The mechanisms of acrylamide axonopathy.
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Acrylamides↗
Biomedical subjects
M S Miller
Publications and source records attributed to M S Miller.
Mechanisms of depletion of substance P by capsaicin.
Capsaicin is a neurotoxin that can deplete sensory nerves of their content of substance P and interfere with certain sensory functions, such as responses of animals to noxious heat stimuli. In adult guinea pigs, a species that is susceptible to the effects of capsaicin on both substance P content and sensory function, capsaicin induces selective depletion of substance P from dorsal root ganglia and the dorsal spinal cord, sites of the cell bodies and central terminals of primary afferent neurons, respectively. As the onset of thermal analgesia in guinea pigs precedes depletion of substance P, direct neural actions of capsaicin probably account for its effects on sensory function. Capsaicin interferes with the retrograde transport of nerve growth factor (NGF) to the cell bodies of sensory nerves. Decreased availability of NGF at the site of neural protein synthesis leads to decreased synthesis of substance P. After failure of synthesis of substance P, the content of the peptide in sensory nerves gradually decreases until depletion occurs.
Analgesia↗
ECG of the month. Sick sinus syndrome.
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Animals↗
Highly phosphorylated region of chicken riboflavin-binding protein: chemical characterization and 31P NMR studies.
Phosphate residues on chicken riboflavin-binding protein (RBP) have been implicated in the recognition and deposition of the protein-vitamin complex in egg yolk by the ovary. We demonstrate that all of the phosphate of RBP is linked to serine and that most if not all of the phosphoserine residues are contained in a single tryptic peptide having a composition SerP8, Glx6, His2, Leu2, Ala, Met, Lys. Despite differences in the tissue of synthesis, RBPs isolated from egg yolk and egg white yield phosphopeptides virtually identical in their amino acid composition and 101-MHz 31P NMR spectra. This implies that posttranslational phosphorylation of RBP is the same in liver and oviduct. The 31P NMR spectrum of the phosphopeptide is quite different from that of the phosphoprotein. The 31P NMR spectra of egg yolk and egg white RBP are quite similar but not identical and are unaffected by the binding of riboflavin. Optimal resolution of seven phosphorus resonances was obtained near pH 7.0. The titration behavior of all the phosphoserine residues is similar. We propose that this highly anionic peptide, exposed at the surface of RBP, is the principal determinant for the uptake of RBP by the vitelline membrane of the ovarian follicle.
Amino Acids↗
Single doses of acrylamide reduce retrograde transport velocity.
Single doses of acrylamide (0-1.3 mmol/kg) produced a dose-dependent decrease in the transport of 125I-tetanus toxin to the perikarya of sensory neurons in dorsal root ganglia and motor neurons in ventral spinal cord. Acrylamide was a more potent inhibitor of retrograde transport in sensory axons than in motor axons. Substantially greater doses of N,N'-methylene-bis-acrylamide, a reportedly non-neurotoxic analog of acrylamide, were required to alter the axonal transport of 125I-tetanus toxin. Velocity of retrograde transport was assessed by determining the position of the leading edge of transported 125I-tetanus toxin at times following single doses of acrylamide. Acrylamide reduced the velocity of 125I-tetanus toxin transport in a dose-dependent manner by up to 75%. No change in neuronal uptake of 125I-tetanus toxin was detected. It is concluded that single doses of acrylamide produce profound alterations in retrograde transport which precede the appearance of structural changes in affected nerve fibers.
Acrylamide↗
Age-related changes in colonic function in rats.
Aging in humans is associated with changes in gastrointestinal function. We wanted to determine whether a similar phenomenon occurs in rats and whether rats would be a suitable model to study changes in the gastrointestinal tract with age. Intestinal transit, response in vitro of circular colon strips to bethanechol and electrical stimulation, and colonic smooth muscle histology were compared for post-pubertal (5-12 mo) and senescent (25-28 mo) male Fischer 344 rats. Colonic transit of 51Cr was decreased 45% in senescent rats in comparison with younger rats. The maximum response of circularly oriented muscle strips from senescent rats to electrical stimulation of nerves was 32% less than the maximum response of strips from postpubertal rats. Likewise, the maximum response of the muscle strips to bethanechol was 16% less in the senescent group compared with the postpubertal group. There was no difference between the two groups in the EC50 of bethanechol. The thickness of the muscle layers and the percent circular muscle of strips fixed at optimum length were the same in both age groups. The senescent rat appears to be a useful model for the study of gastrointestinal changes with aging.
Aging↗
A simple, sensitive method for detecting early peripheral nerve dysfunction in the rat following acrylamide treatment.
The "ocular zingerone test" was employed to detect early alterations in peripheral nerve function which were associated with acrylamide intoxication in the rat. Acrylamide treatment resulted in a dose-related prolongation of the behavioral response to ocular zingerone. Significant alterations in the zingerone response occurred prior to detectable alterations in peripheral sensory and motor nerve function. Acrylamide-induced prolongation of the zingerone response appears to be the result of functional alterations in cholinergic neurotransmission in the autonomic nervous system. It is concluded that the "ocular zingerone test" is a simple, sensitive technique with which the degree of acrylamide intoxication may be quantified in the rat.
Acrylamide↗
Altered retrograde axonal transport of nerve growth factor after single and repeated doses of acrylamide in the rat.
The retrograde axoplasmic transport of iodinated nerve growth factor (125I-NGF) was markedly altered by systemic acrylamide treatment. Single doses of acrylamide (25 to 100 mg/kg, ip) inhibited the retrograde transport of 125I-NGF in a dose-dependent manner within 12 hr after administration. A dose of acrylamide (15 mg/kg, ip) which did not alter retrograde transport when given as a single dose, markedly inhibited retrograde transport when given repeatedly. Alterations in retrograde transport appeared prior to detectable alterations in peripheral nerve function and correlated with cumulative dose of acrylamide. These data suggest that single doses of acrylamide produce a biochemical lesion which accumulates to produce neuropathy. Altered retrograde axoplasmic transport may reflect the primary biochemical event responsible for the induction of neuropathy by acrylamide.
Acrylamide↗
The Mantoux test versus the tine test.
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Child↗
Interaction of capsaicinoids with drug-metabolizing systems. Relationship to toxicity.
The interaction of capsaicin with microsomal drug-metabolizing systems was assessed to determine the role that bioactivation of capsaicin may play in the induction of hepatotoxicity and neurotoxicity. Capsaicin produced a type I spectral change in rat hepatic microsomes in a high affinity (Ks = 8 microM) concentration-dependent manner and was approximately equipotent with SKF-525A in inhibiting ethylmorphine demethylation. Capsaicin (10 mg/kg, s.c.) inhibited biotransformation in vivo as measured by prolongation of pentobarbital sleep time. Reactive metabolites of capsaicin were studied using [3H]dihydrocapsaicin. [3H]Dihydrocapsaicin bound irreversibly to hepatic microsomal protein after in vitro incubation or in vivo administration. No binding was observed in spinal cord or brain. Although the bioactivation and subsequent covalent binding of capsaicin equivalents may initiate events associated with the hepatotoxicity of capsaicin, it appears that capsaicin-induced neuropathy does not involve covalent interactions with neuroproteins in spinal cord or brain.
Animals↗
Betamethasone-mediated activation of biphenyl 2-hydroxylation in rat liver microsomes. Studies on possible mechanisms.
The addition of the steroid betamethasone to intact or detergent-solubilized rat liver microsomes caused a concentration-dependent increase in the rate of biphenyl 2-hydroxylation. Betamethasone (100 microM) increased the apparent Vmax for 2-hydroxybiphenyl formation 2- to 4-fold but had no effect on the apparent Km when either the biphenyl or NADPH concentration was varied. Betamethasone had little or no effect on the apparent Vmax or apparent Km of the 3- and 4-hydroxylations of biphenyl. The steroid did not enhance biphenyl 2-hydroxylation through a peroxidative mechanism. Betamethasone had little or no effect on the rate of the NADPH-dependent reduction of cytochrome c or total microsomal cytochrome P-450. The addition of purified NADPH-cytochrome P-450 reductase to cholate-solubilized liver microsomes increased the rate of hydroxylation of biphenyl in positions 2 and 4. Betamethasone (100 microM) decreased the apparent Km for purified cytochrome P-450 reductase by 48% and increased the apparent Vmax of 2-hydroxybiphenyl formation by 2-fold when the concentration of cytochrome P-450 reductase was varied. The steroid did not alter the Km or Vmax values for the 4-hydroxylation of biphenyl. The data suggest that betamethasone enhances the interaction between the reductase and the form(s) of cytochrome P-450 responsible for the 2-hydroxylation of biphenyl.
Animals↗
Regulation of substance P by nerve growth factor: disruption by capsaicin.
Capsaicin depleted substance P from guinea pig dorsal root ganglia and inhibited the retrograde axoplasmic transport of nerve growth factor (NGF). Doses of capsaicin which depleted substance P also inhibited the retrograde axoplasmic transport of NGF. Inhibition of the retrograde transport of NGF by capsaicin preceded substance P depletion. Supplementation of guinea pigs with mouse NGF completely prevented capsaicin-induced substance P depletion. It is concluded that capsaicin depletes substance P from primary afferent neurons of the adult guinea pig by altering the availability of NGF. The data support a role for NGF in the normal maintenance of neuropeptide levels in some sensory neurons in the adult animal.
Animals↗
Dihydrocapsaicin-induced hypothermia and substance P depletion.
Administration of dihydrocapsaicin to rats resulted in a dose-dependent (0.5-10 mg/kg s.c.) hypothermia. Dihydrocapsaicin was approximately 65% more effective in producing hypothermia than capsaicin. Desensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin. Repeated administration of either dihydrocapsaicin or capsaicin resulted in chemogenic antinociception but not marked thermal antinociception. In addition, repeated administration of dihydrocapsaicin, like capsaicin, resulted in depletion of substance P from dorsal root ganglia and dorsal spinal cord but not from the hypothalamus, corpus striatum or ventral spinal cord. These data indicate that dihydrocapsaicin, or radiolabelled dihydrocapsaicin, may be a useful tool for investigating the mechanisms by which capsaicin alters thermoregulation and primary afferent neuron function.
Animals↗
Competitive binding assays for riboflavin and riboflavin-binding protein.
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Animals↗
Capsaicinoid-induced local and systemic antinociception without substance P depletion.
Capsaicin and its analog, dihydrocapsaicin, produced chemogenic and thermal antinociception and depletion of substance P from the dorsal spinal cord and dorsal root ganglia of guinea pigs following a single parenteral dose. Time course and distribution studies indicated that capsaicinoid-induced antinociception resulted from neither depletion of substance P nor nonspecific actions of capsaicinoids at dorsal root ganglia. A site of action for capsaicinoid-induced antinociception is peripheral to the dorsal root ganglia and may involve covalent binding of capsaicinoids to free nerve endings of the dermis. Depletion of substance P by capsaicinoids appears to be mediated at a site more central than that which mediates antinociception and may involve alterations in the retrograde axoplasmic transport of neurotrophic factors.
Afferent Pathways↗
Dephosphorylation of chicken riboflavin-binding protein and phosvitin decreases their uptake by oocytes.
Riboflavin-binding protein (RBP) and phosvitin are phosphoglycoproteins transferred from the plasma of laying hens into the yolk of developing oocytes. We have examined the effect of phosphate removal on this yolk deposition process. Unmodified yolk RBP and phosvitin contain, respectively, 8.3 and 109 residues of phosphate/molecule. Complete dephosphorylation of yolk RBP caused a 20-min decrease in the plasma clearance half-life an 87% decrease in the uptake of the protein into oocytes in vivo. Although partially desialylated, dephospho-yolk RBP was identical with the native protein by several criteria, including riboflavin-binding capacity, mobility on SDS-polyacrylamide gels, and circular dichroism. A series of partially dephosphorylated yolk RBP samples, prepared by limited enzymatic hydrolysis, was indistinguishable from native yolk RBP by all criteria except phosphate content. Removal of the 1st phosphate residue decreased uptake of yolk RBP into oocytes by about 60%. Uptake into oocytes could not be restored to dephospho-yolk RBP by addition of anionic groups by succinylation. However, succinylation of native yolk RBP decreased its deposition into oocytes to the same extent as dephosphorylation. Partial dephosphorylation of phosvitin also had marked effects. The plasma clearance of dephosphophosvitin (70% of phosphate removed) was much faster than native phosvitin. After 4 h, 15% of injected 125I-phosvitin remained in circulation compared with only 3.8% of 125I-dephosphophosvitin. The uptake of dephosphovosvitin into oocytes was 79% less than that of native phosvitin. In vitro, 125I-phosvitin bound specifically to a preparation of oocyte plasma membranes as indicated by competition with unlabeled phosvitin but not with RBP. The specific binding of dephosphophosvitin was 96% less than that of native phosvitin and it could be displaced equally well by phosvitin or yolk RBP.
Acid Phosphatase↗
Carbohydrate compositional effects on tissue distribution of chicken riboflavin-binding protein.
Riboflavin-binding proteins (RBP) purified from chicken egg white, yolk and the serum of laying hens differ in their carbohydrate compositions reflecting tissue-specific modifications of a single gene product. All three are complex glycoproteins having more than twice as many N-acetylglucosamine residues (greater than 12) as mannose residues (approx. 6). Egg white RBP is distinctive in having only one sialic acid and two galactose residues. Serum RBP contains approx. five sialic acid and seven galactose residues. In addition there is one residue of fucose. The carbohydrate composition of yolk RBP indicated the hydrolysis, respectively, of one, one, two and 3 residues of sialic acid, fucose, galactose, and N-acetylglucosamine from its precursor, serum RBP. The effect of these differing levels of glycosylation on plasma clearance, ovarian uptake and tissue distribution of 125I-labeled riboflavin-binding proteins in laying hens were compared. 2 h after intravenous injection, 19% of the egg white RBP, 29% of the yolk RBP, and 37% of the serum RBP remained in circulation. The kinetics of plasma clearance was distinctly biphasic for each of the radioiodinated proteins. The initial rapid-turnover component (t1/2 = 13 min) ranged from 27% of the serum RBP sample to 48% of the egg white RBP sample. The remaining slow-turnover components were cleared with half-lives of 81 min (egg white RBP), 101 min (yolk RBP), and 121 min (serum RBP). 16 h after injection, only 4% of the egg white RBP was deposited in the yolk of developing oocytes while about 12% of the serum RBP and yolk RBP was deposited. This highly significant difference is apparently due to preferential, carbohydrate-dependent clearance of egg white RBP by the liver rather than preferential uptake of serum and yolk RBP by the ovarian follicle. We find no evidence for carbohydrate-directed uptake of riboflavin-binding protein by the ovarian follicle.
Animals↗
Depletion of primary afferent substance P by capsaicin and dihydrocapsaicin without altered thermal sensitivity in rats.
Systemic administration of capsaicin and dihydrocapsaicin to adult rats of two different strains and of capsaicin to neonatal rats, depleted substance P levels in dorsal roots plus ganglia and in dorsal spinal cord. In no case was this depletion accompanied by substantially altered tail-flick latencies. The results are not consistent with a role of the neuropeptide in nociceptive thermal sensitivity in the rat.
Animals↗