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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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
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
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
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
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
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
Auer RN (1986) Progress review: hypoglyemic brain damage. Stroke 17:699–708
Auer RN, Wieloch T, Olsson Y, Siesjö BK (1984) The distribution of hypoglycemic brain damage. Acta Neuropathol (Berl) 64:177–191
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
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
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
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
Björklund A, Stenevi U (1984) Intracerebral neural transplants: neuronal replacement and reconstruction of damaged circuitries. Ann Rev Neurosci 7:297–803
Bodian D (1936) A new method for staining nerve fibers and nerve endings in mounted paraffin sections. Anat Rec 65:89–97
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
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
Bryan RM, Keefer KA, MacNeill C (1986) Regional cerebral glucose utilization during insulin-induced hypoglycemia in unanesthetized rats. J Neurochem 44:1904–1910
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
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
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
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
Collins RC (1986) Selective vulnerability of brain: new insights form the excitatory synapse. Metab Brain Dis 4:231–233
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
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
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
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
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
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
De Bault LE, Cancilla PA (1980) γ-Glutamyl transpeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science 207:653–655
Dick APK, Harik SI (1986) Distribution of the glucose transporter in the mammalian brain. J Neurochem 46:1406–1411
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
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
Freed WJ, de Medinaceli L, Wyatt RJ (1985) Promoting functional plasticity in the damaged nervous system. Science 227:1544–1552
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
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
Gjedde A (1983) Modulation of substrate transport to the brain. Acta Neurol Scand 67:3–25
Gjedde A (1987) Does deoxyglucose uptake in the brain reflect energy metabolism? Biochem Pharmacol 36:1853–1861
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
Gjedde A, Rasmussen M (1980) Pentobarbital anesthesia reduces blood-brain glucose transfer in the rat. J Neurochem 35:1381–1387
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
Ingvar M, Siesjö BK (1982) Effect of nitrous oxide on local cerebral glucose utilization in rats. J Cereb Blood Flow Metab 2:481–486
Janzer RC, Raff MC (1987) Astrocytes induce blood-brain properties in endothelial cells. Nature 325:253–257
Kalimo H, Olsson Y (1980) Effect of severe hypoglycemia on the human brain. Acta Neurol Scand 62:345–356
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
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
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
Kobayashi H, Magnoni MS, Goroni S, Izumi F, Wada A, Trabucchi M (1985) Neuronal control of brain microvessel function. Experientia 41:427–434
Kogure K, Alonso OF (1978) A pictorial representation of endogenous brain ATP by a bioluminescent method. Brain Res 154:273–284
LaManna JC, Harik SI (1985) Regional comparison of brain glucose influx. Brain Res 326:299–305
Lee HB, Blaufox MD (1985) Blood volume in the rat. J Nucl Med 25:72–76
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
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
Michenfelder JD (1974) The interdependancy of cerebral functional and metabolic effects folowing massive doses of thiopental in the dog. Anesthesiology 41:231–236
Norberg K, Siesjö BK (1976) Oxidative metabolism of the cerbral cortex of the rat in severe insulin-induced hypoglycemia. J Neurochem 26:345–352
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
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
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
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
Paschen W, Siejö BK, Ingvar M, Hossmann K-A (1986) Regional differences in brain glucose content in graded hypoglycemia. Neurochem Pathol 5:131–142
Ratcheson RA, Blank AC, Ferendelli JA (1981) Regionally selective metabolic effects of hypoglycemia in brain. J Neurochem 36:1952–1958
Rothman S, Olney JW (1985) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19:105–111
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
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
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
Siesjö BK (1978) Brain energy metabolism. Wiley, New York, pp 101–131
Siesjö BK (1981) Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1:155–185
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
Simon RP, Schmidley JW, Meldrum BS, Swan JH, Chapman AG (1986) Excitotoxic mechanisms in hypoglycemic hippocampal injury. Neuropathol Appl Neurobiol 12:567–576
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
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
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
Westerberg E, Wieloch T (1986) Lesions in the corticostriatal pathways ameliorate hypoglycemia-induced arachidonic acid release. J Neurochem 47:1507–1511
Wieloch T (1985) Neurochemical correlates to selective neuronal vulnerability. Prog Brain Res 63:69–85
Wieloch T (1985) Hypoglycemia-induced neuronal damage prevented by anN-methyl-d-aspartate antagonist. Science 230:681–683
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
Author information
Authors and Affiliations
Additional information
Supported in part by the Deutsche Forschungsgemeinschaft (SFB 70)
Rights 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
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00687424