المؤلفون: Casselini, Carolina M, Parson, Henri K, Frizzi, Katie E, Marquez, Alex, Smith, Darrell R, Guernsey, Lucie, Nemmani, Rakesh, Tayarani, Alireza, Jolivalt, Corinne G, Weaver, Jessica, Fernyhough, Paul, Vinik, Aaron I, Calcutt, Nigel A

المصدر: Acta Neuropathologica. 147(1)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Peripheral Neuropathy, Clinical Research, Chronic Pain, Diabetes, Clinical Trials and Supportive Activities, Pain Research, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Metabolic and endocrine, Neurological, Diabetic neuropathy, Epidermal nerve fibres, Muscarinic antagonist, Neuropathic pain, Oxybutynin, Randomized clinical trial, Animals, Humans, Mice, Rats, Diabetic Neuropathies, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Mandelic Acids, Receptors, Muscarinic, Muscarinic Antagonists, Quality of Life, Adult, Diabetes Mellitus, Type 1, Neurology & Neurosurgery

الوصف: Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8jf8v1cqTest

المؤلفون: Aghanoori, Mohamad-Reza, Agarwal, Prasoon, Gauvin, Evan, Nagalingam, Raghu S, Bonomo, Raiza, Yathindranath, Vinith, Smith, Darrell R, Hai, Yan, Lee, Samantha, Jolivalt, Corinne G, Calcutt, Nigel A, Jones, Meaghan J, Czubryt, Michael P, Miller, Donald W, Dolinsky, Vernon W, Mansuy-Aubert, Virginie, Fernyhough, Paul

المصدر: Cellular and Molecular Life Sciences. 79(4)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Peripheral Neuropathy, Autoimmune Disease, Neurodegenerative, Diabetes, Genetics, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Neurological, Metabolic and endocrine, Aging, Animals, Antibodies, Neutralizing, Axons, Base Sequence, CCAAT-Enhancer-Binding Protein-beta, Cell Respiration, Cells, Cultured, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Energy Metabolism, Ganglia, Spinal, Gene Expression Regulation, Glycolysis, HEK293 Cells, Humans, Insulin-Like Growth Factor I, Liver, Male, Mitochondria, NFATC Transcription Factors, Neuronal Outgrowth, Polymers, Promoter Regions, Genetic, Protein Transport, Rats, Sprague-Dawley, Sensory Receptor Cells, Signal Transduction, Dorsal root ganglia, Diabetic neuropathy, NFAT1, Neurite outgrowth, Neurotrophic factor, IGF-1, Biochemistry and Cell Biology, Physiology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Oncology and carcinogenesis

الوصف: Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2wk0f3rxTest

المؤلفون: Jolivalt, Corinne G, Han, May Madi, Nguyen, Annee, Desmond, Fiona, Alves Jesus, Carlos Henrique, Vasconselos, Daniela C, Pedneault, Andrea, Sandlin, Natalie, Dunne-Cerami, Sage, Frizzi, Katie E, Calcutt, Nigel A

المصدر: Journal of Clinical Medicine. 11(9)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Ophthalmology and Optometry, Neurodegenerative, Peripheral Neuropathy, Physical Injury - Accidents and Adverse Effects, Prevention, Diabetes, Chronic Pain, Pain Research, Eye Disease and Disorders of Vision, 5.2 Cellular and gene therapies, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Eye, Neurological, diabetic neuropathy, corneal confocal microscopy, CNTF, GLP-1, exendin-4, muscarinic antagonist, cyclopentolate, glycopyrrolate, gallamine, Clinical Sciences, Biomedical and clinical sciences

الوصف: Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy and neurodegenerative disease is less clear but may be supported by preclinical studies of investigational agents. We, therefore, used diverse investigational agents to assess concordance of efficacy against corneal nerve loss and peripheral neuropathy in a mouse model of diabetes. Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy. Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/60v5q7r7Test

المؤلفون: Marquez, Alexandra, Guernsey, Lucie S, Frizzi, Katie E, Cundiff, Morgan, Constantino, Isabel, Muttalib, Nabeel, Arenas, Fernanda, Zhou, Xiajun, Lim, Sze Hway, Ferdousi, Maryam, Ponirakis, Georgios, Silverdale, Monty, Kobylecki, Christopher, Jones, Matthew, Marshall, Andrew, Malik, Rayaz A, Jolivalt, Corinne G

مصطلحات موضوعية: Biomedical and Clinical Sciences, Ophthalmology and Optometry, Aging, Neurosciences, Brain Disorders, Alzheimer's Disease, Acquired Cognitive Impairment, Peripheral Neuropathy, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Eye Disease and Disorders of Vision, Physical Injury - Accidents and Adverse Effects, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Dementia, Frontotemporal Dementia (FTD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Cornea, Female, Frontotemporal Dementia, Humans, Memory Disorders, Mice, Mice, Transgenic, Microscopy, Confocal, Middle Aged, Nerve Degeneration, Peripheral Nervous System Diseases, Tauopathies, tau Proteins, Corneal confocal microscopy, Memory deficits, Neurodegeneration, Peripheral neuropathy, Tau, Clinical Sciences, Neurology & Neurosurgery, Biochemistry and cell biology

الوصف: Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5270r3t3Test

المؤلفون: Lee-Kubli, Corinne A, Zhou, XiaJun, Jolivalt, Corinne G, Calcutt, Nigel A

المصدر: Diagnostics (Basel, Switzerland). 11(2)

مصطلحات موضوعية: GABAB receptor, GABAergic, KCC2, acetazolamide, baclofen, carbonic anhydrase, diabetic neuropathy, painful neuropathy, rate dependent depression, spinal disinhibition, Neurodegenerative, Pain Research, Diabetes, Neurosciences, Peripheral Neuropathy, Chronic Pain, 5.1 Pharmaceuticals, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Neurological, GABA(B) receptor

الوصف: Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABAA and GABAB receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABAA receptor-mediated inhibition. GABAB receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABAA receptor-mediated inhibition. Administration of the GABAB receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3s743378Test

المؤلفون: King, Matthew R, Anderson, Nicholas J, Deciu, Mihaela, Guernsey, Lucie S, Cundiff, Morgan, Hajizadeh, Shohreh, Jolivalt, Corinne G

المصدر: Journal of Neuroscience Research. 98(11)

مصطلحات موضوعية: Biological Psychology, Biomedical and Clinical Sciences, Psychology, Dementia, Nutrition, Alzheimer's Disease, Brain Disorders, Neurodegenerative, Aging, Diabetes, Acquired Cognitive Impairment, Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, 5.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Metabolic and endocrine, Neurological, Amyloid beta-Protein Precursor, Animals, Brain Chemistry, Cognition Disorders, Diabetes Mellitus, Experimental, Exenatide, Female, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Male, Maze Learning, Memory, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Obesity, Psychomotor Performance, tau Proteins, adiponectin, Alzheimer's disease, diabetes, GLP-1 analog, RRID, AB_94944, AB_476730, AB_570891, AB_662807, RRID:AB_476730, RRID:AB_570891, RRID:AB_662807, RRID:AB_94944, Neurology & Neurosurgery, Biological psychology

الوصف: Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/75p026ppTest

المؤلفون: Jolivalt, Corinne G, Frizzi, Katie E, Han, May Madi, Mota, Andre J, Guernsey, Lucie S, Kotra, Lakshmi P, Fernyhough, Paul, Calcutt, Nigel A

المصدر: Journal of Pharmacology and Experimental Therapeutics. 374(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Prevention, Diabetes, Peripheral Neuropathy, Pain Research, Neurodegenerative, Chronic Pain, 5.2 Cellular and gene therapies, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Metabolic and endocrine, Administration, Topical, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Female, Mice, Mice, Inbred C57BL, Muscarinic Antagonists, Peripheral Nervous System Diseases, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences

الوصف: Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8jv6q8krTest

المؤلفون: Jolivalt, Corinne G, Marquez, Alexandra, Quach, David, Diaz, Michelle C Navarro, Anaya, Carlos, Kifle, Betelhem, Muttalib, Nabeel, Sanchez, Gabriela, Guernsey, Lucy, Hefferan, Mike, Smith, Darrel R, Fernyhough, Paul, Johe, Karl, Calcutt, Nigel A

المصدر: Diabetes. 68(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Diabetes, Dementia, Brain Disorders, Peripheral Neuropathy, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Prevention, Alzheimer's Disease, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Metabolic and endocrine, Aminopyridines, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Female, Hippocampus, Male, Mice, Mitochondria, Neurogenesis, Neuronal Outgrowth, Piperazines, Rats, Sensory Receptor Cells, Synapses, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences

الوصف: While peripheral neuropathy is the most common complication of long-term diabetes, cognitive deficits associated with encephalopathy and myelopathy also occur. Diabetes is a risk factor for Alzheimer disease (AD) and increases the risk of progression from mild cognitive impairment to AD. The only current recommendation for preventing or slowing the progression of peripheral neuropathy is to maintain close glycemic control, while there is no recommendation for central nervous system disorders. NSI-189 is a new chemical entity that when orally administered promotes neurogenesis in the adult hippocampus, increases hippocampal volume, enhances synaptic plasticity, and reduces cognitive dysfunction. To establish the potential for impact on peripheral neuropathy, we first showed that NSI-189 enhances neurite outgrowth and mitochondrial functions in cultured adult rat primary sensory neurons. Oral delivery of NSI-189 to murine models of type 1 (female) and type 2 (male) diabetes prevented multiple functional and structural indices of small and large fiber peripheral neuropathy, increased hippocampal neurogenesis, synaptic markers and volume, and protected long-term memory. NSI-189 also halted progression of established peripheral and central neuropathy. NSI-189, which is currently in clinical trials for treatment of major depressive disorder, offers the opportunity for the development of a single therapeutic agent against multiple indices of central and peripheral neuropathy.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8xs9k5d6Test

المؤلفون: Marshall, Andrew G, Worthington, Anne, Jolivalt, Corinne G

مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Autoimmune Disease, Diabetes, Chronic Pain, Pain Research, Physical Injury - Accidents and Adverse Effects, Peripheral Neuropathy, Spinal Cord Injury, Traumatic Head and Spine Injury, Metabolic and endocrine, Neurological

وصف الملف: application/pdf

العلاقة: qt0nc0k461; https://escholarship.org/uc/item/0nc0k461Test

الإتاحة: https://escholarship.org/uc/item/0nc0k461Test

المؤلفون: Aghanoori, Mohamad-Reza, Agarwal, Prasoon, Gauvin, Evan, Nagalingam, Raghu S., Bonomo, Raiza, Yathindranath, Vinith, Smith, Darrell R., Hai, Yan, Lee, Samantha, Jolivalt, Corinne G., Calcutt, Nigel A., Jones, Meaghan J., Czubryt, Michael P., Miller, Donald W., Dolinsky, Vernon W., Mansuy-Aubert, Virginie, Fernyhough, Paul

المصدر: Cellular and Molecular Life Sciences (CMLS). 79(4)

مصطلحات موضوعية: Dorsal root ganglia, Diabetic neuropathy, Mitochondria, NFAT1, Neurite outgrowth, Neurotrophic factor, IGF-1

الوصف: Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBP beta, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBP beta can be a promising therapeutic approach.

وصف الملف: print

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-310649Test
https://doi.org/10.1007/s00018-022-04201-9Test