Neuro-glyo-capillary interactions between the sciatic nerve and its segmental centers at the experimental etoposide-induced neuropathy

Abstract

The neurological symptoms that appear during therapy are sufficiently described in the literature, but the long-term results require a more detailed study, as systematic studies of the pathogenesis  of toxic neuropathy that have arisen as a result of chemotherapy are few.

The purpose of the work is to study the morphofunctional state of the nerve fibers of the sciatic nerve and pericarions of the neurons of its segmental centers (motor and sensory) under the conditions of experimental etoposide-induced neuropathy.

Materials and methods. The neurotoxic influence of etoposide was studied in the experiment with one-time intravenous administration of the preparation in dose 22 mg/kg of the body mass of an animal (30 outbred rats of Wistar line). The research terms – 3, 7 and 15 days. The object light-optic and electron-microscopic study was sciatic nerves, cerebrospinal nodes L₂-L₅ and the lumbar-sacral part of the cerebral spine (L₂-S₁ segments).

Results. For the 3-th day morphological changes of myelin nerve fibers of the sciatic nerve are unessential – on the cross cut they take the incorrect form with creating isolated not deep protrusions and invaginations, wrinkling of separate axial cylinders appear. The endoneural connective tissue is in the stage of moderate edema. At the electron-microscopic study the increase of electronic density of hyaloplasm and growth of the number of microtubules and neurophylaments, swelled mitochondria and cisterns of the smooth endoplasmic reticulum are observed in axoplasm of some myelin nerve fibers. The basal membrane in capillaries is thickened, somewhere scarified. In cytoplasm of endotheliocytes - the increased vesicule formation with predominance of micropinocytotic vesicles that are nearer to the lumenal plasmalemma.

On the 7-th day of the experiment the expressed edema was observed in the connective tissue base of the nerve. Most myelin nerve fibers are characterized by the round form, edema of axial cylinders, but there are also fibers with axons in the atrophy state that take the incorrect form. Fissions of myelin lamellas appear in the myelin sheath. The part of mitochondria in axial cylinders is wrinkled with combs homogenization, their vacuole transformation is sometimes observed. Endotheliocytes of endoneurium have invaginations of the nuclear envelope. Numerous finger- and sail-like shoots form on the lumenal plasmalemma. The number of lisosomas grows in cytoplasm of endotheliocytes. Most mitochondria are swelled. Elements of the endoplasmatic reticulum and Golgi apparatus are increased; some of them are vacuole transformed: the expressed micropinocytosis is observed. The basal membrane is thickened, somewhere dissociated.

For the 15-th day the edema of connective tissue increases. Myelin nerve fibers with abruptly disturbed ratios between the myelin sheath and axial cylinder (the latter is often thickened and in atrophy state) are revealed in certain parts of the nerve. Many axons have signs of degeneration. Lamellas are placed disorderedly in the thickened myelin sheath, vesicular broad and narrow spots are observed between them. Separate fragments of myelin are detected in axons of the part of fibers at the background of their electron density growth, that is degenerative changes in axons and myelin sheath are present. At the same time there are observed signs of edema and the disordered disposition of neurotubules and neurophylaments. Neurolemmocytes demonstrate macrophagic activity and take products of myelin tunic disintegration. Deep invaginations of nucleus of endotheliocytes and rough peripheral condensation of chromatin are observed in separate hemocapillaries. Lumenal plasmolemma is labile, numerous protrusions form on it.

Unessential changes are observed in the state perikaryons of neurons of the segmentary motor center of the sciatic nerve in the spinal cord at the 3-d day (moderate broadening of saccules of the endoplasmatic reticulum, vacuole transformation of cisterns of Golgi apparatus). Manifestations of chromatolysis and increase of lisosomas number are intensified up to the 7-th day. At the 15-th day cells with chromatolysis phenomena and hypochromic nucleus form most neurons.

The stroma edema is detected in sensory ganglions. From the 3-rd day takes place neuron bodies deformation with the uneven distribution of clots of Nissl substance. Chromatolysis at the background of large clots of chromatophilic substance, after which neuron wrinkling takes place, is observed at the 7-th day. At the 15-th day phenomena of tigrolysis of basophilic substance with deepening of dystrophic changes in neurons take place. “Light” and “dark” neurons are observed. The processes of cytoplasm vacuolization take place in “light” neurons at the expanse of transformation of mitochondria and cisterns of the endoplasmatic net. The expressed micropinocytosis is revealed in cytoplasm of endotheliocytes of the wall of blood capillaries.

Conclusions. It was established, that one-time intravenous administration of etoposide in dose 22 mg/kg of the body mass causes the decrease of the moving activity in experimental animals, starting from the 7-th day of the experiment, for the 15-th day – paresis of lumbar extremities that corresponds to ІІ–ІІІ degree of neurotoxicity.

Thus, the dynamics of the experiment, as a result of the toxic influence of etoposide, combines the tendency to the injury and at the same time to the use of compensatory possibilities to provide the life ability of structural components of peripheral nerves and its segmental centers.