Distal degenerative sensory neuropathy in a long-term type 2 diabetes rat model.

Objective: Peripheral neuropathy associated with type 2 diabetes (DPN) is not widely modeled. We describe unique features of DPN in type 2 diabetic Zucker diabetic fatty (ZDF) rats.

Research Design And Methods: We evaluated the structural, electrophysiological, behavioral, and molecular features of DPN in ZDF rats and littermates over 4 months of hyperglycemia.

Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy.

Objective: Heightened expression of the receptor for advanced glycation end products (RAGE) contributes to development of systemic diabetic complications, but its contribution to diabetic neuropathy is uncertain. We studied experimental diabetic neuropathy and its relationship with RAGE expression using streptozotocin-induced diabetic mice including a RAGE(-/-) cohort exposed to long-term diabetes compared with littermates without diabetes.

Research Design And Methods: Structural indexes of neuropathy were addressed with serial (1, 3, 5, and 9 months of experimental diabetes) electrophysiological and quantitative morphometric analysis of dorsal root ganglia (DRG), peripheral nerve, and epidermal innervation.

Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression.

Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developed ex vivo and in vivo models of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons.

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.

Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin.

Insulin peptide, acting through tyrosine kinase receptor pathways, contributes to nerve development or repair. In this work, we examined the direction, impact and repertoire of insulin signaling in vivo during peripheral nerve regeneration in rats. First, we demonstrated that insulin receptor is expressed on lumbar dorsal root ganglia neuronal perikarya using immunohistochemistry.

Remote neurotrophic support of epidermal nerve fibres in experimental diabetes.

Aims/hypothesis: The support of distal regenerating axons and epidermal nerve fibres through growth factor delivery may depend on the site of delivery. While low-dose systemic insulin provides trophic support for regenerating axons or axons from diabetic animals, its potential action upon the most distal neurites within the epidermis is unknown. In diabetic neuropathy, distal loss of axons is an important clinical and pathological feature.

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.

Diabetes mellitus and the sensory neuron.

Sensory neurons in diabetes may be primarily targeted by diabetes and their involvement may account for prominent sensory loss and pain in diabetic patients. Previous studies demonstrating evidence of excessive polyol flux, microangiopathy, and oxidative stress involving sensory axons and ganglia have been joined by more recent work demonstrating altered neuron phenotype, mitochondrial dysfunction, ion channel alterations, and abnormal growth factor signaling. As such, an interesting and unique panoply of molecular changes in primary sensory neurons has been identified in diabetic models.

Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli.

Proteinase-activated receptor-1 (PAR-1) is activated by thrombin and can be selectively activated by synthetic peptides (PAR-1-activating peptide: PAR-1-AP) corresponding to the receptor's tethered ligand. PAR-1 being expressed by afferent neurons, we investigated the effects of PAR-1 agonists on nociceptive responses to mechanical and thermal noxious stimuli. Intraplantar injection of selective PAR-1-AP increased nociceptive threshold and withdrawal latency, leading to mechanical and thermal analgesia, while control peptide had no effect.

Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway.

Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists.

Systemic production of human granulocyte colony-stimulating factor in nonhuman primates by transplantation of genetically modified myoblasts.

Clinical use of human granulocyte-colony stimulating factor (hG-CSF) to treat various diseases involving neutropenia has been previously shown to (1) successfully increase circulating neutrophils, (2) reduce condition-related infections, and (3) cause few side effects in patients. To alleviate the symptoms of neutropenia, the patient must receive frequent injections of recombinant hG-CSF. Permanent ways to deliver stable levels of the molecule to the patient are being investigated.

Successful myoblast transplantation in fibrotic muscles: no increased impairment by the connective tissue.

Background: Implantation of normal myoblasts may eventually be a treatment for inherited myopathies such as Duchenne muscular dystrophy.

Methods: We report a comparative study of the effectiveness on myoblast implantation: (1) into the muscles of young (2 months) mdx mice nonirradiated and noninjected with notexin (group 1), (2) into muscles of old mdx mice (15 months) nonirradiated and noninjected with notexin (group 2), and (3) into muscles of 5 months mdx mice irradiated 3 months before the transplantation (group 3). Roughly 3 million cells were injected with bFGF in the Tibialis anterior.

Normal myoblast implantation in MDX mice prevents muscle damage by exercise.

One consequence of the lack of dystrophin is a higher vulnerability of myofibers to eccentric exercise. In this study, we compared the effect of downhill running on Biceps brachii of MDX mice with or without transplantation of normal myoblasts. Exercise induced damaged was detected by Evans blue staining.

Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise.

Duchenne muscular dystrophy is an X-linked devastating disease due to the lack of expression of a functional dystrophin. Unfortunately, the dystrophin-deficient mdx mouse model does not present clinical signs of dystrophy before the age of 18 months, and the role of dystrophin in fiber integrity is not fully understood. The fragility of the skeletal muscle fibers was investigated in transgenic mice expressing beta-galactosidase under the control of a muscle specific promoter.

Muscle fibers of mdx mice are more vulnerable to exercise than those of normal mice.

It is well known that eccentric exercise induces muscle damage by disrupting the sarcolemma. The aim of this study was to analyze the effects of downhill running on several locomotor and respiratory muscles of normal and mdx mice. Degenerating muscle fibers in the skeletal muscles of mice were visualized by in vivo staining with Evans blue.

[Dystrophin expression in skeletal muscles in endurance-trained hypo-hyperthyroid and growth-hormone treated rats].

The aim of this study was to determine the effect of chronic muscular exercise, thyroid status and growth hormone administration on skeletal muscle dystrophin expression. Relative abundance of dystrophin (quantity in arbitrary units/50 micrograms of protein) was measured by immunoblotting and densimometry. Our results indicate that relative abundance of dystrophin in slow-or fast-twicht muscle was not modified by chronic muscular exercise (5 weeks), thyroxine administration (4 weeks), antithyroid drug treatment (6 weeks) or growth hormone administration (6 weeks).