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D G Graham

Publications and source records attributed to D G Graham.

At least 73 records · Page 4Linked to original sources
PubMed1987

dl- versus meso-3,4-dimethyl-2,5-hexanedione: a morphometric study of the proximo-distal distribution of axonal swellings in the anterior root of the rat.

The neurotoxicity of the dl and meso diastereomers of the gamma-diketone 3,4-dimethyl-2,5-hexanedione (DMHD) was studied to determine if the difference in rates of pyrrole derivatization would influence the clinical and morphological appearance of the neuropathy associated with these gamma-diketones. Two groups of rats received 0.2 mmol/kg/day intraperitoneal injections of their respective diastereomer, and two groups of control rats received comparable volumes of water. The dl-DMHD treated group reached the clinical end-point of hindlimb paralysis in a period of time threefold shorter than the meso-DMHD treated group, paralleling the in vitro kinetics of pyrrole formation with a model amine. A computerized morphometric analysis of cross-sectional axonal areas along the lengths of L4 and L5 anterior roots revealed that the dl-DMHD treated rats had axonal swellings more proximal and of smaller caliber than the meso-DMHD treated rats. 14C-labeled dl and meso diastereomers were synthesized and used to determine relative ability of the diastereomers to gain access to the nervous system. There was approximately 25% more dl-DMHD in the brain after 2 hr. The brain:serum ratios of the diastereomers, however, were equivalent. The more distal location of the neurofilament-filled swellings after meso-DMHD intoxication corroborates previous findings regarding toxicant potency and location of axonal swellings and suggests that the rate of neurofilament crosslinking determines the location of swellings along the length of the axon in the neurofilamentous axonopathies.

Animals↗
PubMed1987

Hyperbaric oxygen accelerates the neurotoxicity of 2,5-hexanedione.

The molecular pathogenesis of n-hexane neurotoxicity has been postulated to proceed as follows: The gamma-diketone metabolite, 2,5-hexanedione (HD), reacts with lysyl-amino groups on neurofilaments to form imines. The imines cyclize to form pyrroles. The pyrroles autoxidize, resulting in covalent protein-protein crosslinking within or between neurofilaments. A resultant impairment of neurofilament transport is proposed to lead to neurofilament-filled axonal swellings. This experiment was designed to test whether oxidation is a necessary pathogenetic step in vivo by comparing time of onset of paralysis of an HD treated group of rats to that of a group receiving HD plus oxygen under high pressure (OHP). The group of rats receiving the hyperbaric oxygen treatment reached the endpoint of hindlimb paralysis significantly sooner than the group receiving none. The fact that OHP does accelerate HD neuropathy points towards an oxidative step in the molecular pathogenesis of gamma-diketone neuropathy.

Animals↗
PubMed1987

Infiltrative polyneuropathy due to acute monoblastic leukemia in hematologic remission.

A 66-year-old man with acute monoblastic leukemia developed acute polyneuropathy with quadriplegia, autonomic instability, and respiratory failure while he was in hematologic remission following both systemic and intrathecal chemotherapy. Autopsy revealed dense infiltration of somatic and autonomic peripheral nerves, sparing the meninges. There was a small peripheral infiltrate in one of four dorsal root ganglia, but, otherwise, sensory and autonomic ganglia were normal. The blood-nerve barrier may allow some malignant cells to escape cytotoxic agents. The epineurium and ganglia lack a blood-tissue barrier, and malignant cells could have been eradicated at those sites.

Action Potentials↗
PubMed1987

Hereditary motor and sensory neuropathy, X-linked: a half century follow-up.

The existence of an X-linked sensorimotor peripheral neuropathy has been debated. We reevaluated the original family, and present data on 13 affected males and 25 obligate or probable heterozygous females, documenting the devastating nature of the disease in the men and the extremely variable degree of clinical involvement in the carriers. Use of DNA probes indicates that the gene lies in the DXYS1-p58-1 region of the X-chromosome.

Adolescent↗
PubMed1986

Electromyographic, neuropathologic, and functional correlates in the cat as the result of tri-o-cresyl phosphate delayed neurotoxicity.

To investigate the cat as a test animal for organophosphorous compound-induced delayed neurotoxicity, tri-o-cresyl phosphate (TOCP) was applied directly on the unprotected back of the neck of young adult cats. Single dermal doses, ranging from 250 to 2000 mg/kg TOCP, or subchronic daily administration of 1 to 100 mg/kg produced delayed neurotoxic effects in the cat. Severity of delayed neurotoxicity depended on the dose and duration. Clinical signs were characterized by hindlimb weakness, ataxia, and paresis. Electromyographic abnormalities resulting from acute denervation were observed in most cats that developed a neurologic deficit. No changes were seen in the motor nerve conduction, thus suggesting that the deficits were in the terminal branch rather than being diffuse lesions in the peripheral nerves. These results correlated well with histopathologic results showing lesions in the most distal portion of the longest tracts in both central and peripheral nervous systems. In the spinal cord, histopathologic studies showed that the ascending tracts of the upper cervical levels and descending tracts of the lumbosacral regions were affected most frequently. Although this study shows that the cat, like the chicken, is susceptible to TOCP-induced delayed neurotoxicity, it demonstrates two differences between the cat and the chicken: greater sensitivity of the cat to the acute effect of TOCP, and greater extent of recovery or improvement of the cat from delayed neurotoxicity. This recovery was demonstrated by: improvement of clinical signs, gain in body weight, disappearance of electromyographic abnormalities, and regeneration of peripheral nerves. Dermal administration of a single 100-mg/kg dose or subchronic 0.5-mg/kg doses of TOCP did not produce delayed neurotoxicity.

Administration, Topical↗
PubMed1985

Congenital giant axonal neuropathy.

Giant axonal neuropathy (GAN) is a distal sensorimotor neuropathy, characterized by neurofilamentous axonal swellings, with usual onset at 2 to 3 years of age. We report a case of congenital GAN with hypotonia at birth. At 7 months of age, nerve conduction studies showed almost complete lack of sensory and motor responses in the lower extremities. A sural nerve biopsy specimen disclosed absence of myelinated axons. Autopsy, following death at 15 months of age, revealed axonal swellings in peripheral nerves and distal degeneration of long spinal cord tracts. The neurofilamentous content of the axonal swellings was confirmed by Glees-Marsland staining and immunoperoxidase reaction with antibodies to neurofilaments. Axonal swellings did not stain with periodic acid-Schiff and were not seen in the cerebral cortex or brain stem, distinguishing this process from infantile neuroaxonal dystrophy. This patient illustrates congenital GAN with subsequent rapid progression.

Axons↗
PubMed1985

The morphology of carbon disulfide neurotoxicity.

The morphology of carbon disulfide induced peripheral neuropathy was studied in rats exposed to three concentrations of carbon disulfide by inhalation for 90 days. Rats exposed to 800 ppm developed neurofilamentous axonal swellings in the distal portions of long fibers, including the dorsal ascending sensory and corticospinal tracts of the spinal cord. In peripheral nerve the predominant effect was seen at the level of the posterior tibial nerve. Teased fiber preparations of the muscular branch of the posterior tibial nerve showed numerous paranodal and internodal swellings as well as Wallerian degeneration. Ultrastructurally the swellings were characterized by neurofilament accumulations, decreased numbers of microtubules and thin myelin. Other features included segregation of axoplasmic organelles and cytoskeletal components, intrusion of Schwann cell processes into the axoplasm, Schwann cells with increased cytoplasmic contents, and Schwann cell proliferation around many swollen and demyelinated axons. These features draw important parallels between the morphology of carbon disulfide neuropathy and the neurofilamentous neuropathies induced by hexacarbons and beta,beta' iminodipropionitrile (IDPN).

Animals↗
PubMed1985

Covalent crosslinking of neurofilaments in the pathogenesis of n-hexane neuropathy.

These studies test the hypothesis that in n-hexane neuropathy the gamma-diketone metabolite 2,5-hexanedione (2,5-HD) results in covalent crosslinking of neurofilaments via nucleophilic attack on oxidized pyrrole rings formed from the reaction of 2,5-HD with epsilon-amino groups of lysyl residues. The 2,5-HD analogue and gamma-diketone,3,4-dimethyl-2,5-hexanedione (DMHD), was found to result in more rapid pyrrole formation, pyrrole autoxidation, and protein crosslinking when compared with 2,5-HD. DMHD was 20-30 times more potent than 2,5-HD in producing hindlimb paralysis. Following 2,5-HD intoxication the neurofilament filled axonal swellings were found in the distal, subterminal axon. After treatment with DMHD, swellings were present in the proximal axon, similar to those seen after intoxication with beta,beta'-iminodipropionitrile (IDPN). DMHD was proposed as a connecting link between the proximal neurofilamentous axonopathy caused by IDPN and the distal neurofilamentous axonopathies from n-hexane, acrylamide, and carbon disulfide intoxication. [14C]DMHD was found to alkylate nerve protein and to result in polymers of radiolabeled protein too large to pass through nitrocellulose filters with pore sizes as large as 12 nm. An even greater proportion of radiolabeled protein was retained by nitrocellulose filters when DMHD was reacted with nerve in which SCa (slow component a of axonal transport) had been pulse-labeled with [35S] methionine. Radiolabeled nerve proteins acylated with [125I]Bolton-Hunter reagent were minimally retained by nitrocellulose filters, suggesting that filter retention reflects polymerization rather than non-specific adsorption.

Acrylamide↗
PubMed1984

A 13-week vapor inhalation study of n-hexane in rats with emphasis on neurotoxic effects.

Male and female Fischer 344 rats were exposed to 0-, 3000-, 6500-, or 10,000-ppm n-hexane vapors 6 hr per day, 5 days per week, for 13 weeks. The 13-week exposures had no adverse effect on the growth of female rats. However, the mean body weight gain of male rats in the 10,000-ppm group was significantly lower than for controls at 4 weeks of exposure and thereafter. In addition to the depression of body weight gain, the male exposed to 10,000 ppm had slightly but significantly lower brain weights at necropsy. No adverse testicular effects were noted. Axonopathy was observed in the tibial nerve in four of five male rats from the 10,000-ppm group and one of five male rats in the 6500-ppm group and in the medulla from one male rat in the 10,000-ppm group. These axonal changes were detectable only in teased nerve fiber preparations or in Epon embedded specimens. Histopathologic studies on Formalin fixed tissues did not reveal any lesions that were attributed to n-hexane exposure.

Air↗
PubMed1984

In vitro evidence that covalent crosslinking of neurofilaments occurs in gamma-diketone neuropathy.

We have postulated that the toxic neuropathies associated with neurofilament-filled axonal swellings have a common pathogenesis, the covalent crosslinking of neurofilaments during anterograde transport. The newly described gamma-diketone, 3,4-dimethyl-2,5-hexanedione (DMHD), is a more potent analogue of the toxic metabolite of n-hexane, 2,5-hexanedione. The axonal swellings observed in DMHD toxicity are in the proximal axon, as seen in intoxication with beta, beta'-iminodipropionitrile, rather than in the distal axon, where neurofilamentous swellings are observed in n-hexane, carbon disulfide, and acrylamide neurotoxicity. In these studies, 14C-labeled DMHD and 2-butanone were synthesized and allowed to react with peripheral nerve. Only 14C-labeled DMHD resulted in stable radiolabeled protein polymers, which were retained by nitrocellulose filters with pore sizes as large as 12 microns. More specific evidence for covalent crosslinking of neurofilaments was obtained when DMHD was allowed to react with peripheral nerve in which the neurofilaments had been pulse-labeled with L-[35S]methionine.

Animals↗
PubMed1984

3,4-Dimethyl-2,5-hexanedione impairs the axonal transport of neurofilament proteins.

Accumulations of neurofilaments are observed in a variety of neurological disorders, and their pathogenesis is a fundamental problem of neuropathology. 2,5-Hexanedione (HD) neurotoxicity provides an extensively studied model of axonal neurofibrillary changes in which the pathogenetic mechanisms have been conjectural. Chronic exposure to HD results in neurofilament-filled swellings in the distal regions of large axons of exposed humans and experimental animals. In this report we describe the changes produced by a potent analogue of HD, 3,4-dimethyl-2,5-hexanedione ( DMHD ), in slow axonal transport in the rat sciatic motor axons. Young rats received 0.6 mmol/kg of DMHD for 5 days before [35S]methionine was injected into the lumbar ventral horns. Slow axonal transport of the neurofilament proteins, tubulin, and selected slow component b (SCb) proteins in DMHD -treated animals was compared to the profiles found in age-matched control animals. DMHD administration reduced the rate of transport of the neurofilament proteins 75 to 90%, while tubulin and the SCb proteins were only modestly retarded. No alterations in electrophoretic mobilities of slowly transported proteins were found, nor were any proteins accelerated in transport. These findings were systematically compared to the changes produced by administration of beta,beta'- immino - dipropionitrile (IDPN) (2.0 gm/kg, i.p.), an agent known to impair neurofilament transport. Although slightly less severe, the changes produced by DMHD were nearly identical to those of IDPN. In correlative morphological studies, the neurofilamentous changes were also comparable. The results indicate that DMHD and IDPN share the capacity to interfere selectively with neurofilament transport and thereby share pathogenetic mechanisms. DMHD provides a new agent for exploration of the organization and transport of the neuronal cytoskeleton.

Animals↗
PubMed1984

Catecholamine toxicity: a proposal for the molecular pathogenesis of manganese neurotoxicity and Parkinson's disease.

An hypothesis is presented which attempts to relate the pathogenesis of both manganese neurotoxicity and Parkinson's disease to cytotoxicity from products of catecholamine oxidation. These include the products resulting from the partial reduction of oxygen (superoxide anion, hydroxyl radical, and hydrogen peroxide) and the semiquinones and ortho quinones produced during autoxidation or oxidation of catecholamines initiated by trivalent manganese.

Adolescent↗
PubMed1983

Sensitivity of the cat to delayed neurotoxicity induced by O-ethyl O-4-nitrophenyl phenylphosphonothioate.

Delayed neurotoxicity was produced in cats following the administration of either a single dermal dose of 22.5 to 225 mg/kg (0.2 to 5.0 times the LD50) or subchronic (90 days) administration of 0.5 to 2.0 mg/kg of technical grade O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN). The study showed three differences from the condition produced in the chicken: difficulty to protect from acute poisoning, slower progression of delayed neurotoxicity, and propensity for improvement. These animals received atropine sulfate and pyridine-2-aldoxime methyl chloride (PAM) to protect them against acute poisoning, but most developed signs of acute cholinergic neurotoxicity, the degree of severity being dose dependent. Also cats given small single doses of EPN showed only leg weakness, while those treated with large doses progressed to severe ataxia and death. In cats treated with subchronic dermal daily doses of EPN, the extent and permanence of injury and progression or improvement of neurologic deficit also depended on the dose size and duration of exposure. Histopathologic changes were present in the most distal portion of the longest tracts in both the central and peripheral nervous system. Ascending tracts were most affected in the cervical spinal cord, while change in the descending tracts was concentrated in the lumbosacral spinal cord. Recovery to a varying degree from delayed neurotoxicity was seen in all surviving cats. The recovery was demonstrated as improvement in clinical signs, increase in body weight, and regeneration of peripheral nerves.

Animals↗
PubMed1983

The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings.

The neurotoxicity of the gamma-diketone, 3,4-dimethyl-2,5-hexanedione, was studied in rats and compared to the known neurotoxicity of the parent compound, 2,5-hexanedione. The test compound was found to be 20 to 30 times more potent on a molar basis than hexanedione. In addition, unlike the distal axonal changes associated with hexanedione, the neurofilamentous swellings following exposure to the dimethyl analog occurred more proximally in the axon, with a preponderance in the anterior horn and lateral tracts of the spinal cord, and in the anterior roots. Since alkyl substitution causes branched-chain compounds to cyclize more rapidly than unbranched analogs, the greater neurotoxicity of the dimethyl compound implicates pyrrole formation in the pathogenesis of n-hexane neuropathy. Furthermore, the location of the axonal swellings induced with 3,4-dimethyl 2,5-hexanedione suggests that there is a common mechanism of injury for the entire class of neurofilament neuropathies, providing a continuum between the intraspinal swellings of beta, beta'-iminodipropionitrile (IDPN) and the distal axonopathies of 2,5-hexanedione, carbon disulfide, and acrylamide. In addition, lower doses of 3,4-dimethyl-2,5-hexanedione for longer periods of time led to a shift in the location of the axonal swellings to include more distal sites. These observations support the hypothesis that covalent crosslinking of the stable neurofilament is the primary event in the molecular pathogenesis of these toxic neuropathies, and that the rate of crosslinking of neurofilaments determines the proximodistal location of the axonal swelling.

Animals↗
PubMed1983

The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. II. Dimethyl substitution accelerates pyrrole formation and protein crosslinking.

3,4-Dimethyl-2,5-hexanedione and 2,5-hexanedione were reacted with model amines to yield N-substituted 2,3,4,5-tetramethylpyrroles and 2,5-dimethylpyrroles, respectively. When compared to the unsubstituted parent compound 2,5-hexanedione, 3,4-dimethyl-2,5-hexanedione was found to cyclize approximately eight times as rapidly on a molar basis at 37 degrees C, with an activation energy of 3290 cal/mole less than 2,5-hexanedione. In addition, 1-benzyl-2,3,4,5-tetramethylpyrrole oxidized more readily than 1-benzyl-2,5-dimethylpyrrole with a difference in the half-wave potentials of 0.29 V. Both gamma-diketones led to progressive crosslinking of proteins in vitro, with the dimethyl substitution accelerating this process by a factor of 40. The formation of pyrrolyl derivatives in vivo was demonstrated by the characteristic absorption spectra obtained following reaction of erythrocyte proteins from intoxicated rats with Ehrlich's reagent. There was progressive formation of protein-bound dimethylpyrroles following exposure to 2,5-hexanedione and formation of tetramethylpyrroles following exposure to 3,4-dimethyl-2,5-hexanedione in vivo. Preparations of axonal pads also demonstrated pyrrole derivatization in vivo. In addition, spectrin preparations of erythrocytes from intoxicated rats showed a large amount of high molecular weight protein (400,000 Da), corresponding to dimerized spectrin. Thus, 3,4-dimethyl-2,5-hexanedione, which is 20 to 30 times more potent on a molar basis than 2,5-hexanedione in leading to a neurofilamentous neuropathy, is associated with more rapid pyrrole formation and protein crosslinking in vitro, and it has been demonstrated that these processes occur in vivo. These observations support the hypothesis that pyrrole formation and autoxidation occur following exposure to gamma-diketones, leading to covalent crosslinking of proteins in vivo, a process which may explain the pathogenesis of neurofilament accumulation in these neuropathies.

Animals↗
PubMed1983

The spatio-temporal pattern of the axonopathy associated with the neurotoxicity of 3,4-dimethyl-2,5-hexanedione in the rat.

The neurotoxicity of the gamma-diketone 3,4-dimethyl-2,5-hexanedione(DMHD) was studied to determine the distribution of the neuropathologic changes and the temporal sequence during the intoxication period and following five and 15 weeks of recovery. Intoxication with 3,4-dimethyl-2,5-hexanedione at a daily dose of 0.25 mmoles/kg led to a profound clinical neuropathy, resulting in paralysis of all four limbs after 12-15 days. The cumulative toxic dose for this gamma-diketone was 3-4 mmoles/kg, indicating that dimethyl substitution increased the neurotoxicity of gamma-diketones by a factor of 20-30. The neuropathy was characterized histologically by giant axonal swellings in the proximal axon of the lower motor neuron in a distribution similar to IDPN (beta,beta'-iminodipropionitrile)-neuropathy, with swellings in the anterior horn, intraspinal anterior root, and the proximal anterior root. These swellings developed from six to 12 days of intoxication and were still evident after 15 weeks of recovery. The fact that dimethyl substitution of 2,5-hexanedione accelerated the neuropathy and was characterized by proximal axonal swellings has two important implications: 1) that formation of pyrrole derivatives may be an important step in the pathogenesis of gamma-diketone neuropathies, and 2) that the neurofilament neuropathies may represent a continuum of toxic neuropathies in which the rate of action of the neurotoxin ultimately determines the proximo-distal location of the axonal swellings.

Animals↗
PubMed1983

Effect of subchronic dermal application of O-ethyl O-4-nitrophenyl phenylphosphonothioate on producing delayed neurotoxicity in hens.

Daily dermal administration for 90 days of 0.01 to 10 mg/kg of O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) technical grade (85%) in acetone (0.1 ml) on the unprotected back of the neck produced delayed neurotoxicity. Hens given 2.5 to 10 mg/kg daily doses also received daily doses of atropine sulfate for 5 or 6 days to protect against cholinergic acute toxicity. Severity of the clinical condition depended on the concentration of the daily dermal dose of EPN; i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. The most consistent histopathologic alteration was the degeneration of axons and myelin in the spinal cord which was identical to that found in positive control hens that received daily dermal doses of 5 or 10 mg/kg tri-o-cresyl phosphate (TOCP). Some of the hens treated daily with the smallest tested dose of EPN (0.001 mg/kg) which did not show clinical signs of delayed neurotoxicity showed equivocal histological changes in the spinal cord. EPN and TOCP treatments had a more profound effect on the activity of plasma butyrylcholinesterase than that of brain acetylcholinesterase (AchE). by contrast O,O,-diethyl O-4-nitrophenyl phosphorothioate (parathion) was more inhibitory to brain AChE. Negative control hens that were treated with 90 daily dermal doses of 1 mg/kg of parathion initially showed leg weakness followed by recovery. A group of hens that received the same volume of acetone (0.1 ml) daily remained normal.

Animals↗