Summary
The present study is concerned with the question of whether or not amphiphilic drugs (chloroquine, quinacrine, perhexiline) that fail to induce general lipidosis in the central nervous system (CNS) of adult rats can produce lipidosis in a circumventricular organ (area postrema) not furnished with a blood-brain barrier. Chlorphentermine known to induce general lipidosis in CNS of adult rats served as reference compound. All drugs, when chronically applied in high oral doses, induced significant perikaryal lipidosis in the area postrema. In the adjacent nuclei (nucleus tractus solitarii, nucleus dorsalis nervi vagi, nucleus nervi hypoglossi, nucleus gracilis), only chlorphentermine caused generalized lipidosis, whereas the other drugs had either limited or no effects. The present findings strongly suggest that the exemption, of most regions of the CNS of adult rats, from lipidosis induced by chloroquine and others is due to hindered drug distribution across the blood-brain barrier, rather than being due to non-susceptibility of central neurons toward the lipidosis-inducing action of the drugs.
Similar content being viewed by others
References
Allison AC, Young MR (1964) Uptake of dyes and drugs by living cells in culture. Life Sci 3:1407–1414
Bastos AL, Terrinha AM, Vigario JD, Moura Nunes JF, Nunes Petisca JL (1966) UV-induced changes in lysosomes tagged with quinacrine. Exp Cell Res 42:84–88
De Duve C, De Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F (1974) Lysosomotropic agents. Biochem Pharmacol 23:2495–2531
Dempsey EW (1973) Neural and vascular ultrastructure of the area postrema in the rat. J Comp Neurol 150:177–200
Frisch W, Lüllmann-Rauch R (1981) Effects of several lipidosis-inducing drugs upon the area postrema and adjacent medullary nuclei of adult rats. II. Axonal alterations. Acta Neuropathol (Berl) (in press)
Gleiser CA, Bay WW, Dukes TW, Brown RS, Read WK, Pierce KR (1968) Study on chloroquine toxicity and a drug-induced cerebrospinal lipodystrophy in swine. Am J Pathol 53:27–45
Gonatas NK, Baird HW, Evangelista I (1968) The fine structure of neocortical synapses in infantile amaurotic idioxy. J Neuropathol Exp Neurol 27:39–49
Grundmann M, Mikulikova I, Vrublovsky P (1972) Tissue distribution of chloroquine in rats in the course of long-term application. Arch Int Pharmacodyn 197:45–52
Hecht G (1936) Die Verteilung des Atebrins im Organismus. Naunyn-Schmiedebergs Arch Exp Path Pharmakol 183:87–105
Igarashi M, Suzuki K, Chen SM, Suzuki K (1975) Changes in brain hydrolytic enzyme activities in rats treated with cholesterol biosynthesis inhibitor, AY994. Brain Res 90:97–114
Jung HJ, Suzuki K (1978) Morphological changes in CNS of rats treated with perhexiline maleate (pexid). Acta Neuropathol (Berl) 42:159–164
Klara PM, Brizzee KR (1975) The ultrastructural morphology of the squirrel monkey area postrema. Cell Tissue Res 160:315–326
Klara PM, Brizzee KR (1977) Ultrastructure of the feline area postrema. J Comp Neurol 171:409–432
Klinghardt GW (1974) Experimentelle Schädigungen von Nervensystem und Muskulatur durch Chlorochin: Modelle verschiedenartiger Speicherdystrophien. Acta Neuropathol (Berl) 28:117–141
Klinghardt GW (1976) Lysosomen bei experimenteller Speicherdystrophie durch chronische Intoxikation mit Chlorochin. Verh Dtsch Ges Path 60:229–232
Klinghardt GW (1977a) Neuronal storage dystrophy in chronic chloroquine intoxication. In: Roizin L, Shiraki H, Grcevic N (eds), Neurotoxicology. Raven Press, New York, pp 371–380
Klinghardt GW (1977b) Zur Selektivität des Befalles von Ganglienzellsystemen und Ganglienzelltypen durch experimentelle Residualkörperdystrophie. Verh Dtsch Ges Path 61:448
Lüllmann H, Lüllmann-Rauch R (1978) Perhexiline induces generalized lipidosis in rats. Klin Wochenschr 56:309–310
Lüllmann H, Lüllmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27:1103–1108
Lüllmann-Rauch R (1974a) Lipidosis-like alterations in spinal cord and cerebellar cortex of rats treated with chlorphentermine or tricyclic antidepressants. Acta Neuropathol (Berl) 29:237–249
Lüllmann-Rauch R (1974b) Lipidosis-like alterations in hypothalamic neurosecretory cells of rats treated with chlorphentermine or iprindole. Cell Tissue Res 149:587–590
Lüllmann-Rauch R (1976) Alterations in the neurohypophysis of rats treated with chlorphentermine or tricyclic antidepressants. Cell Tissue Res 169:501–514
Lüllmann-Rauch R (1979) Drug-induced lysosomal storage disorders. In: Dingle JT, Jacques PJ, Shaw IH (eds) Lysosomes in applied biology and therapeutics, vol 6. North Holland, Amsterdam, pp 49–130
McChesney EW, McAuliff JP (1961) Laboratory studies of the 4-aminoquinoline antimalarials. Antibiot Chemother 11:800–810
Rohrschneider, I, Schinko I, Wetzstein R (1972) Der Feinbau der Area postrema der Maus. Z Zellforsch 123:251–276
Routledge PA, Shand DG (1979) Presystemic drug elimination. Ann Rev Pharmacol Toxicol 19:447–468
Špaček, J, Pařizek J (1969) The fine structure of the area postrema of the rat. Acta Morphologica Acad Sci Hung 17:17–34
Suzuki K, Zagoren JC, Gonatas J, Suzuki K (1973) Ultrastructural study of neuronal cytoplasmic inclusions produced by hypocholesterolemic drug, AY 9944. Acta Neuropathol (Berl) 26:185–197
Wibo M, Poole B (1974) Protein degradation in cultured cells. II: The uptake of chloroquine by rat fibroblasts and the inhibition of cellular protein degradation and cathepsin B1. J Cell Biol 63:430–440
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Frisch, W., Lüllmann-Rauch, R. Effects of several lipidosis-inducing drugs upon the area postrema and adjacent medullary nuclei of adult rats. Acta Neuropathol 52, 179–187 (1980). https://doi.org/10.1007/BF00705806
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00705806