Mechanisms of disease

Verge, Valerie M. K.; Andreassen, Christer S.; Arnason, Terra; Andersen, Henning

doi:10.1016/b978-0-444-53480-4.00032-1

Cited by 19 publications

(7 citation statements)

References 204 publications

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“…We have investigated skin expression of selected neurotrophic factors and their receptors in subjects with advanced peripheral diabetic neuropathy. In agreement with the experimental data and prevailing clinical views [9, 18, 19, 30], we expected lower expression that would correspond to tissue injury caused by longstanding hyperglycemia and multifaceted metabolic disorders. This assumption, however, was not confirmed.…”

Section: Discussionsupporting

confidence: 90%

Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation

Saudek

Cahová

Havrdova

et al. 2018

Journal of Diabetes Research

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Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6–12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05–0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.

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Section: Discussionsupporting

confidence: 90%

Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation

Saudek

Cahová

Havrdova

et al. 2018

Journal of Diabetes Research

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“…BDNF and its receptor TrkB mediate aspects of neuronal development and differentiation and are involved in whole-body energy homeostasis ( Hutchison, 2012 , 2013 ) and diabetes ( Verge et al, 2014 ). BDNF can indirectly regulate islet hormones, like glucagon, through actions in the hypothalamus and innervation of the islet ( Gotoh et al, 2013 ) and was suggested to have direct effects on α cells ( Hanyu et al, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling

Kalwat

Huang

Binns

et al. 2020

Front. Cell Dev. Biol.

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Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the G i/o -linked α 2 -adrenergic receptor, which upon activation suppresses insulin secretion. The use of the adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating β cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the β cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 β cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on β cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be G i/o -dependent using pertussis toxin, arguing against an off-target effect of high-dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine; however, these did not rescue TrkB signaling in our experiments. Taken together, these results show that (1) TrkB kinase signaling occurs in β cells and (2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in β cells may underlie pro-survival or growth signaling and warrants further study.

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“…Studies of systemic diseases (i.e., diabetes mellitus and osteoarthritis) have revealed an interaction between NGF and TGF-β ( 62 , 63 ). Neurotrophins play a crucial role in the differentiation and survival of nerve cells.…”

Section: Ngf Immune Response and Leprosymentioning

confidence: 99%

“…The borderline form of leprosy is immunologically dynamic and oscillates between the two polar forms. In patients with borderline-tuberculoid, borderline, and borderline-lepromatous leprosy, the progressive reduction in the cell-mediated response from the borderline-tuberculoid to the borderline-lepromatous form is accompanied by more extensive skin lesions and nerve damage, as well as increased bacillary burden and antibody levels ( 63 , 64 ). In borderline forms of the disease, neurological manifestations resulting from immunological instability are characterized by nerve trunk impairment and frequent reactional episodes, which lead to early and asymmetrical nerve injuries and physical disability.…”

Section: Ngf Immune Response and Leprosymentioning

confidence: 99%

Nerve Growth Factor and Pathogenesis of Leprosy: Review and Update

et al. 2018

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Neurotrophins are a family of proteins that regulate different aspects of biological development and neural function and are of great importance in neuroplasticity. This group of proteins has multiple functions in neuronal cells, as well as in other cellular populations. Nerve growth factor (NGF) is a neurotrophin that is endogenously produced during development and maturation by multiple cell types, including neurons, Schwann cells, oligodendrocytes, lymphocytes, mast cells, macrophages, keratinocytes, and fibroblasts. These cells produce proNGF, which is transformed by proteolytic cleavage into the biologically active NGF in the endoplasmic reticulum. The present review describes the role of NGF in the pathogenesis of leprosy and its correlations with different clinical forms of the disease and with the phenomena of regeneration and neural injury observed during infection. We discuss the involvement of NGF in the induction of neural damage and the pathophysiology of pain associated with peripheral neuropathy in leprosy. We also discuss the roles of immune factors in the evolution of this pathological process. Finally, we highlight avenues of investigation for future research to broaden our understanding of the role of NGF in the pathogenesis of leprosy. Our analysis of the literature indicates that NGF plays an important role in the evolution and outcome of Mycobacterium leprae infection. The findings described here highlight an important area of investigation, as leprosy is one of the main causes of infection in the peripheral nervous system.

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Mechanisms of disease

Cited by 19 publications

References 204 publications

Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation

Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation

α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling

Nerve Growth Factor and Pathogenesis of Leprosy: Review and Update

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