Summary
In the course of a study on the pathogenesis of neuronal necrosis in severe hypoglycemia, the morphological characteristics reflecting reversible and irreversible neuronal lesions were examined as a function of time following normalization of blood glucose. To that end, closely spaced time intervals were studied in the rat cerebral cortex before, during, and up to 1 year after standardized pure hypoglycemic insults of 30 and 60 min of cerebral isoelectricity.
Both the superficial and deep layers of the cerebral cortex showed dark and light neurons during and several hours after the insult. By electron microscopy (EM) the dark neurons were characterized by marked condensation of both karyoplasma and cytoplasm, with discernible, tightly packed cytoplasmic organelles. The light neurons displayed clustering of normal organelles around the nucleus with clearing of the peripheral cytoplasm. Some cells, both dark neurons and neurons of normal electron density, contained swollen mitochondrial with fractured cristae.
Light neurons disappeared from the cerebral cortex by 4 h of recovery. Some dark neurons in the superficial cortex and almost all in the deep cortex evolved through transitional forms into normal neurons by 6 h recovery. Another portion of the dark neurons in the superficial cortex became acidophilic between 4 and 12 h, and by EM they demonstrated karyorrhexis with stippled electron-dense chromatin. The plasma membrane was disrupted, the cytoplasm was composed of amorphous granular debris, and the mitochondria contained flocculent densities. These definitive indices of irreversible neuronal damage were seen as early as 4–8 h recovery. Subsequently, the acidophilic neurons were removed from the tissue, and gliosis ensued.
Thus, even markedly hyperchromatic “dark” neurons are compatible with survival of the cell, as are neurons with conspicuous mitochondrial swelling. Definite nerve cell death is verified as the appearance of acidophilic neurons at which stage extensive damage to mitochondria is already seen in the form of flocculent densities, and cell membranes are ruptured.
Our previous results have shown that hypoglycemic neocortical damage affects the superficial laminae, chiefly layer 2. The present results demonstrate that, following the primary insult, this damage evolves relatively rapidly within the first 4–12 h. We have obtained no evidence that additional necrotic neurons are recruited after longer recovery periods.
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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) Reply to the remarks by J. B. Brierley and A. W. Brown. Acta Neuropathol (Berl) 55:323–325
Agardh C-D, Chapman AG, Pelligrino D, Siesjö BK (1982) Influence of severe hypoglycemia on mitochondrial and plasma membrane function in rat brain. J Neurochem 38:662–668
Auer RN, Olsson Y, Siesjö BK (1984) Hypoglycemic brain injury in the rat: Correlation of density of brain damage with the EEG isoelectric time. A quantitative study. Diabetes 33:1090–1098
Auer RN, Kalimo H, Olsson Y, Siesjö BK (1984) The distribution of hypoglycemic brain damage. Acta Neuropathol (Berl) 64:177–191
Auer RN, Kalimo H, Olsson Y, Siesjö BK (1984) The temporal evolution of hypoglycemic brain damage. II. Light- and electron-microscopic findings in the hippocampal gyrus of the rat. Acta Neuropathol (Berl) 67:25–36
Baleydier C (1972) Electron-microscopic alterations of the cerebral cortex of the cat in the vicinity of epileptogenic alumina cream focus. Acta Neuropathol (Berl) 20:11–21
Banker BQ (1967) The neuropathological effects of anoxia and hypoglycemia in the newborn. Dev Med Child Neurol 9:544–550
Bigotte L, Olsson Y (1983) Cytotoxic effects of adriamycin on mouse hypoglossal neurons following retrograde axonal transport from the tongue. Acta Neuropathol (Berl) 61:161–168, Fig. 4
Brierley JB, Brown AW (1981) Remarks on the papers by C.-D. Agardh et al./H. Kalimo et al. “Hypoglycemic brain injury, I, II”. Acta Neuropathol (Berl) 55:319–322
Bubis JJ, Fujimoto T, Ito U, Mrsulja B, Spatz M, Klatzo I (1976) Experimental cerebral ischemia in Mongolian gerbils. V. Ultrastructural changes in H3 sector of the hippocampus. Acta Neuropathol (Berl) 36:285–294
Cammermeyer J (1938) Über Gehirnveränderungen, entstanden unter Sakelscher Insulintherapie bei einem Schizophrenen. Z Ges Neurol Psychiat 163:617–633
Cammermeyer J (1961) The importance of avoiding “dark” neurons in experimental neuropathology. Acta Neuropathol (Berl) 1:245–270
Collan Y, McDowell E, Trump BE (1981) Studies on the pathogenesis of ischemic cell injury. VI. Mitochondrial flocculent densities in autolysis. Virchows Arch B [Cell Pathol] 35:189–199
Folbergrová J, MacMillan V, Siesjö BK (1972) The effect of moderate and marked hypercapnia upon the energy state and upon cytoplasmic NADH/NAD+ ratio of the rat brain. J Neurochem 19:2497–2505
Garcia JH, Lossinsky AS, Kauffman FC, Conger KA (1978) Neuronal ischemic injury: light microscopy, ultrastructure, and biochemistry. Acta Neuropathol (Berl) 43:85–95
Grayzel DM (1934) Changes in the central nervous system due to convulsions due to hyperinsulinism. Arch Int Med 54:694–701
Harris RJ, Wieloch T, Symon L, Siesjö BK (1984) Cerebral extracellular calcium activity in severe hypoglycemia: relation to extracellular potassium and energy state. J Cerebr Blood Flow Metab 4:187–193
Jennings RB, Shen AC, Hill ML, Ganote CE, Herdson PB (1978) Mitochondrial matrix densities in myocardial ischemia and autolysis. Exp Mol Pathol 29:55–65
Kalimo H, Olsson Y (1980) Effect of severe hypoglycemia on the human brain. Acta Neurol Scand 62:345–356
Kalimo H, Garcia JH, Kamijyo Y, Tanaka J, Trump BF (1977) The ultrastructure of brain death II. Electron microscopy of feline cortex after complete ischemia. Virchows Arch [Cell Pathol] 25:207–220
Kalimo H, Agardh C-D, Olsson Y, Siesjö BK (1980) Hypoglycemic brain injury. II. Electron-microscopic findings in rat cerebral cortical neurons during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. Acta Neuropathol (Berl) 50:43–52
Kalimo H, Auer RN, Olsson Y, Siesjö BK (1985) The temporal evolution of hypoglycemic brain damage. III. Light- and electron-microscopic findings in the caudate nucleus. Acta Neuropathol (Berl) 67:37–50
Kastein GW (1938) Insulinvergiftung. II. Neurologische und anatomisch-histologische Beschreibung. Z Ges Neurol Psychiat 163:342–361
Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol (Berl) 62:201–208
Kirino T, Sano K (1984) Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus. Acta Neuropathol (Berl) 62:209–218
Kirino T, Tamura A, Sano K (1984) Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol (Berl) 64:139–147
Lee JC, Olszewski J (1960) Penetration of radioactive bovine albumin from cerebrospinal fluid into brain tissue. Neurology 10:814–822
Miyakawa T, Sumiyoshi S, Deshimaru M, Suzuki T, Tomonari H, Yasuoka F, Tatetsu S (1972) Electron microscopic study on schizophrenia. Acta Neuropathol (Berl) 20:67–77
Myers RE, Kahn KJ (1971) Insulin-induced hypoglycemia in the non-human primate. II. Long-term neuropathological consequences. In: Brierley JB, Meldrum BS (eds) Brain hypoxia, chapt 20. Heinemann, London, pp 195–206
Parnavelas JG, McDonald JK (1983) The cerebral cortex. In: PC Emson (ed) Chemical neuroanatomy, Raven Press, New York, pp 505–549
Petito CK, Pulsinelli WA (1984) Sequential development of reversible and irreversible neuronal damage following cerebral ischemia. J Neuropathol Exp Neurol 43:141–153
Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498
Siesjö BK (1981) Cell damage in the brain: A speculative synthesis. J Cereb Blood Flow Metab 1:155–185
Söderfeldt B, Kalimo H, Olsson Y, Siesjö BK (1983) Bicuculline-induced epileptic brain injury. Transient and persistent cell changes in rat cerebral cortex in the early recovery period. Acta Neuropathol (Berl) 62:87–95
Stief S, Tokay L (1932) Beitrag zur Histopathologie der experimentellen Insulinvergiftung. Z Ges Neurol Psychiat 139:434–461
Torvik A, Skjörten F (1971) Electron-microscopic observations on nerve cell regeneration and degeneration after axon lesions. I. Changes in nerve cell cytoplasm. Acta Neuropathol (Berl) 17:248–264
Trump BF, McDowell EM, Arstila AU (1980) Cellular reaction to injury. In: Hill RB, LaVia MF (eds) Principles of pathobiology, 3rd edn, chapt 2). Oxford University Press, New York Oxford, pp 20–111
Weil A, Liebert E, Heilbrunn G (1938) Histopathologic changes in the brain in experimental hyperinsulinism. Arch Neurol Psychiatr 39:467–481
Wieloch T, Harris RJ, Symon L, Siesjö BK (1984) Influence of severe hypoglycemia on brain extracellular calcium and potassium activities, energy and phospholipid metabolism. J Neurochem 43:160–168
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Supported by the Swedish Medical Research Council (projects 12X-03020, 12X-07123, 14X-263), the Finish Medical Research Council, and the National Institutes of Health of the United States Public Health Service (grant no. 5 R01 NS07838)
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Auer, R.N., Kalimo, H., Olsson, Y. et al. The temporal evolution of hypoglycemic brain damage. Acta Neuropathol 67, 13–24 (1985). https://doi.org/10.1007/BF00688120
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DOI: https://doi.org/10.1007/BF00688120