Experimentelle Schädigungen von Nervensystem und Muskulatur durch Chlorochin: Modelle verschiedenartiger Speicherdystrophien

Summary

The neuronal storage dystrophy produced experimentally by chloroquine, contains models for quite a number of well known neurological storage diseases, almost all of which can be traced back to genetically determined defects of various lysosomal enzymes. Within the nervous system the neurones of the posterior root and trigeminal ganglia are predominantly affected in the experimental disease. Electronmicroscopically one finds unusually complex and regionally differing combinations of various types of storage bodies. In rats, the perikarya of posterior root and trigeminal nerve cells contained predominantly the concentrically layered type of membranous cytoplasmic bodies (MCBs) such as seen in infantile amaurotic idiocy. In rabbits, on the other hand, the majority of MCBs consisted of the “zebra body” type, as seen especially in gargoylism. Within the frequent axonal balloonings of these cells there are, in both species, additional small to very large accumulations of glycogen granules or particles usually surrounded by one or several membranes; in type II glycogenosis such glycogen deposits are also stored within neurones. Storage bodies with extensive curvilinear segments are found exclusively within the affected perikarya of neurones in the trigeminal ganglia of rats; they lay either massed together or scattered amongst the layered MCBs. Similar cytosomes are found in some forms of neuronal ceroid-lipofuscinosis.

Thin layer chromatography of lipid extracts showed an unequivocal increase of a substance with theR _F-value between gangliosideG _D1a andG _D1b in materials derived from spinal ganglia of four of our experimental rabbits. An increase of phospholipids within the storage areas of neurones of posterior root ganglia was, so far, only suggested by the histochemical test with acid hematein.

The number of cytoplasmic granules with intensive yellow fluorescence within the pyramidal cells of the cornu ammonis was considerably increased. However only a small proportion of these granules could be related to layered MCBs; moreover MCBs within this location often differed in origin from the type observed in nerve cells of the sensory ganglia. Likewise the axonal dystrophy of neurones within the central nervous system differed already under the light microscope from comparable changes in cells of the posterior root and trigeminal ganglia.

The vacuoles present in the “red myopathy” were due principally to a phospholipidosis. At the same time there was a selective evenly disseminated glycogenosis of the affected type I muscle fibres as seen in Pompe's disease in all fibre types. In young rats there was relatively little degeneration of the type I muscle fibres, however these fibres showed a greatly increased activity of phosphorylase which even exeeded that found in the type II fibres. This may be a consenquence of the glycogenosis.

The distal chloroquine neuropathy was accentuated in those muscles which showed the greatest lesions. It consisted, in the main, of myelin breakdown which never reached the state of neutral fat. The myopathy was not neurogenic. In man its unusual localization and progression is likewise explained by the predominant affection of the red muscle fibres.

Almost all the histological changes noted within the nervous and muscular system could be explained through a molecular interaction between phospholipids and chloroquine due to the amphiphilic character of the drug and through the accumulation of the drug in lysosomes and an impairment in their digestive capacity.