142 research outputs found
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Peripheral Neuropathy and Sexual Dimorphism in Prion Disease Mouse Models
No full textIn this study, I characterize peripheral neuropathic phenotypes in F35 mice (knock-out model of prion disease) and 93N mice (novel knock-in model of prion disease) using various behavioral assays, electrophysiology, and histology. F35 mice and 93N mice show significant impairment of small unmyelinated C-fibers without systemic loss of nerve density in either the foot skins or the cornea. In analyzing large fiber function, F35 mice and 93N mice show significant slowing of motor nerve conduction velocity. However, only 93N male mice show significant impairment in large sensory nerve fiber function, suggesting a model- and sex-specific peripheral neuropathic phenotype in the knock-in model. Structural analysis of axon caliber distribution in sciatic nerves show significantly smaller mean axonal diameter in diseased mice, but no difference in total amount of large myelinated fibers. Overall, axonal size-frequency in sciatic nerves of diseased mice appear heavily skewed toward smaller nerve fibers. Analysis of myelin sheath g-ratio show thinner axon diameters in only F35 mice compared to wild type mice, but post-hoc analysis of only male mice shows that F35 and 93N males both have smaller axonal diameters compared to wild types. The presence of peripheral nerve pathology in both mice despite a lack of prion aggregates in the central nervous systems of both mouse models suggests that prion aggregates may not be necessary to activate prion neurotoxic pathways
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Effects of M1R Antagonism in Treating Chemotherapy Induced Peripheral Neuropathy
No full textChemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that affects up to 70% of patients undergoing chemotherapy treatment. CIPN causes a mix of small and large fiber damage as well as motor dysfunction that occurs less frequently but varies patient to patient. CIPN is categorized as a “dying-back” axonal degeneration in which neurodegeneration proceeds in a distal-to-proximal manner. There is currently no FDA-approved prophylactic or treatment for CIPN. In vitro research has shown that rat sensory neurons exposed to chemotherapeutics exhibited reduced neurite outgrowth, but neurons that were concurrently exposed to the muscarinic acetylcholine receptor 1 (M1R) antagonist pirenzepine (PZ) were protected from chemotoxicity. To investigate the practical application of this effect, indices of CIPN were measured in Swiss Webster mice treated with chemotherapeutics paclitaxel, oxaliplatin, and bortezomib. Subcutaneous PZ treatment prevented and reversed indices of neuropathy and neuropathic pain in each drug class. The translational therapeutic potential of PZ was explored by testing varied routes of administration and dose frequencies. Topical PZ had no effect on transient tactile allodynia but was able to reverse MNCV slowing in mice with paclitaxel induced CIPN. Dose frequency was examined as a possible variable in topical PZ efficacy. Topical PZ reversed tactile allodynia at each dose frequency and reversed mild MNCV slowing. My data suggests that M1R may be a viable target in preventing and reversing CIPN
Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms?
No full textNeuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain
Tolerating Diabetes: An Alternative Therapeutic Approach for Diabetic Neuropathy
No full textIt is becoming apparent that a number of pathogenic mechanisms contribute to diabetic neuropathy, so that therapeutic interventions that target one particular mechanism may have limited success. A recently published preclinical study has adopted an alternative approach by using a novel small molecule to induce heat-shock protein 70. This confers upon neurons, and perhaps other cells of the nervous system, the ability to better tolerate the diverse stresses associated with diabetes rather than intervening in their production
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HIV-Associated Distal Sensory Polyneuropathy Induced by HIV-Associated gp120 and Tat proteins
No full textAbout one third of HIV patients suffer from HIV-associated distal sensory polyneuropathy (HIV-DSP), for which there is currently no FDA approved treatment. HIV viral proteins (HIV-1 envelope glycoprotein gp120 and trans-activator of transcription Tat) are known to be associated with mitochondrial dysfunction and neurotoxicity in the brain, but the pathogenic roles of the proteins in peripheral nerves are still unclear. To study if gp120 and/or Tat plays a role in HIV-DSP, indices of peripheral neuropathy were measured in gp120 transgenic (tg) mice, gp120 tg mice treated with Tenofovir disproxil fumarate (TDF, antiretroviral drug), Tat eye drop treated mice and doxycycline-inducible Tat tg mice. Pirenzepine (PZ), a selective muscarinic subtype-1 receptor (M1R) antagonist that reduces cholinergic constraint of mitochondrial function in sensory neurons and enhances nerve growth, was investigated as a potential therapeutic for HIV-DSP in these mouse models of HIV. Eight-month-old gp120 tg mice developed MNCV slowing which was exaggerated by concurrent TDF therapy. Interestingly, TDF also induced both MNCV slowing and thermal hyperalgesia in wild type (WT) mice suggesting novel neurotoxicity of this antiretroviral. Efficacy of PZ against indices of neuropathy in gp120 tg mice was inconclusive. Tat protein delivered by eye drops did not induce neuropathy in WT mice, whereas Tat tg mice developed MNCV slowing, thermal hypoalgesia and corneal nerve loss. These indices of neuropathy were prevented by PZ, which also induced tactile allodynia in WT mice when given by eye drop concurrent with Tat. My data suggested that gp120, TDF and Tat may all contribute to HIV-DSP, and that M1R antagonists may be a viable therapy against HIV-DSP but also have the potential to cause allodynia as a side effect
Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system
No full textINTRODUCTION: Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective. AREAS COVERED: The authors review literature on metformin treatment in Parkinson’s disease, Huntington’s disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol. EXPERT OPINION: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection
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