This study deals with the effects of two amphiphilic lipidosis-inducing drugs (chlorphentermine, iprindole) upon the ultrastructure of peripheral nerves of rats. After prolonged drug treatment the preterminal and terminal axoplasm of motor and sensory nerves within skeletal muscles contain numerous abnormal inclusions (osmiophilic conglomerates, autophagic vacuoles, lamellated bodies). By contrast, the axons within large peripheral nerves are little effected. The present observations are tentatively interpreted as resulting from interference with catabolic processes involved in the normal turnover of axoplasmic constituents at the nerve terminal. The exact pathogenesis and the functional significance of these alterations remain to be elucidated.

Animals↗

PubMed1976

Alterations in the neurohypophysis of rats treated with chlorphentermine or tricyclic antidepressants.

Rats were treated with several amphiphilic, cationic compounds that are known to cause generalized lipidosis (chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine). After prolonged drug treatment the neurohypophysis showed severe morphologic alterations particularly in Herring bodies (HB), perivascular cells, and pituicytes. HBs displayed the following abnormalities: (a) great accumulation of autophagic vacuoles that contained neurosecretory granules (NSG); (b) numerous coarse osmiophilic conglomerates; (c) masses of multilamellated material; (d) reduced numbers of intact NSGs. Perivascular cells accumulated large lamellated inclusion bodies. Pituicytes contained membrane-bound crystalloid inclusion bodies. The noxious effect of chlorphentermine and l-chloro-amitriptyline was more pronounced than that of iprindole and clomipramine. The alterations in perivascular cells and in pituicytes are typical of drug-induced lipidosis. The lesions in HBs are tentatively explained as follows: HBs were previously proposed to be the sites of normally occurring intraaxonal disposal of excess neurosecretory material. The present experimental conditions interfere with this catabolic process. Incomplete digestion of the axo-plasmic constituents due for disposal might result in abnormal accumulation of NSG-containing autophagic vacuoles, osmiophilic conglomerates, and multilamellated material. This eventually leads to degeneration of HBs. The functional implications of the neurohypophysial lesions remain to be elucidated by functional experiments.

Animals↗

PubMed1976

Myopathy in rats treated with chlorphentermine or iprindole.

Muscular lesions were induced in rats by prolonged administration of chlorphentermine and iprindole. The alterations consisted of longitudinal fibre splitting, fibre degeneration and necrosis, and of formation of dense cytoplasmic inclusions and large cytoplasmic vacuoles. The soleus muscle was more severely affected than were extensor digitorum longus (EDL), gastrocnemius, and lumbrical muscles. This myopathy closely resembles that induced by chloroquine. The pathogenesis of the muscular lesions, and causal relationship between myotoxic and lipidosis-inducing effects of the drugs under study remain to be elucidated.

Animals↗

PubMed1976

Retinal lipidosis in albino rats treated with chlorphentermine and with tricyclic antidepressants.

Retinal pigment epithelium is known to be engaged in continuous phagocytosis and digestion of old discs of visual cell outer segments, which have a high phospholipid content. The present ultrastructural study was focused mainly on the effects, upon pigment epithelium, of several drugs that are thought to interfere with the enzymatic degradation of phospholipids. Albino rats received high oral doses of chlorphentermine, iprindole, 1-chloroamitriptyline, imipramine, or clomipramine. After treatment for several weeks the pigment epithelial cells were doubled in height due to deposition of excessive amounts of abnormal cytoplasmic inclusions which had a crystalloid substructure. Such inclusions which are known from previous studies to be associated with drug-induced phospholipid storage are suggested to contain nondigestible phospholipids, which in pigment epithelium originate mainly from phagocytosed outer segment discs. The alterations were reversible by withdrawal of the drugs. The functional implications of the epithelial alterations remain to be elucidated. Additional examination of the neuroretina revealed numerous abnormal inclusions, mainly of multilamellated structure. Ganglion cells were affected most. The neuroretinal alterations were reminiscent of those described in human cases of inherited lipidoses.

Amitriptyline↗

PubMed1976

The effects of taipoxin and notexin on the function and fine structure of the murine neuromuscular junction.

The isolated neurotoxins taipoxin and notexin from the venoms of the Elapidae, Oxyuranus scutellatus and Notechis scutatus scutatus respectively cause a neuromuscular block when administered to the mouse in vivo or to the phrenic nerve-hemidiaphragm preparation in vitro. The block is preceded by a latency period during which the toxins bind irreversibly to the nerve. The period is shortened by nerve activity. The frequency of the miniature end-plate potentials is gradually reduced, almost to zero, and their amplitude distribution is altered; small and very large miniature endplate potentials appearing. Ultrastructurally the endplates are altered in the presynaptic portion but not in the postsynaptic part. In an early stage of poisoning the axolemma has an increased number of omega-shaped indentations similar in size to synaptic vesicles. At a later stage, when the animals die of respiratory paralysis, the axolemmal indentations are more numerous and the synaptic vesicles greatly reduced in number, the remaining vesicles having a variable and frequently larger than normal size. When impulse activity in the phrenic nerve is stopped by cutting the nerve before the administration of toxin there is no reduction in the number of synaptic vesicles, only the appearance of an increased number of axolemmal indentations. It is suggested that taipoxin and notexin irreversibly interfere with the formation of synaptic vesicles by arresting vesicle membrane recycling at the level of the axolemma. When the pre-existing store of vesicles is depleted, by nerve activity, a neuromuscular block results.

Acetylcholine↗

PubMed1976

Lysosomal alterations in cultured macrophages exposed to anorexigenic and psychotropic drugs.

Cultured rat macrophages were used for an in vitro study of drug-induced lipidosis. Cells were exposed for 24 hours to equimolar concentrations (5 X 10(-5) and 1 X 10(-4) M) of the following amphiphilic (amphipathic) cationic drugs: chlorphentermine, amitriptyline, 1-chloro-amitriptyline, iprindole, noxiptiline, chlorpromazine. In addition the less amphiphilic drug phentermine was used. Ultrastructurally, the cytologic changes essentially consisted of formation of multilamellated cytoplasmic inclusions, which possessed acid phosphatase activity. The abnormal inclusions are interpreted to result from intralysosomal accumulation of polar lipids. Under the present in vitro conditions all drugs except phentermine, had similar potencies to induce such lysosomal alterations, quite in contrast to the great quantitative differences previously observed under in vivo conditions. The present results lend further support to a concept that regards a pronounced amphiphilic (amphipathic) character to be responsible for the lipidosis-inducing action of various cationic compounds. Cultured macrophages are suggested as a useful tool to investigate this structure-activity relationship, which under in vivo conditions may be obscured by superimposed parameters such as drug metabolism.

Acid Phosphatase↗

PubMed1975

Intraalveolar foam cells associated with lipidosis-like alterations in lung and liver of rats treated with tricyclic psychotropic drugs.

Histological, histochemical, and ultrastructural examinations were performed on pulmonary and hepatic tissues of rats after prolonged oral treatment with several tricyclic antidepressants and two neuroleptics, which are all of amphiphilic character. The antidepressants ipindole, imipramine, clomipramine, 1-chloro-amitriptyline, and 1-chloro-10,11-dehydro-amitriptyline were found to cause an accumulation of intraalveolar foam cells accompanied by the formation of abnormal lamellated and crystalloid cytoplasmic inclusions in most pulmonary and hepatic cell types. The ultrastructural and histochemical findings in both tissues point to generalized, abnormal intracellular storage of polar lipids, i.e. to drug-induced lipidosis. The foam cells are not regarded as an isolated pulmonary alteration but rather as an easily obtainable indication of generalized lipidosis, under the present conditions. They are thought to represent alveolar macrophages stuffed with non-digestible phospholipids. On the other hand, the tricyclic antidepressants noxiptiline and amitriptyline, and the neuroleptics chlorpromazine and thioridazine caused neither formation of foam cells nor of any lipidosis-like ultrastructural alterations. These negative results are tentatively ascribed to a more rapid biotransformation of the amphiphilic drug molecules into more hydrophilic metabolites which no longer have a high affinity to polar lipids. Two main conclusions can be drawn from the present ovservations: (1) Intraalveolar foam cells must not be regarded as a fortuitous alteration but rather as a first indication of generalized phospholipidosis, when they are found in animals treated with an amphiphilic drug. (2) Closely related compounds of amphiphilic character do not necessarily have the same potency to induce a phospholipidosis under in vivo conditions.

Amitriptyline↗

PubMed1975