Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes

Griggs, Ryan B.; Santos, Diogo F. S.; Laird, D.; Doolen, Suzanne; Donahue, Renée R.; Wessel, Caitlin R.; Fu, Weisi; Sinha, Ghanshyam P.; Wang, Pingyuan; Zhou, Jia; Brings, Sebastian; Fleming, Thomas; Nawroth, Peter P.; Susuki, Keiichiro; Taylor, Bradley K.

doi:10.1016/j.nbd.2019.02.019

Cited by 30 publications

(36 citation statements)

References 75 publications

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“…This is consistent with 8-16% AIS shortening in the prefrontal cortex of type 2 diabetic db/db mice at 10 weeks of age with lack of apoptotic cell death (Yermakov et al, 2018). Methylglyoxal elevation leads to accumulation of MG-H1 in patients with type 2 diabetes (Schalkwijk and Stehouwer, 2020) and both methylglyoxal (Bierhaus et al, 2012) and MG-H1 (Griggs et al, 2019) are elevated in db/db mice. Adding methylglyoxal to culture media increased MG-H1 in vitro (Fig.…”

Section: Methylglyoxal Mediates Ais Shorteningsupporting

confidence: 79%

“…6,7). Importantly, methylglyoxal is increased in db/db mice (Bierhaus et al, 2012;Griggs et al, 2019) with cognitive impairment and shortened AIS in the prefrontal cortex and hippocampus (Yermakov et al, 2018(Yermakov et al, , 2019, suggesting a connection between methylglyoxal, type 2 diabetes, AIS shortening, and cognitive impairment. Strengthening a mechanistic link between subtle changes in AIS geometry and CNS dysfunction, pharmacological treatment of nerve-injured mice simultaneously alleviated both AIS shortening and cognitive impairment (Shiers et al, 2018).…”

Section: Ais Shortening May Contribute To Cognitive Impairment and Neuronal Network Dysfunctionmentioning

confidence: 97%

“…The copyright holder for this preprint (which this version posted May 11, 2021. ; https://doi.org/10.1101/2021.05.10.443439 doi: bioRxiv preprint Griggs et al 13 of methylglyoxal in rodents and humans in vivo (Bierhaus et al, 2012;Sveen et al, 2013;Griggs et al, 2016Griggs et al, , 2019Huang et al, 2016) and increasing the glucose concentration in culture media from 5 to 20 mM results in a 2-fold intracellular and 5-fold extracellular increase of methylglyoxal in vitro (Irshad et al, 2019). Thus, we speculated that accumulation of methylglyoxal caused by the substantial increase of glucose may contribute to mild AIS shortening.…”

Section: Glucose Does Not Appreciably Change Ais Lengthmentioning

confidence: 99%

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The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Griggs

et al. 2021

Preprint

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Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or position along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. The key type 2 diabetes-related factor that alters AIS geometry is unknown. Here, we tested whether modifying the levels of insulin, glucose, or methylglyoxal, a reactive carbonyl species that is a metabolite of glucose, changes AIS geometry in mature cultures of dissociated postnatal mouse cortex using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification appreciably altered AIS length. Elevation of methylglyoxal produced reversible AIS shortening without cell death. Multi-electrode array recordings revealed a biphasic effect of methylglyoxal on neuronal network activity: an immediate, transient ~300% increase in spiking and bursting rates was followed by a ~20% reduction from baseline at 3 h. AIS length was unchanged at 0.5 h or 3 h after adding methylglyoxal, whereas development of AIS shortening at 24 h was associated with restoration of spiking to baseline levels. Immunostaining for the excitatory neuron marker Ca2+/calmodulin-dependent protein kinase II alpha revealed AIS shortening in both excitatory and inhibitory neuron populations. This suggests that complex mechanisms maintain neuronal network operation after acute exposure to the disease metabolite methylglyoxal. Importantly, our results indicate that methylglyoxal could be a key mediator of AIS shortening during type 2 diabetes.

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Section: Methylglyoxal Mediates Ais Shorteningsupporting

confidence: 79%

Section: Ais Shortening May Contribute To Cognitive Impairment and Neuronal Network Dysfunctionmentioning

confidence: 97%

Section: Glucose Does Not Appreciably Change Ais Lengthmentioning

confidence: 99%

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The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Griggs

et al. 2021

Preprint

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“…MGO enhanced Ca 2þ responses of sensory neurons. Griggs et al 163,164 MGO sensitizes lamina II SDH neurons of db/db mice via the TRPA1-AC1-Epac pathway. Spinal neurons demonstrate enhanced Ca 2þ responses upon stimulation.…”

Section: Peripheral Nerve Injury Painmentioning

confidence: 99%

“…Methylglyoxal (MGO), a common metabolite present in high concentrations (up to 5 mM) in the plasma of diabetic patients, is known to induce heat, mechanical, and affective pain in DM by activating peripheral and spinal TRPA1 channels. [161][162][163][164][165][166] Recently, the involvement of the UPR in MGO-induced pain hypersensitivity was postulated. 165 Intraplantar injection of MGO induces rapid and transient mechanical hypersensitivity in rats and mice that is associated with increased phosphorylation of PERK and eIF2a, particularly in the IB4þ nociceptors.…”

Section: Peripheral Nerve Injury Painmentioning

confidence: 99%

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

et al. 2020

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Chronic pain is a debilitating condition that affects roughly a third to a half of the world’s population. Despite its substantial effect on society, treatment for chronic pain is modest, at best, notwithstanding its side effects. Hence, novel therapeutics are direly needed. Emerging evidence suggests that calcium plays an integral role in mediating neuronal plasticity that underlies sensitization observed in chronic pain states. The endoplasmic reticulum and the mitochondria are the largest calcium repositories in a cell. Here, we review how stressors, like accumulation of misfolded proteins and oxidative stress, influence endoplasmic reticulum and mitochondria function and contribute to chronic pain. We further examine the shuttling of calcium across the mitochondrial-associated membrane as a mechanism of cross-talk between the endoplasmic reticulum and the mitochondria. In addition, we discuss how endoplasmic reticulum stress, mitochondrial impairment, and calcium dyshomeostasis are implicated in various models of neuropathic pain. We propose a novel framework of endoplasmic reticulum–mitochondria signaling in mediating pain hypersensitivity. These observations require further investigation in order to develop novel therapies for chronic pain.

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Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

Wang

2023

ChemMedChem

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Transient receptor potential (TRP) channels are cation channels that regulate key physiological and pathological processes in response to a broad range of stimuli. Moreover, they systemically regulate the release of hormones, metabolic homeostasis, and complications of diabetes, which positions them as promising therapeutic targets to combat metabolic disorders. Nevertheless, there are significant challenges in the design of TRP ligands with high potency and durability. Herein we summarize the four challenges as hydrophobicity, selectivity, mono‐target therapy, and interspecies discrepancy. We present 1134 TRP ligands with diversified modes of TRP‐ligand interaction and provide a detailed discussion of the latest strategies, especially cryogenic electron microscopy (cryo‐EM) and computational methods. We propose solutions to address the challenges with a critical analysis of advances in membrane partitioning, polypharmacology, biased agonism, and biochemical screening of transcriptional modulators. They are fueled by the breakthrough from cryo‐EM, chemoinformatics and bioinformatics. The discussion is aimed to shed new light on designing next‐generation drugs to treat obesity, diabetes and its complications, with optimal hydrophobicity, higher mode selectivity, multi‐targeting and consistent activities between human and rodents.

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Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes

Abstract: Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal

Cited by 30 publications

References 75 publications

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

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