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Biomedical subjects

Douglas W Zochodne

Publications and source records attributed to Douglas W Zochodne.

At least 19 recordsLinked to original sources
PubMed2006

Primary angiitis of the spinal cord presenting as a conus mass: long-term remission.

BACKGROUND: Primary angiitis of the central nervous system (CNS) is a rare vasculitic disorder that typically involves the brain and, less frequently, the spinal cord without involvement of the blood vessels outside the CNS. CASE DESCRIPTION: We present a case of a 52-year-old woman who developed a conus syndrome linked to an enhancing mass of her lower thoracic spinal cord, lumbar cord, and conus. Spinal cord biopsy performed for diagnostic purposes in the setting of progressive neurological deficit confirmed angiitis of the spinal cord. Therapy with steroid and cyclophosphamide was associated with long-term (3 years) clinical and imaging remission of the lesion. CONCLUSIONS: The prognosis of primary CNS angiitis is dismal with most cases progressing to death. Long-term remission is unusual. Aggressive therapy with steroid and cytotoxic agents may improve survival.

Adult↗
PubMed2006

Diabetes, leukoencephalopathy and rage.

Longstanding diabetes mellitus damages kidney, retina, peripheral nerve and blood vessels, but brain is not usually considered a primary target. We describe direct involvement of the brain, particularly white matter, in long-term (9 months) experimental diabetes of mice, not previously modeled, correlating magnetic resonance (MR) imaging with quantitative histological assessment. Leukoencephalopathy and cerebral atrophy, resembling that encountered in diabetic humans, developed in diabetic mice and was accompanied by time-related development of cognitive changes in behavioural testing. Increased RAGE (receptor for advanced glycation end products) expression, a mediator of widespread diabetic complications, increased dramatically at sites of white matter damage in regions of myelination. RAGE expression was also elevated within neurons, astrocytes and microglia in grey matter and within oligodendrocytes in white matter. RAGE null diabetic mice had significantly less neurodegenerative changes when compared to wild-type diabetic mice. Our findings identify a robust and novel model of cerebral, particularly white matter, involvement with diabetes associated with abnormal RAGE signaling.

Animals↗
PubMed2006

Neurological complications of infliximab.

The use of anti-tumor necrosis factor-a (TNF-a) therapies has led to improved outcomes in the treatment of rheumatoid arthritis (RA). However, the use of these new therapeutic agents requires careful monitoring for adverse effects. We describe 3 patients who developed neurological disease closely associated with the use of infliximab, a monoclonal antibody that binds to and inactivates TNF-a. All had evidence of polyneuropathy, demyelinating in one and axonal in 2. One patient had a central nervous system syndrome. Physicians should be aware of these potential adverse effects when treating patients with infliximab.

Aged↗
PubMed2005

Neurotrophin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient receptor potential vanilloid receptor-1 expression in adult sensory neurons.

Neurotrophin-3 (NT-3) negatively modulates nerve growth factor (NGF) receptor expression and associated nociceptive phenotype in intact neurons, suggesting a beneficial role in treating aspects of neuropathic pain mediated by NGF. We report that NT-3 is effective at suppressing thermal hyperalgesia associated with chronic constriction injury (CCI); however, NT-3 does not alter the mechanical hypersensitivity that also develops with CCI. Thermal hyperalgesia is critically linked to expression and activation of the capsaicin receptor, transient receptor potential vanilloid receptor-1 (TRPV1). Thus, its modulation by NT-3 after CCI was examined. CCI results in elevated TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons, with the percentage of neurons expressing TRPV1 remaining unchanged at approximately 56%. Attenuation of thermal hyperalgesia mediated by NT-3 correlates with decreased TRPV1 expression such that only approximately 26% of neurons ipsilateral to CCI expressed detectable TRPV1 mRNA. NT-3 effected a decrease in expression of the activated component of the signaling pathway linked to regulation of TRPV1 expression, phospho-p38 MAPK (Ji et al., 2002), in neurons ipsilateral to CCI. Exogenous NT-3 could both prevent the onset of thermal hyperalgesia and reverse established thermal hyperalgesia and elevated TRPV1 expression 1 week after CCI. Continuous infusion is required for suppression of both thermal hyperalgesia and TRPV1 expression, because removal of NT-3 resulted in a prompt reestablishment of the hyperalgesic state and corresponding CCI-associated TRPV1 phenotype. In conclusion, although NGF drives inflammation-associated thermal hyperalgesia via its regulation of TRPV1 expression, NT-3 is now identified as a potent negative modulator of this state.

Animals↗
PubMed2005

Axon and Schwann cell partnership during nerve regrowth.

Regeneration of peripheral nerve involves an essential contribution by Schwann cells (SCs) in collaboration with regrowing axons. We examined such collaboration between new axons and Schwann cells destined to reform peripheral nerve trucks in a regeneration chamber bridging transected rat sciatic nerves. There was a highly intimate "dance" between axons that followed outgrowing and proliferating SCs. Axons without SCs only grew short distances and almost all axon processes had associated SC processes. When regeneration chambers were infused through an external access port with local mitomycin, a mitosis inhibitor, SC proliferation, migration and subsequent axon regrowth were dramatically reduced. Adding laminin to mitomycin did not reverse this regenerative lag and indicated that SCs provide more than laminin synthesis alone. Laminin infused alone supplemented endogenous laminin and facilitated first SC then axon regrowth. "Wrong way" misdirected axons were associated with misdirected SC processes and were more numerous in bridges exposed to mitomycin, but were fewer in laminin supplemented bridges. Later, by 21 days, there was myelinated axon repopulation of regenerative bridges but those exposed to mitomycin alone at early time points had substantial impairments in axon investment. Reforming peripheral nerve trucks involves a very close and intimate relationship between axons and SCs that must proliferate and migrate, facilitated by laminin.

Animals↗
PubMed2005

Impaired peripheral nerve regeneration in diabetes mellitus.

Diabetes mellitus impairs peripheral nerve regeneration. Regenerative failure likely exacerbates deficits from polyneuropathy or focal neuropathies in patients who might otherwise exhibit spontaneous improvement. Some focal neuropathies, like carpal tunnel syndrome, are common, yet render ongoing disability because of their delayed recovery. Why diabetic nerves fail to regenerate is an interesting question to consider because several mechanisms likely contribute. In this review, we examine a number of these causes. These causes include microangiopathy or disease of small blood vessels, failure to provide proper metabolic support for repair, defects in the entry and actions of inflammatory cells within the injury milieu, less robust support of axons by their Schwann cells, and lack of a full repertoire of trophic factors. A number of the mechanisms that generate neuropathy in the first place also likely contribute to failed regenerative programs, but how they do so is not clear.

Animals↗
PubMed2005

Experimental diabetic neuropathy with spontaneous recovery: is there irreparable damage?

Progressive diabetic neuropathy has hitherto been irreversible in humans. New approaches raise the question of whether islet cell reconstitution rendering euglycemia can reverse specific features of neuropathy. We evaluated physiological and structural features of experimental neuropathy in a long-term murine model of diabetes induced by streptozotocin. By serendipity, a subset of these diabetic mice spontaneously regained islet function and attained near-euglycemia. Our hypotheses were that this model might better reflect axon loss observed in human disease and that spontaneous recovery from diabetes might identify the features of neuropathy that are reversible. In this model, experimental neuropathy closely modeled that in humans in most critical aspects: declines in motor conduction velocities, attenuation of compound muscle (M waves) and nerve action potentials, axon atrophy, myelin thinning, loss of epidermal axons, and loss of sweat gland innervation. Overt sensory neuron loss in dorsal root ganglia was a feature of this model. In mice with recovery, there was robust electrophysiological improvement, less myelin thinning, and remarkable epidermal and sweat gland reinnervation. There was, however, no recovery of populations of lost sensory neurons. Our findings identify a robust model of human diabetic neuropathy and indicate that overt, irretrievable loss of sensory neurons is one of its features, despite collateral reinnervation of target organs. Sensory neurons deserve unique protective strategies irrespective of islet cell reconstitution.

Action Potentials↗
PubMed2004

Accelerated diabetic neuropathy in axons without neurofilaments.

Diabetic neuropathy is characterized by slowing of conduction velocity and axonal atrophy. Both of these cardinal features of neuropathy might be linked to impaired neurofilament investment of axons. Since neurofilaments form the critical structural latticework of axons, their importance in neuropathy is of interest. We tested directly the relationship of neurofilaments to diabetic neuropathy by superimposing streptozotocin-generated diabetes on a unique but viable transgenic mouse described by Eyer and Peterson. These mice express a fusion protein in which the carboxyl terminus of the high molecular weight neurofilament protein (Nf-H) was replaced by beta-galactosidase, in turn blocking normal neurofilament export and rendering axons completely lacking neurofilaments. Despite similar levels of hyperglycaemia, diabetic mice lacking neurofilaments developed progressive slowing of conduction velocity in their motor and sensory fibres between 4 and 8 weeks after the onset of diabetes (P < 0.05), unlike diabetic mice with normal neurofilaments, who developed only mild evidence of neuropathy over the same time-frame. Diabetic mice without neurofilaments, but not those with neurofilaments, had a progressive decline in the amplitude of the caudal nerve compound action potential and there were trends toward increased axonal atrophy in diabetics lacking neurofilaments. Single daily doses of insulin that restored normoglycaemia (0.1 IU subcutaneous insulin daily 5 of 7 days weekly for 4 weeks) reversed conduction slowing and restored sensory axon calibre. Our findings indicate that abnormalities in neurofilament export or transport alone cannot account for features of diabetic neuropathy. Instead, neurofilaments may allow axons to better resist the ravages of diabetes. Our findings also confirm the impact of insulin on reversing the phenotype.

Action Potentials↗
PubMed2004

Peripheral neuropathy in lentivirus infection: evidence of inflammation and axonal injury.

OBJECTIVE: As distal sensory polyneuropathy (DSP) is a major neurological complication of HIV-1 infection, we investigated the extent of peripheral nervous system disease in animals infected with the lentivirus, feline immunodeficiency virus (FIV), because it causes neurological disease and immunosuppression in cats similar to HIV-1 in humans. METHODS: After infection with a neurovirulent FIV molecular clone, neurobehavioral testing, nerve morphology, viral detection and load measurements were performed. RESULTS: Neurobehavioral studies showed delayed withdrawal in response to a noxious stimulus among FIV-infected animals compared with sham-infected controls (P < 0.05). Dorsal root ganglia and sciatic nerves from FIV-infected ammals showed activated macrophages that were increased in number and size compared with controls. In addition, TNF-alpha messenger RNA was detectable in most nerves and spinal cords from the FIV-infected group, but was infrequently detected in controls. Viral RNA copy numbers in plasma and sciatic nerves were detectable in all FIV-infected animals at high levels. Studies of sural nerves identified myelinated fiber atrophy in 12-week FIV-infected animals compared with age-matched control animals, which was accompanied by reduced myelin sheath thickness (P < 0.05). The footpads of FIV-infected animals displayed reduced intraepidermal fiber density compared with control animals (P < 0.01). CONCLUSION: FIV infection results in the rapid onset of peripheral neuropathy, defined by axonal injury and macrophage activation, together with abundant virus within the nerve, indicating that it may serve as a model of HIV-related DSP.

Animals↗
PubMed2004

Heightened pain and delayed regeneration of galanin axons in diabetic mice.

Galanin peptide in primary sensory neurons may confer analgesia following injury. Its presence in regenerative axon sprouts where pain may be initiated has not been examined. We examined very early outgrowth of peptidergic axon sprouts after sciatic nerve crush in mice with experimental streptozotocin-induced diabetes. Diabetic mice had a retarded wave of outgrowing galanin axons, but those expressing calcitonin gene-related peptide grew normally. Diabetic mice also developed early, then persistent excessive autotomy behaviour, an index of pain behaviour in complete nerve lesions. Diabetes is associated with variations in the early outgrowth of peptide-containing axons. A relative delay in galanin axon outgrowth could contribute to heightened neuropathic pain in diabetes.

Animals↗
PubMed2004

CGRP peptide and regenerating sensory axons.

CGRP peptide, a widely expressed constituent of sensory neurons, plays important roles in nerve function and repair when axons are severed. CGRP synthesis declines, yet peptide nonetheless accumulates in severed axon endbulbs. In this work we explore an apparent selective and ongoing expression of CGRP peptide in regenerative sensory axon sprouts. Following sural nerve crush in rats out to 14 days, regenerating and branching sensory axons had intense and selective expression of CGRP, not associated with endbulbs. Parent L4 and L5 perikarya and axons in the sural nerve proximal to crush, however, did not exhibit such heightened CGRP presence. Instead, back labeling of regenerating axons with fluorogold or diamidino yellow labeled perikarya with reduced CGRP expression. Similarly, ATF-3, a robust marker of axotomized neurons, was associated with reduced, rather than elevated expression of alphaCGRP mRNA. Unexpectedly, however, we identified an enlarged secondary population of intact uninjured neurons, frequently smaller and projecting to the dorsal horn with new and heightened intense CGRP expression but not ATF-3- or tracer-labeled. Distal regenerating sensory axons selectively express CGRP peptide despite reduced perikaryal content, a phenomenon not explained by simple accumulation. Having an injured neighbor neuron, however, may also paradoxically alter how CGRP is expressed in intact neurons.

Animals↗
PubMed2004

NO pain: potential roles of nitric oxide in neuropathic pain.

The disabling human syndrome of "neuropathic pain" is an intractable complication of peripheral nerve injury or degeneration. A complex interaction between injured peripheral axons, sensory neurons and central nervous system signaling is thought to account for it. In this brief review, we present evidence that the free radical signaling molecule, nitric oxide (NO) may act at several levels of the nervous system during the development of experimental neuropathic pain. For example, NO may directly influence injured axons in the periphery, may indirectly influence pain by its role in the process of Wallerian degeneration, and may signal in the dorsal horn of the spinal cord. While it is premature to argue for therapeutic approaches that alter NO actions, it may be an important player in the cascade of events that generate neuropathic pain.

Journal Article↗
PubMed2004

Direct insulin signaling of neurons reverses diabetic neuropathy.

Diabetic polyneuropathy is the most common acquired diffuse disorder of the peripheral nervous system. It is generally assumed that insulin benefits human and experimental diabetic neuropathy indirectly by lowering glucose levels. Insulin also provides potent direct support of neurons and axons, and there is a possibility that abnormalities in direct insulin signaling on peripheral neurons relate to the development of this disorder. Here we report that direct neuronal (intrathecal) delivery of low doses of insulin (0.1-0.2 IU daily), insufficient to reduce glycemia or equimolar IGF-I but not intrathecal saline or subcutaneous insulin, improved and reversed slowing of motor and sensory conduction velocity in rats rendered diabetic using streptozotocin. Moreover, insulin and IGF-I similarly reversed atrophy in myelinated sensory axons in the sural nerve. That intrathecal insulin had the capability of signaling sensory neurons was confirmed by observing that fluorescein isothiocyanate-labeled insulin given intrathecally accessed and labeled individual lumbar dorsal root ganglion neurons. Moreover, we confirmed that such neurons express the insulin receptor, as previously suggested by Sugimoto et al. Finally, we sequestered intrathecal insulin in nondiabetic rats using an anti-insulin antibody. Conduction slowing and axonal atrophy resembling the changes in diabetes were generated by anti-insulin but not by an anti-rat albumin antibody infusion. Defective direct signaling of insulin on peripheral neurons through routes that include the cerebrospinal fluid may relate to the development of diabetic peripheral neuropathy.

Animals↗
PubMed2003

Clinical and serological associations of autoantibodies to GW bodies and a novel cytoplasmic autoantigen GW182.

A novel autoantigen named GW182 was recently identified when the serum from a patient with a sensory ataxic polyneuropathy was used to immunoscreen a HeLa cDNA library. Unique features of the GW182 protein include 39 repeats of glycine (G) and tryptophan (W) residues, binding to a subset of messenger RNA and localization to unique structures within the cytoplasm that were designated GW bodies (GWBs). The goal of the present study was to identify the clinical features of patients with anti-GW182 antibodies and to characterize the B cell anti-GW182 response by defining the epitopes bound by human autoantibodies. The most common clinical diagnosis of patients with anti-GW182 antibodies was Sjögren's syndrome followed by mixed motor/sensory neuropathy, and systemic lupus erythematosus. Of interest, 5 (28%), 9 (50%), and 3 (17%) of the 18 sera that react with GWBs had autoantibodies to the GW182 and the 52 kDa and 60 kDa SS-A/Ro autoantigens, respectively. Epitopes bound by the human autoantibodies were mapped to the GW-rich middle part of the protein, the non-GW rich region, and the C-terminus of GW182 protein. None of the GW182 epitopes had significant sequence similarities to other known proteins. GW182 represents a new category of ribonucleoprotein autoantigens.

Adult↗