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• W3212156225 abstract "Diabetic neuropathy (DN) is a common complication of diabetes, which is often associ-ated with a loss of peripheral sensitivity, but pain is also a common symptom and early manifestation of DN. Detailed mechanisms responsible for the neuropathy and the painful symptoms in diabetes are unknown. Earlier work suggested that methylglyoxal (MG), a highly reactive molecule formed during hyperglycemia, evokes pain by stimulating transient receptor potential A1 (TRPA1). MG is found in elevated concentrations in diabetes and its electrophilicity and reactivity can form protein adducts and promote formation of free radicals in the kidney and small C fibers, contributing to the pathogenesis and other complications of DN. TRPA1 is an ion channel expressed in small peripheral nerve fibers and can be activated by electrophilic compounds to transmit a noxious pain signal or may act as a mediator for peripheral nerve damage. However, MG occurs in lower concentrations in cells than those required to activate TRPA1 in experiments on isolated cells. It has been suggested that other electrophilic endogenous molecules and low pH, mimicking diabetic acidosis, might synergize with MG as a TRPA1 activator. The results of this study show that these factors do not sensitize the MG-induced TRPA1 activation. The majority of previous experimental studies of diabetic pain in animals have used the toxin streptozotocin (STZ) to destroy pancreatic beta cells in rodents. However, STZ stimulates TRPA1 in sensory neurons directly, which leads to rapid loss of pain sensitivity in mice. Therefore, the sensory behavioral profile and sensory neuron and nerve fiber properties in the novel diabetic Ins2+/Akita mouse model have been examined in the current studies, which carries a spontaneous loss-of-function mutation in the insu-lin gene, as well as the density of intraepidermal nerve fibers in diabetic neuropathy. Furthermore, the role of TRPA1 in the development of sensory neuropathy was examined in Ins2+/Akita/Trpa1-/- mice, to avoid the complications of STZ. The results show that Ins2+/Akita mice are less sensitive to mechanical and thermal stimuli in behavioral assays and that isolated sensory neurons from Ins2+/Akita mice display a loss of temperature sensitivity. Recordings of skin-nerve preparations show a reduced firing pattern of action potentials in the Ins2+/Akita mouse and anatomically there is a great loss of in-traepidermal nerve fibers in skin sections compared to wild-type littermates. These findings accurately translate symptoms of polymodal hyposensitivity that are found in patients. In order to investigate the possible involvement of TRPA1 in DN, Ins2+/Akita mice were crossed with Trpa1-/- animals and sensory functions were tested behaviorally and in vitro compared to Ins2+/Akita mice. Behaviorally, diabetic animals that lack TRPA1 showed decreased sensitivity to heat and cold in comparison to Ins2+/Akita mice but dis-played no differences in the withdrawal threshold to mechanical stimuli. Results of the investigation of skin sections in the crossbred phenotype Ins2+/Akita/Trpa1-/- indicate that inactivation of TRPA1 protects IENFs from the damage usually observed in diabetes. Moreover, [Ca2+]i measurements on DRG neurons revealed a significant increase in thresholds and a decrease in amplitudes to heat stimuli in Ins2+/Akita/Trpa1-/- mice as well as a marginally but significant decrease in cold evoked response amplitudes. Taken together, these data suggest that knocking out TRPA1 in diabetic Ins2+/Akita animals leads to a loss of sensitivity to noxious heat as well as a normal density of IENFs in the paw skin in comparison to the Ins2+/Akita phenotype. However, in dorsal rot ganglia (DRG) neuron level, data suggests no reduced number of cold sensitivities in Trpa1-/-, consistent with earlier studies showing that TRPA1 does not itself respond to cold tem-peratures (Jordt et al., 2004a; Bautista et al., 2006). The mechanisms behind these results are subject of ongoing investigations.Another part of this dissertation investigated the effect of drugs that are or have been used for the treatment of type 2 diabetes on TRPA1. Endogenous electrophilic TRPA1 agonists such as 15-deoxy-Δ12,14-prostaglandin (15d-PGJ2) and 4-hydroxynonenal (4-HNE) are also ligands of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Thiazolidinedione drugs (glitazones), that act as insulin sensitizers through PPARγ, have been reported to evoke some sensory side effects consistent with an ac-tion on sensory neurons. To test the hypothesis that glitazones exert their actions via activation of TRPA1, this part of the study investigated measurements of [Ca2+]i in different cell lines as well as DRG neurons to test the effect of different PPARγ ligands on TRPA1. Data confirmed the tested compounds to activate TRPA1 potently by binding to the channel non-covalently and independently of cysteine involvement. Electrophysio-logical patch clamp experiments determined TRPA1 channel properties upon stimula-tion with troglitazone and showed robust inward currents. Results of in vivo studies show an increased pain behaviour upon paw injection of troglitazone in mice, as well as reduced pain behavior in TRPA1 knockout mice. Overall, this approach discovered a group of novel non-covalently binding compounds to the ion-channel TRPA1 and might explain sensory side effects of some glitazone drugs. The apparent potency and selec-tivity of these novel TRPA1 agonists compare favorably with previously identified ligands and may therefore be exploited as pharmacological tools for mechanistic studies." @default.
• W3212156225 created "2021-11-22" @default.
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• W3212156225 date "2019-01-01" @default.
• W3212156225 modified "2023-09-24" @default.
• W3212156225 title "Transient Receptor Potential Ankyrin 1 in Diabetes" @default.
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