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PubMed1986

Fast anterograde axonal transport in wasted and non-wasted diabetic rats; effects of aldose reductase inhibition.

This study measured the velocity of the fast anterograde axonal transport of [3H]-proline-labelled proteins in sciatic motoneurones of rats with streptozotocin diabetes of 12 weeks duration and in age matched controls. Four groups of diabetic animals were studied. One of these groups remained untreated whilst 2 diabetic groups received a long-acting insulin twice weekly to limit body wasting, but to permit regular hyperglycaemia. One insulin-treated group and one other diabetic group received an aldose reductase inhibitor, "Statil" (ICI 128436) by dietary admixture. Neither diabetes alone nor any of the treatment regimes produced any significant alteration of axonal transport velocity. Sciatic nerve temperature was measured concomitantly. A slight nerve hypothermia was seen in the untreated diabetic rats, but not in either insulin-treated group. It is concluded that 2 aspects of diabetes mellitus, namely persistent hyperglycaemia and polyol pathway activity in nervous tissue are without effect on the velocity of fast orthograde axonal transport of proteins.

Aldehyde Reductase↗
PubMed1982

Reduced protein synthesis in diabetic retina and secondary reduction of slow axonal transport.

Protein synthesis in the retina in diabetic rabbits decreased as the severity of the diabetes increased, but protein degradation and replacement were not affected. The reduction in the amount of orthograde slow axonal transport in diabetic rabbits closely paralleled the reduction in the amount of fast axonal transport and protein synthesis in the retina. The reduction in slow flow is most probably a simple reflection of reduced protein synthesis in the retinal ganglion cells. The relationships among reduction in axon diameter, volume of perikaryon, slow axonal transport and diabetic neuropathy are discussed.

Animals↗
PubMed1997

Transient damage to the axonal transport system without Wallerian degeneration by acute nerve compression.

The aim of this study was to examine whether acute nerve compression damages an axonal transport system based on microtubules and how the fibers recover after the compression. A 5-mm segment of the tibial nerve of male wistar rat was compressed with a specially designed clip. Functional recovery was assessed using Tibial Nerve Functional Index (TFI). Rats were sacrificed each day from Day 0 to Day 2 and every 2 days between Day 4 and Day 10. For immunohistochemical analysis of the tibial nerve, the proximal uncompressed, the middle compressed, and the distal uncompressed segments of each section were assessed under immunofluoroscent microscopy for anti-dynein, anti-tubulin, and anti-neurofilament antibodies staining. In rats whose tibial nerve was compressed by 25 g/mm2 of pressure for 5 min, staining of dynein and mirotubules in the compressed portion were obscure on Days 4-8, suggesting that the microtubules based axonal transport system was temporarily damaged, while neurofilaments were retained. In contrast, in the distal portion, anti-neurofilament staining showed no abnormality throughout the experimental period, indicating that Wallerian degeneration did not occur. We conclude that acute nerve compression can cause transient damage to the axonal transport system in nerve fibers without Wallerian degeneration.

Acute Disease↗
PubMed1994

Retrograde axonal transport of locally synthesized proteins, e.g., actin and heat shock protein 70, in regenerating adult frog sciatic sensory axons.

The local synthesis and subsequent retrograde axonal transport of [35S]methionine-labelled proteins was studied in the in vitro regenerating adult frog sciatic sensory axons. By the use of a three compartment culture system, proteins in the outgrowth region were selectively labelled. After 2 days in culture a rise in TCA-insoluble radioactivity was detected in the dorsal root ganglia, which could be prevented by the addition of vinblastine or 2,4-dinitrophenol to the nerve proximal to the crush site. Two-dimensional polyacrylamide gel electrophoresis of ganglionic proteins revealed a pattern of 35 labelled polypeptides with apparent molecular masses (Mm) ranging from < 15 to 95 kDa and with isoelectric points (pI) ranging from 4.5 to 6.5. The major ones, representing about 75% of the activity in a gel, were of Mm/pI 47/5.4, 48/6.1,. 57/6.0, 62/5.2, 65/4.9-5.0, 65/5.2, and 81/5.4 respectively. One of these polypeptides (47/5.4) was identified as actin and another (81/5.4) as a member of the heat shock protein 70 family. The spots at 65/4.9-5.0 were tubulin isoforms. There was a striking similarity between transported proteins on one hand, and proteins synthesized in the injured nerve on the other, with respect to the Mm/pI of at least 14 protein species. The results suggest that a selected set of proteins, synthesized by non-neuronal cells, e.g., Schwann cells, is transferred to the ganglionic cell bodies by retrograde axonal transport.

Actins↗
PubMed1990

In vivo anterograde and retrograde axonal transport of the fluorescent rhodamine-dextran-amine, Fluoro-Ruby, within the CNS.

A number of fluorescent dextrans were screened for axonal transport properties within the rat CNS. One compound, Fluoro-Ruby (FR), was found to be particularly sensitive for demonstrating retrograde and particularly anterograde axonal transport. The tracer may be either pressure or iontophoretically injected, and the fixed tissue can be examined without histochemical processing. The technique can be combined with a wide variety of other neuroanatomical methods.

Animals↗
PubMed1995

Further characterization of axonally transported proteoglycans.

We report further analysis of axonally transported proteoglycans in soluble and membranous subfractions of goldfish optic tectum. Distribution of transported 35SO4 radioactivity was 35.2% soluble, 63.4% Triton-NaCl extractable and 1.4% unextracted. Proteoglycans isolated on DEAE cellulose were treated with chondroitinase AC or nitrous acid and remaining heparan sulfate proteoglycans (HSPGs) and chondroitin sulfate proteoglycans (CSPGs) were sized on Sepharose CL-6B. Kav values and estimated molecular weights were: Soluble CSPG-0.36 (160 kDa), Triton-NaCl extracted CSPG-.031 (200 kDa), Soluble HSPG-0.37 (150 kDa), Triton-NaCl extracted HSPG-0.37 (150 kDa). For constituent CS and HS chains the Kav values and estimated molecular weights on CL-6B were: Soluble CS-0.55 (15 kDa), Triton-NaCl extracted CS-0.55 (15 kDa), Soluble HS-0.59 (13 kDa) and Triton-NaCl extracted HS-0.65 (9 kDa). CS was shown to be sulfated exclusively at carbon 4 for both soluble and Triton NaCl extracted fractions.

Animals↗
PubMed1983

Inhibition of fast axonal transport in vitro by the local anesthetics prilocaine, mepivacaine, and bupivacaine.

The aim of the present study was to establish the concentrations of prilocaine, mepivacaine, and bupivacaine which are effective at blocking fast axonal transport, to determine whether prilocaine and mepivacaine offer a better prospect of dissociating conduction block and transport block in vivo than does lidocaine and whether bupivacaine offers a better prospect than etidocaine in the same context. Fast axonal transport of [3H]leucine-labeled proteins was studied in vitro in bullfrog spinal nerves and quantitated by liquid scintillation counting. Exposure of spinal nerves to 14 mM prilocaine reduced the quantity of 3H-labeled proteins which accumulated at a ligature by 86%, and exposure to 14 mM mepivacaine reduced it by 70%; 10 mM prilocaine reduced this same parameter by 54%, a degree of inhibition close to the 44% reduction caused by 14 mM lidocaine. The D(-) and L(+) stereoisomers of mepivacaine each reduced transport to the ligature by approximately 50% at a concentration of 14 mM. Bupivacaine reduced the accumulation of 3H-labeled proteins at the ligature by 49% at a 10 mM concentration (pH 6.2); its potency is close to that found for etidocaine in a previous study. Since prilocaine and mepivacaine are at least as potent as lidocaine as transport inhibitors and at blocking impulse conduction, these two anesthetics offer no advantage over lidocaine to achieve dissociation of conduction block from transport block in vivo. Bupivacaine appears to offer no advantage over etidocaine in the same context, as the two agents have a similar potency as local anesthetics and a similar potency as inhibitors of fast axonal transport.

Animals↗
PubMed2001

Inhibitory effect of histamine on axonal transport in cultured mouse dorsal root ganglion neurons.

Histamine is important in mediating peripheral sensory information such as inflammation, allergic hypersensitivity, and itch. In the present study, using video-enhanced microscopy, we investigated the effect of histamine on axonal transport in cultured dorsal root ganglion (DRG) neurons of the mouse. Application of histamine (100 microM) reversibly reduced the number of particles transported within neurites in both anterograde and retrograde directions. The histamine H(1)-receptor agonist 2-thiazolylethylamine (100 microM) and the H(3)-receptor agonist R-alpha-methylhistamine (100 microM) also reduced anterograde and retrograde axonal transport, whereas the histamine H(2)-receptor agonist dimaprit (100-1000 microM) had no effect. The effect of histamine was partially blocked by pretreatment with H(1)-receptor antagonist pyrilamine (1 microM) or the H(3)-receptor antagonist thioperamide (1 microM). Pretreatment with a combination of pyrilamine (1 microM) and thioperamide (1 microM) completely blocked the response to histamine. The H(2)-receptor antagonist cimetidine (1 microM) was ineffective. These results suggest that histamine inhibits axonal transport of cultured mouse DRG neurons via the activation of H(1)- and H(3)-receptors.

Animals↗
PubMed1983

Chronic impairment of axonal transport eliminates taste responses and taste buds.

A Silastic nerve cuff containing colchicine (1% w/v) was placed around the combined lingualchorda tympani nerve of the Mongolian gerbil (Meriones unguiculatus) to evaluate the role of axonal transport in the maintenance of taste buds. After 3 days the summated gustatory impulse discharges recorded from the chorda tympani nerve were reduced by 60%, while compound action potentials had not changed appreciably. The lingual-chorda tympani nerve underwent ultrastructural changes including a loss of microtubules, an increased prominence and disorientation of neurofilaments, and a significant shrinkage in the cross-sectional area of axoplasm. The shrinkage of axoplasm and the accumulation of mitochondria and cholinesterase at the nerve cuff provided evidence that the colchicine treatment acted to impair axonal transport. More substantial pathological changes were evident in nerve ultrastructure by 15 days when both the ipsilateral chorda tympani taste responses and fungiform taste buds were nearly absent. Control cuffs lacking colchicine had little effect on chorda tympani taste responses, taste buds, or nerve ultrastructure. Eight or 15 days of nerve exposure to lumicolchicine, an isomer of colchicine with low affinity for tubulin, had no significant effect on taste responses. [3H]Colchicine was used in the nerve cuff to demonstrate that colchicine must have acted directly upon the nerve trunk, rather than the taste buds, to cause the loss of taste responses and taste buds. [3H]Colchicine levels were equal in the two sides of the tongue, whereas both the functional and structural deterioration of the taste buds were restricted to the ipsilateral side. We conclude that the loss of taste responses and taste buds was caused by chronically impaired axonal transport in gustatory axons.

Animals↗
PubMedDate not supplied

Axonal transport and nerve conduction and their relation to nerve polyol and myo-inositol levels in spontaneously diabetic BB/D rats.

This study examined orthograde axonal transport of choline acetyltransferase activity and motor nerve conduction velocity in insulin-treated diabetic and nondiabetic rats of the BB/D strain. In the same animals sciatic nerve contents of glucose, fructose, sorbitol, and myo-inositol were measured to determine whether any functional defects coexisted with polyol pathway activity or myo-inositol depletion. There were no differences between controls and diabetics in conduction velocity or the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction. The latter finding implies no defect of axonal transport of the enzyme. At death the control rats were normoglycemic (mean blood glucose, 6.2 +/- 0.3 mmol/L) and the diabetic rats were moderately hyperglycemic (mean blood glucose, 18.1 +/- 1.3 mmol/L). The sciatic nerves of the diabetic rats showed marked elevation of glucose levels, moderate fructose accumulation and slight sorbitol accumulation. However, the myo-inositol levels were similar to those of control nerves. The findings suggest that, in BB rats with the degree of insulin treatment used here, myo-inositol levels were normal and that this co-existed with nerve conduction and axonal transport measurements which were similar to controls.

Animals↗
PubMed1986

Nerve repair and axonal transport: outgrowth delay and regeneration rate after transection and repair of rabbit hypoglossal nerve.

The axonal transport and distribution of the fast phase of [3H]leucine-labeled proteins were used to monitor the outgrowth delay and regeneration rate in rabbit hypoglossal nerves 5-21 days after crush or transection. The transected nerves were repaired with mesothelial chambers or epineurial sutures. Radiolabeled proteins were transported into regenerating axons in the distal nerve segment after an initial delay of 2.5 days for crushed nerves and after a delay (initial and scar delays) of 4.8 and 5.7 days for sutured and mesothelial chamber-reconnected nerves, respectively. Regeneration rate was 3.5 mm/day after a crush and 2 mm/day after a transection with either type of repair. Total radioactivity was greater in both crushed and repaired nerves than in their contralateral controls. Transported radioactivity accumulated at the site of the lesions. This accumulation was greater and persisted longer in repaired nerves than in crushed ones. The difference in regenerative response after different types of trauma with respect to changes in axonal transport is emphasized.

Animals↗
PubMed1986

Changes in axonally transported proteins in the rat visual system following systemic methyl mercury exposure.

In an effort to understand the effect of methylmercury on protein synthesis and axonal transport, we have analysed the composition and rate of axonally transported proteins in the retinal ganglion cells of the mature rat. By means of scintillation spectrometry and autoradiography, it was established that systemic exposure to 4 mg Hg/kg/day for four to six days, or twelve days, resulted in an increased rate and volume of transported protein-bound radioactivity in the visual system of the mature rat. In an effort to characterize these changes, the composition of transported polypeptides was analysed by means of SDS polyacrylamide gel electrophoresis. Selective changes in the composition of transported polypeptides were evident. These changes of a small subset of proteins known as GAPs (growth-associated proteins) are consistent with the suggestion that they may have been involved in growth-specific functions during the early stages of methyl mercury exposure. We concluded that, during this period, retinal ganglion cells may express growth-related genes and engage in regenerative processes.

Animals↗
PubMed1992

Subacute ethanol consumption reverses p-xylene-induced decreases in axonal transport.

Human exposure to organic solvents is often complicated by ethanol ingestion and the literature is replete with demonstrations of metabolic interactions between ethanol and organic solvents at a pharmacokinetic level. Because of the possible modulation of xylene toxicity by ethanol consumption, the present group of studies characterizes the effect of ethanol on the p-xylene-induced decrease in axonal transport in the rat optic system previously reported by our laboratory. Long-Evans, hooded, male rats were divided randomly into two groups: those receiving 10% ethanol in their drinking water and those receiving water only. These two groups were further subdivided into two groups which were either exposed by inhalation to 1600 ppm p-xylene for 6 h/day, 5 days/week for 8 exposure-days or were treated identically except that they were exposed to air while in the inhalation chambers. The ethanol-drinking rats were given ethanol 6 days prior to and on the days of the inhalation exposure. Immediately after removal from the inhalation chambers on the last exposure day, the animals were injected intraocularly with [35S]methionine and [3H]fucose to measure the synthesis and rapid axonal transport of proteins and glycoproteins, respectively, in the retinal ganglion cells. The animals were sacrificed 20 h later, and the amount of radioactivity in different areas of the retinal ganglion cells was determined by liquid scintillation counting. As in previous experiments, the xylene exposure group showed a significant reduction in axonal transport of proteins and glycoproteins, whereas the ethanol exposure alone produced no significant reductions in the transport of either proteins or glycoproteins. In the animals receiving both ethanol and xylene, however, the ethanol treatment prevented the decreased transport characteristic of the xylene only animals, i.e. in all areas of the optic projections the level of transport were similar to the level present in the control groups. These data suggest that the xylene-induced reduction in rapid axonal transport was reversed (or prevented) by subacute ethanol consumption.

Alcohol Drinking↗
PubMed1981

Ca2+- or Mg2+-stimulated ATPase activity in bullfrog spinal nerve: relation to Ca2+ requirements for fast axonal transport.

Adenosine triphosphatase (ATPase) activity stimulated by Ca2+ or Mg2+ was characterized in spinal nerve and spinal sensory ganglion of bullfrog. Enzyme activity of homogenates from both sources reached a maximum at a 1-2 mM concentration of either cation, although the level of maximal activity in nerve trunks was approximately twice that in ganglia. Enzyme activation was not observed with 2 mM-Sr2+ or Ba2+. Co2+ or Mn2+, at 2 mM, depressed Ca2+ activation of the enzyme by 50-60% in nerve but had no inhibitory effect on ganglia activity. In intact spinal ganglion/spinal nerve preparations, incubated for 20 h in medium containing 0.2 mM-Co2+, no effect was detected on Ca2+/Mg2+ ATPase activity in ganglia or nerve trunks whereas fast axonal transport was inhibited by 80%. Incubation in medium containing 0.02 mM-Hg2+ depressed enzyme activity in ganglia by 64% and in nerve trunks by 44%, whereas fast transport was again inhibited by 80%. When only nerve trunks were exposed to these ions, Hg2+ but not Co2+ was observed to slow the rate of fast axonal transport. The divalent cation specificity of the Ca2+/Mg2+ ATPase activity is distinct from the ion specificities, determined in previous work, of the Ca2+ requirement during initiation of fast axonal transport in the soma, and of the Ca2+ requirement during translocation in the axon. Thus, previous observations of Ca2+-dependent events in fast axonal transport cannot be taken per se to suggest the involvement of Ca2+/Mg+ ATPase in the transport process.

Adenosine Triphosphatases↗
PubMed1980

Slow components of axonal transport: two cytoskeletal networks.

We have identified two slowly moving groups of axonally transported proteins in guinea pig retinal ganglion cell axons (4). The slowest group of proteins, designated slow component a (SCa), has a transport rate of 0.25 mm/d and consists of tubulin and neurofilament protein. The other slowly transported group of proteins, designated slow components b (SCb), has a transport rate of 2-3 mm/d and consists of many polypeptides, one of which is actin (4). Our analyses of the transport kinetics of the individual polypeptides of SCa and SCb indicate that (a) the polypeptides of SCa are transported coherently in the optic axons, (b) the polypeptides of SCb are also transported coherently but completely separately from the SCa polypeptides, and (c) the polypeptides of SCa differ completely from those comprising SCb. We relate these results to our general hypothesis that slow axonal transport represents the movements of structural complexes of proteins. Furthermore, it is proposed that SCa corresponds to the microtubule-neurofilament network, and that SCb represents the transport of the microfilament network together with the proteins complexed with microfilaments.

Actins↗
PubMed2002

Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau.

Transmissible spongiform encephalopathies often are caused by peripheral uptake of infectious prions, and the peripheral nervous system is involved in prion spread to the brain. Although the cellular prion protein is subjected to fast axonal transport, the mechanism of intranerval transport of infectious prions is unclear. Here we administered prions intranervally to transgenic mice overexpressing the four-repeat human tau protein, which exhibit defective fast axonal transport. These mice showed unaltered neuroinvasion, suggesting that transport mechanisms distinct from fast axonal transport effect prion neuroinvasion along peripheral nerves. Surprisingly, scrapie-sick tau transgenic mice accumulated intraneuronal deposits of hyperphosphorylated tau protein. The coincidence of tau and prion pathology resembled Gerstmann-Sträussler-Scheinker syndrome. These findings identify tau pathology as a possible end stretch of prion-induced neurodegeneration.

Animals↗
PubMed1984

Axonal transport of a subclass of tau proteins: evidence for the regional differentiation of microtubules in neurons.

Tubulin, the major constituent of microtubules, is anterogradely transported within the axon as part of slow component a (SCa; 0.2-1.0 mm/day). This raises the possibility that the microtubule-associated proteins (MAPs) may be transported at the same rate. To examine this question, the high molecular weight and tau MAPs obtained from whole brain preparations of microtubules were compared with the proteins of SCa in guinea pig retinal ganglion cell axons by using phosphocellulose chromatography and one- and two-dimensional polyacrylamide gel electrophoresis. Only two of the tau proteins were found to be cotransported with axonal tubulin, although four tau and two high molecular weight MAPs were synthesized in the retina. This result suggests either that the retinal ganglion cell synthesizes only those two tau proteins or that it synthesizes several of the MAPs, but commits to axonal transport just two of the tau proteins. In either case, these observations are consistent with the transport of intact microtubules and demonstrate that axonal microtubules represent a distinct subset of brain microtubules. Such a distinction may be related to unique properties of the axonal cytoskeleton.

Animals↗
PubMed1986

Intraocular tetrodotoxin reduces axonal transport and transcellular transfer of adenosine and other nucleosides in the visual system of goldfish.

Intraocular injection of tetrodotoxin (TTX) in goldfish, which abolishes physiological activity in the optic axons, decreased by up to about 30% the amount of radioactively labeled adenosine, uridine and guanosine (and their nucleotide derivatives) that was axonally transported in the optic nerve. The amount of labeled nucleoside that reached the optic tectum and became incorporated into RNA in the postsynaptic tectal neurons and glial cells was reduced by up to about 50%. There was no change, however, in the amount of transported nucleoside that became incorporated into RNA in the optic nerve glia. The TTX-induced changes were eliminated when axonal transport was blocked with vincristine, indicating that this change did not involve material moving along the nerve by diffusion. If the TTX injection was delayed until several hours after labeling of the transported materials, the transported labeled nucleoside in the nerve was reduced very little, but the RNA labeling in the tectum was reduced just as much as when TTX was given prior to labeling. This indicates that the labeling of the tectal cells was affected more by the level of activity in the pathway than by the amount of transported nucleoside reaching the optic nerve terminals. It appears likely, therefore, that the process most affected by the decrease in physiological activity is the release of nucleoside from the terminals of the presynaptic neurons or its uptake into postsynaptic tectal neurons and glia. The fact that physiological activity may modify the amount of axonally transported nucleosides made available for metabolism (including RNA synthesis) in postsynaptic neurons may provide an explanation for activity-linked neurotrophic effects.

Adenosine↗