    Google Scholar 

  72. Westerberg E, Wieloch T (1986) Lesions in the corticostriatal pathways ameliorate hypoglycemia-induced arachidonic acid release. J Neurochem 47:1507–1511

    Google Scholar 

  73. Wieloch T (1985) Neurochemical correlates to selective neuronal vulnerability. Prog Brain Res 63:69–85

    Google Scholar 

  74. Wieloch T (1985) Hypoglycemia-induced neuronal damage prevented by anN-methyl-d-aspartate antagonist. Science 230:681–683

    Google Scholar 

  75. Wieloch T, Engelsen B, Westerberg E, Auer R (1985) Lesions of the glutamatergic cortico-striatal projections ameliorate hypoglycemic brain damage in the striatum. Neurosci Lett 58:25–30

    Google Scholar 

Download references

Author information

Author notes

  1. M. Kiessling

    Present address: Abt. Neuropathologie, Pathol., Institut der Universität des Saarlandes, D-6650, Homburg/Saar, Germany

Authors and Affiliations

  1. Labor für Neuropathologie, Institut für Pathologie, Universität Freiburg, Albertstrasse 19, D-7800, Freiburg i. Br., Germany

    M. Kiessling, R. Thilmann & M. Detmar

  2. Abteilung für Experimentelle Neurologie, Max-Planck-Institut für Neurologische Forschung, D-5000, Köln, Germany

    G. Mies, W. Paschen & K. -A. Hossmann

Authors
  1. M. Kiessling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Mies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Paschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Thilmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Detmar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. -A. Hossmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by the Deutsche Forschungsgemeinschaft (SFB 70)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiessling, M., Mies, G., Paschen, W. et al. Blood flow and metabolism in heterotopic cerebellar grafts during hypoglycemia. Acta Neuropathol 77, 142–151 (1988). https://doi.org/10.1007/BF00687424

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00687424

Key words

Search

Navigation