Biomedical subjects
B Csillik
Publications and source records attributed to B Csillik.
Ultrastructure of normal and degenerating glomerular terminals of dorsal root axons in the substantia gelatinosa of the rhesus monkey.
The fine structure of primary sensory terminals within glomerular complexes of lamina II of Rexed (substantia gelatinosa Rolandi) in the spinal cord was investigated in normal adult rhesus monkeys and in monkeys subjected to thoracic or lumbosacral dorsal root transection. Three types of "scalloped" primary sensory terminals were distinguished on the basis of their ultrastructural characteristics, size, and distribution of synaptic vesicle population: (1) dense sinusoid axon (DSA) terminals contain medium-sized (42--46 nm and 58--62 nm) and large (80 nm) clear synaptic vesicles; (2) large dense-core vesicles (LDCV) terminals are equipped with empty synaptic vesicles ranging from 30 to 106 nm, large, (80 nm) and very large, (100 nm) dense-core vesicles; and (3) regular synaptic vesicles (RSV) terminals contain a homogeneous population of 45--50 nm clear synaptic vesicles. Following transection of the dorsal roots, all three types of primary afferents degenerate and become engulfed and phagocytosed by glial cells. However, each type of terminal displays a different mode and tempo of degeneration as seen in monkeys sacrificed 36, 48, and 72 hours following rhizotomy. DSAs follow the osmiophilic degeneration pattern; LDCVs are characterized by a gradual increase in the number of "electron-dense bodies" and, less frequently, by a progressive osmiophilic process; RSVs exhibit signs of a filamentous degeneration, accompanied by clusters of synaptic vesicles. The three types of terminals are distributed in an overlapping but distinct pattern within the posterior horn. Thus DSAs are present in highest numbers in lamina II where they constitute the most frequent terminal type. LDCVs also occur in lamina II in its outer half but are most concentrated in lamina I. RSVs predominate in the deeper layers of the dorsal horn (lamina III) but are also found in the internal half of lamina II. On the basis of these ultrastructural data and a comparison with afferent profiles impregnated according to the Golgi method, it appears that DSAs and LDCVs correspond respectively to superficial and marginal collaterals of small, thin dorsal root fibers whereas RSVs represent terminals of deep collaterals from large, thick dorsal root axons.
Periterminal synaptology of dorsal root glomerular terminals in the substantia gelatinosa of the spinal cord in the rhesus monkey.
The synaptic glomerular complexes surrounding dorsal root terminals in the substantia gelatinosa were reconstructed from six sets of 50--140 gapless ultrathin serial sections prepared in the transverse plane of the spinal cord in adult rhesus monkeys. All three types of glomerular terminals described in the preceding paper (Knyihar-Csillik et al., '82) were identified: (1) DSA (endings of superficial collaterals); (2) LDCV (endings of marginal collaterals); and (3) RSV (endings of deep collaterals). Each type of terminal forms a glomerular complex which invariably includes presynaptic dendrites which are intercalated between primary terminals and the postsynaptic (conventional) dendrite. Since the latter also receives direct input from the primary sensory terminal the synaptic organization assumes triadic arrangements, suggesting that primary afferent impulses may be subjected to a postsynaptic modulation through inhibitory action of presynaptic dendrites. In glomeruli with DSA as the central element, several triadic systems are usually interrelated, possibly as a structural basis for prolonged retardation of impulses. Adjacent glomeruli, containing DSA and LDCV terminals, are coupled together by a series of triadic systems fed by DSA terminals enabling association between superficial and marginal collaterals. RSV terminals are presynaptic to somata and dendrites of substantia gelatinosa cells that presumably exert inhibition upon terminals of all three kinds of primary sensory collaterals. In addition RSV terminals are postsynaptic to numerous F boutons which presumably derive mainly from axons of substantia gelatinosa cells; similar F boutons impinge upon presynaptic and other dendrites surrounding DSA terminals. The complicated but orderly synaptic architecture of these types of primary afferents may be regarded as a structural basis for first-order analysis and modulation of the nociceptive information within the primate central nervous system.
Treatment of chronic pain syndromes with iontophoresis of vinca alkaloids to the skin of patients.
Repeated iontophoretic administration of the microtubule inhibitors vinblastine or vincristine to the segmentally related dermatomes of patients suffering from postherpetic, trigeminal and other neuralgias permanently alleviates chronic, autochthonous pain. The beneficial effect of this therapy is probably due to transganglionic degenerative atrophy of primary central sensory terminals in the Rolando substance by blockade of retrograde axoplasmic transport in sensory nerves.
Effect of transganglionic degenerative atrophy on opiate receptors in the dorsal horn of the spinal cord.
We investigated alterations in opiate-binding sites in the upper dorsal horn after transection of the related peripheral sensory nerve in rats. The binding of (3H)diprenorphine was measured autoradiographically. The findings indicated a shift of the binding sites, rather than a degenerating disappearance, with a decrease in nerve fibers but an increase in nerve cells. This may be due to latent opiate-binding sites becoming manifest.
Reversibility of microtubule inhibitor-induced transganglionic degenerative atrophy of central terminals of primary nociceptive neurons.
Microtubule inhibitor Vinca alkaloids applied around a peripheral nerve induce transganglionic degenerative atrophy of the central terminals of primary nociceptive neurons. This effect is reversible: 40-50 days later the original histochemical structure of the central terminals is restored. Restoration of fluoride-resistant acid phosphatase activity (the marker enzyme of primary nociceptive neurons) in the Rolando substance is due to regenerative sprouting of the formerly atrophied central terminals. Since peripherally-applied Vinca alkaloids induce transganglionic degenerative atrophy of the central terminals without inducing Wallerian degeneration of the peripheral nerve, and since this effect (virtually a synaptic uncoupling) is only temporary, this approach may be used in the treatment of otherwise intractable neuralgias without inducing irreparable alterations.
Iontophoretically applied microtubule inhibitors induce transganglionic degenerative atrophy of primary central nociceptive terminals and abolish chronic autochtonous pain.
Transcutaneous iontophoresis of microtubule inhibitors (Vinblastin, Vincristin, Formyl-Leurosin) in rats induces depletion of fluoride-resistant acid phosphatase (FRAP) and transganglionic degenerative atrophy (trggl. deg. atr.) of the central terminals of primary nociceptive neurons, probably via blockade of axoplasmic transport in the peripheral sensory nerves. Radiochemical experiments prove that about 0.2% of the microtubule inhibitors applied iontophoretically at the skin reach the level of nociceptive axon terminals. 40 out of 48 patients suffering from chronic intractable pain of diverse etiology (postherpetic, paresthetic, ischaemic and trigeminal neuralgia, alcoholic and diabetic polyneuropathy, meralgia, brachialgia, discopathia, arthropathia and terminal pain) were successfully treated with Vinblastin or Vincristin iontophoresis. Iontophoretically applied microtubule inhibitors do not affect the blood cell count, have no side-effects and do not impair the skin at the site of application.
Blockade of retrograde axoplasmic transport induces transganglionic degenerative atrophy of central terminals of primary nociceptive neurons.
If applied locally around a peripheral sensory nerve, Formyl-Leurosin, a semi-synthetic diindol alkaloid of Vinca rosea--that, just like other mitotic spindle inhibitors, induces blockade of axoplasmic transport via inhibiting microtubular function--causes transganglionic degenerative atrophy of central terminals of primary nociceptive neurons in the substantia gelatinosa Rolandi of the spinal cord. In contrast, if applied to dorsal roots, Formyl-Leurosin fails to induce such alterations. Based upon these observations it is postulated that blockade of retrograde axoplasmic transport, rather than that of the orthograde one, is the decisive factor in the pathomechanism of transganglionic degenerative atrophy.
Transganglionic degenerative atrophy and regenerative proliferation in the Rolando substance of the primate spinal cord: discoupling and restoration of synaptic connectivity in the central nervous system after peripheral nerve lesions.
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Selective "labeling' by transsynaptic degeneration of substantia gelatinosal cells: an attempt to decipher intrinsic wiring in the Rolando substance of primates.
Transganglionic degenerative atrophy of primary sensory terminals in the head of the spinal dorsal horn that follows transection of the segmentally related peripheral sensory nerve, induces transsynaptic degeneration of substantia galatinosal (SG) cells, as was studied here in monkeys. On the basis of increased electron density as a selective "labelling', SG cells are shown to be postsynaptic both to thin (A delta and C) and to thick (A beta) afferents as well as to descending (or propriospinal) fibres, while their recurrent axon collaterals establish inhibitory synapses upon somata of neighbouring SG cells and upon A beta terminals. SG cells are envisaged as biasing elements with a contrast-enhancing function that, by means of inhibitory dendro-dendritic and axo-axonal synapses, realize a gating mechanism.
Regenerative synaptoneogenesis in the Mammalian spinal cord: dynamics of synaptochemical restoration in the Rolando Substance after transganglionic degenerative atrophy.
Crush injury of the sciatic nerve, that results in Wallerian degeneration of axons in the peripheral stump, induces, within 10-14 days, transganglionic degenerative atrophy of central terminals of primary nociceptive neurons in the ipsilateral substantia gelatinosa Rolandi of the segmentally related region of the spinal cord. Transganglionic degenerative atrophy is characterized by disappearance of fluoride-resistant acid phosphatase (FRAP) from the Rolando substance, normally exerted by primary nociceptive terminals. From the 40th postoperative day on, FRAP reaction starts to reappear in the formerly depleted Rolando substance. Restoration of FRAP reactivity reflects regenerative sprouting of formerly atrophied primary nociceptive terminals. Growth cones of primary nociceptive axons establish synapses with dendritic growth cones of substantia gelatinosal gelatinosal cells. Synaptoneogenesis in the Rolando substance follows medio-lateral and caudo-rostral gradients.
FRAP: histochemistry of the primary nociceptive neuron.
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Effects of perineurally applied cytostatic, cytotoxic and chelating agents upon peripheral and central processes of primary nociceptive neurons.
After perineural application, the effects of mannomustine, cyclophosphamide, tetrameskylmannite, 6-mercaptopurine, azathioprine and d-penicillamine upon structure of peripheral nerves and the substantia gelatinosa Rolandi were studied by means of neurohistochemical techniques and compared to those of the microtubule inhibitors Vinblastine, Vincristine and colchicine. While the cytostatic and cytotoxic drugs induced only sporadic degeneration in the structure of the peripheral nerve and, accordingly, caused only a minor extent of transganglionic degenerative atrophy in the Rolando substance, the chelating agent d-penicillamine causes massive Wallerian degeneration after perineural application and, consequently, induces an extensive degenerative atrophy in the Rolando substance. The destructive effect of d-penicillamine upon conduction properties of the impaired nerve has been established also by means of electrophysiological recording. All the drugs studied differ fundamentally from microtubule inhibitors like the Vinca alcaloids that, by virtue of their blocking effect of axoplasmic transport, induce degenerative atrophy in the Rolando substance after perineural application without causing Wallerian degeneration in the peripheral nerve. Accordingly Vinca alcaloids are the most promising candidates as locally applied therapeutics in intractable pain.
Fine structural localization of calcium binding sites in the neuromuscular junction.
By means of electron cytochemical analysis of rat neuromuscular junctions subjected to perfusion with a calcium-containing (5 mM) aldehyde fixative, two kinds of presynaptic calcium binding sites were demonstrated. "A" sites are located above openings of junctional folds; these triangular elements are identical with presynaptic protrusions of the active zone and probably comprise calcium channels of the presynaptic membrane, "B" sites, located within the terminal axoplasm, are associated to multivesicular bodies probably accumulating surplus intracellular calcium. This fine structural arrangement enables a highly parsimonious usage of extracellular calcium in inducing release of acetylcholine from synaptic vesicles. Junctional folds of the postsynaptic membrane may funnel calcium ions exactly to spatially restricted calcium channels. Having entered the terminal through the channels opened by the arrival of nerve action potential, calcium ions may exert their action upon synaptic vesicles accumulated in the closest vicinity by means of stripping off hydration barriers and by inducing membrane fusions, that finally result in quantal release of acetylcholine from the terminal.
Structural localization of calcium binding sites in the neuromuscular junction after supramaximal stimulation.
Rat motor end plates were supramaxillary stimulated by means of acute systemic inhibition of acetylcholinesterase. Electron micrographs obtained from samples subjected to perfusion with a calcium-containing (5 mM) aldehyde fixative demonstrates profound alterations in the fine structures and localization of calcium binding sites, markedly differring from those prevailing in the resting state and/or under conditions of physiological function. Neither "A" sites at the active zones of the synapse, nor "B" sites within the terminal proper, which are apparent in the resting state, do bind calcium after supramaximal stimulation which is characterized by a conspicuous vacuolization of the sole plate, brought about by destruction of the post-synaptic mitochondria. Calcium binding after supramaximal stimulation is partly postsynaptic (in granules of varying sizes within the sole plate) partly presynaptic (in synaptic vesicles, as well as in the whole extent of the presynaptic membrane). Limited resolving power of light microscopy and artificial translocation of the reaction product of the histochemical reaction may account for the earlier interpretation of exclusively post-synaptic localization of calcium after supramaximal stimulation.
Extra-lysosomal, fluoride-resistant acid phosphatase-active neuronal system subserving nociception in the rat cornea.
Perikarya as well as central and peripheral terminals of nociceptive neurons innervating the rat cornea are genuinely labelled by an extra-lysosomal, fluoride resistant iso-enzyme of acid phosphatase. This enzyme seems to be related to the metabolism of transmitter oligopeptides characterizing such neurons.
Topographic analysis of AChE-positive Renshaw elements: a light- and electronmicroscopic histochemical study on the morphological basis of recurrent inhibition.
Light and electron microscopic structures of Renshaw elements as the morphological basis of the recurrent inhibition were studied by means of the histochemical localization of AChE. Renshaw elements were identified as periodically repeating bulbous dendritic dilatations of AChE-negative interneurons, equipped with numerous AChE-positive motoneuronal axon collaterals. Cumulative patterns obtained by analyzing consecutive sections from segment L5 of the cat spinal cord show that the area of the most frequent occurrence of Renshaw elements nearly coincides with the dendritic arborization of the 3. type interneuron described by MATSUSHITA. The role of the Renshaw elements in recurrent inhibition is supported by the fact that they occur in largest number in those areas of the ventral horn where the Renshaw inhibition can be elicited electrophysiologically.
Transient synapses in the embryonic primate spinal cord.
Electron microscopic and tritiated thymidine autoradiographic analysis of the embryonic spinal cord in the rhesus monkey reveals considerable rearrangement of cellular and synaptic relationships in the posterior (sensory) quadrant during early developmental stages. This remodeling involves the death of an entire population of neurons that received synapses from sensory afferent axons and the possible relocation of these afferents upon subsequently generated viable substantia gelatinosa neurons.