Summary
To evaluate the development of striatal ischemic cell damage in relation to alterations in dopamine (DA) transmission, one year old male Wistar rats underwent a 15 min incomplete cerebral ischemia (ICI) induced by occlusion of the common carotid arteries and by hypovolemic hypotension. The animals were divided into the following experimental groups: sham operated rats, rats with ICI without reperfusion, and rats with ICI followed by 60 min, 24 h, 72 h and 144 h of recirculation. The ischemia induced striatal lesions were investigated in serial coronal brain sections, stained with cresylviolet or immunostained for dopamine and cAMP regulated phosphoprotein (DARPP-32), for tyrosine hydroxylase (TH) and for glial fibrillary acidic protein (GFAP) immunoreactivities (IR). Measurements of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were made on analogous experimental groups using HPLC methods. Signs of degeneration in small to medium sized neurons were already seen after 60 min of postischemic reperfusion together with slight decreases of DARPP-32 IR and increases of GFAP IR. The damage continued to increase up to 144 h, and after 24 h of recirculation there were clearly defined areas of reduced DARPP-32 IR, overlapping with increased TH IR and increased GFAP IR. The levels of DA, DOPAC and HVA increased sharply after 60 min (151%, 462% and 201%, respectively) remained high after 24 h and normalized after 72 h of recirculation. The DA metabolism was high after 60 min and had already normalized after 24 h of recirculation. The increased DA metabolism in striatal nerve terminals in response to ischemic injury may reflect an early degenerative change in the DA terminals. The long-lasting increase in TH IR may to some extent represent an adaptive change in response to the disappearance of DA receptor-containing nerve cells. Based on the present findings it is possible that an increased D1 transmission in neostriatum immediately following the ischemic injury may contribute to striatal nerve cell degeneration in which an enhancement of NMDA receptor transduction may be implicated.
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References
Agnati LF, Fuxe K, Calza L, Benfenati F, Battistini N, Zini I, Fabri L, Goldstein M (1983) Characterization of striatal ibotenate lesions and of 6-hydroxydopamine induced nigral lesions by morphometric and densitometric approaches. In: Fuxe K, Roberts P, Schwarcz R (eds) Excitotoxins. Macmillan, London, pp 239–250
Agnati LF, Fuxe K, Zoli M, Ferraguti F, Benfenati F, Ouimet CC, Walaas SI, Hemmings HC, Goldstein M, Greengard P (1988) Morphometrical evidence for a complex organization of Tyrosine hydroxylase-, enkephalin- and DARPP-32-like immunoreactive patches and their codistribution at three rostrocaudal levels in the rat neostriatum. Neuroscience 27:785–797
Agnati LF, Fuxe K (1990) Biology of disease. Nigrostriatal dopamine neurons, Dl transmission in basal and ischemic states and protective effects of gangliosides. Lab Invest 63:283–297
Andén N-E, Corrodi H, Fuxe K, Ungerstedt U (1971) Importance of nervous impulse flow for the neuroleptic induced increase in amine turnover in central dopamine neurons. Eur J Pharmacol 15:193–199
Andén N-E, Bédard P, Fuxe K, Ungerstedt U (1972) Early and selective increase in brain dopamine levels after axotomy. Experiencia 28:300–301
Benfenati F, Merlo Pich E, Grimaldi R, Zoli M, Fuxe K, Toffano G, Agnati LF (1989) Transient forebrain ischemia produces multiple deficits in dopamine D1 transmission in the lateral neostriatum of the rat. Brain Res 498:376–380
Bouyer JJ, Park DH, Joh TH, Pickel VM (1984) Chemical and structural analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum. Brain Res 302:267–275
Brown JR, Arbuthnott GW (1983) The electrophysiology of dopamine (D2) receptors: a study of the actions of dopamine on corticostriatal transmission. Neuroscience 10:349–355
Brown AW, Brierley JB (1973) The earliest alterations in rat neurones and astrocytes after anoxia-ischaemia. Acta Neuropath 23:9–22
Busto R, Dietrich WD, Globus MY-T, Valdés I, Scheinberg P, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729–738
Calderini G, Carlsson A, Nordstrom C-H (1978) Influence of transient ischemia on monoamine metabolism in the rat brain during nitrous oxide and phenobarbitone anaesthesia. Brain Res 157:303–310
Dahl D, Bignami A (1976) Immunogenic properties of the glial fibrillary acidic protein. Brain Res 116:150–157
Duchesne PY, Gerebtzoff MA, Brotchi J (1981) Four types of reactive astrocytes. Biblthca Anat 19:313–316
Eklöf B, Siesjö BK (1972) The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiol Scand 86:155–165
Francis A, Pulsinelli W (1982) The response of GABAergic and cholinergic neurons to transient cerebral ischemia. Brain Res 243:271–278
Freund TF, Powell JF, Smith AD (1984) Tyrosine hydroxylase immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience 13:1189–1215
Fuxe K, Hökfelt T, Ungerstedt U (1971) Localization of monoamines in the central nervous system. In: de Ajuriaguerra, Gauthier G (eds) Monoamines noyaux gris centraux et syndrome de Parkinson, Georg & Cie SA, Geneve, pp 23–60
Gerfen CR (1984) The neostriatal mosaic: compartmentalization of corticostriatal input and striatonigral output systems. Nature 311:461–464
Globus MY-T, Ginsberg MD, Dietrich WD, Busto R, Scheinberg P (1987) Substantia nigra lesion protects against ischemic damage in the striatum. Neurosci Lett 80:251–256
Globus MY-T, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51:1455–1464
Globus MY-T, Dietrich WD, Busto R, Valdes I, Ginsberg MD (1989) The combined treatment with a dopamine D1 (SCH-23390) and NMDA receptor blocker (MK-801) dramatically protects against ischemia-induced hippocampal damage. J Cerebral Blood Flow 9(Suppl 1):S 5
Graybiel AM, Ragsdale CW (1978) Histochemically distinct compartments in the striatum of human, monkeys, and cat demonstrated by acetylthiocholinesterase staining. Proc Natl Acad Sci (USA) 75:5723–5726
Greengard P (1986) Protein phosphorylation and neuronal function. In: Costa E (eds) Fidia research foundation neuroscience award lectures. Liviana Press, Pádova, pp 52–100
Greengard P (1987) Receptor-receptor interactions mediated by protein phosphorylation. In: Fuxe K, Agnati LF (eds) Receptor-receptor interactions: a new intramembrane integrative mechanism. Macmillan, London, pp 444–453
Grimaldi R, Zoli M, Agnati LF, Ferraguti F, Fuxe K, Toffano G, Zini I (1990) Effects of transient forebrain ischemia on peptidergic neurons and astroglial cells: evidence for recovery of peptide immunoreactivities in neocortex and striatum but not hippocampal formation. Exp Brain Res 82:123–136
Harik SI, Yoshida S, Busto R, Ginsberg MD (1986) Monoamine neurotransmitters in diffuse reversible forebrain ischemia and early recirculation: increased dopaminergic activity. Neurology 36:971–976
Hemmings HC Jr, Greengard P, Tung HYL, Cohen P (1984) DARPP-32, a dopamine-regulated neuronal phosphoprotein is a potent inhibitor of protein phosphatase-1. Nature 310:502–505
Hillered L, Hallström Å, Segersvärd S, Persson L, Ungerstedt U (1989) Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J Cereb Blood Flow Metab 9:607–616
Iijima S, Hara K, Suga H, Nakamura S, Kameyama M (1986) Effect of ischemia on hydroxylase cofactor. Stroke 17:529–533
Joh TH, Park DH, Reis DJ (1978) Direct phosphorylation of brain tyrosine hydroxylase by cyclic AMP-dependent protein kinase: mechanism of enzyme activation. Proc Natl Acad Sci USA 75:4744–4748
Joyce JN, Marshall JF (1987) Quantitative autoradiography of dopamine D2 sites in rat caudate-putamen: localization to intrinsic neurons and not to neocortical afferents. Neuroscience 20:773–795
Kobaiashi M, Lust WD, Passoneau JV (1977) Concentrations of energy metabolites and cyclic nucleotides during and after bilateral ischemia in the gerbil cerebral cortex. J Neurochem 29:53–59
Markey K, Kondo A, Schenkmann L, Goldstein M (1980) Purification and characterization of tyrosine hydroxylase from a clonal chromocytoma cell line. Mol Pharmacol 17:79–85
Mullen RJ, Smith AM, Buck CR (1989) An antibody that recognizes neuronal cell nuclei: cell specificity and developmental regulation. Soc Neurosci Abstr 15:204.9, p 499
Németh G, Cintra A, Fuxe K, Persson L, Agnati LF, Goldstein M, Hoyer S (1989) Immunocytochemical studies on some brain regions in a rat model of incomplete cerebral ischemia: relationship to behavior and aging. In: Hartmann A, Kuschinsky W (eds) Cerebral ischemia and calcium. Springer, Berlin Heidelberg, pp 83–96
Ouimet CC, Miller P, Hemmings HC, Walaas SI, Greengard P (1984) DARPP-32, a dopamine and adenosine 3′:5′-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci 4:111–124
Paschen W, Röhn G, Meese CO, Djuricic B, Schmidt-Kastner R (1988) Polyamine metabolism in reversible cerebral ischemia: effect of α-difluoromethylornithine. Brain Res 453:9–16
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2ed, Academic Press, Sidney
Pontén U, Ratcheson RA, Salford LG, Siesjö BK (1973) Optimal freezing conditions for cerebral metabolites in rats. J Neurochem 21:1127–1138
Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498
Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19:105–111
Schwarcz R, Hökfelt T, Fuxe K, Jonsson G, Goldstein M, Terenius L (1977) Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study. Exp Brain Res 37:199–216
Smith M-L, Auer RN, Siesjö BK (1984a) The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol (Berl) 64:319–332
Smith M-L, Bendek G, Dahlgren N, Rosén I, Wieloch T, Siesjö BK (1984b) Models for studying long-term recovery following forebrain ischemia in the rat. A 2-vessel occlusion model. Acta Neurol Scand 69:385–401
Takamiya Y, Kohsaka S, Toya S, Otani M, Tsukada Y (1988) Immunohistochemical studies on the proliferation of reactive astrocytes and the expression of cytoskeletal proteins following brain injury in rats. Dev Brain Res 38:201–210
Thilmann R, Xie Y, Kleihues P, Kiessling M (1986) Persistent inhibition of protein synthesis precedes delayed neuronal death in postischemic gerbil hippocampus. Acta Neuropathol (Berl) 71:88–93
Walaas SI, Greengard P (1984) DARPP-32, a dopamineand adenosine 3′:5′-monophosphate regulated phosphoprotein enriched in dopamineinnervated brain regions. I. Regional and cellular distribution in the rat brain. J Neurosci 4:84–98
Weinberger J, Nieves-Rosa J (1988) Monoamine neurotransmitters in the evolution of infarction in ischemic striatum: morphologic correlation. J Neural Transm 71:133–142
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Németh, G., Cintra, A., Herb, J.M. et al. Changes in striatal dopamine neurohistochemistry and biochemistry after incomplete transient cerebral ischemia in the rat. Exp Brain Res 86, 545–554 (1991). https://doi.org/10.1007/BF00230527
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DOI: https://doi.org/10.1007/BF00230527