Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

Naruse, Keiko; Sato, Jun; Funakubo, Megumi; Hara, Masaki; Nakamura, Nobuhisa; Kobayashi, Yasuko; Kawanishi, Hideki; Shibata, Tsutomu; Kondo, Masaki; Himeno, Tatsuhito; Matsubara, Tatsuaki; Oiso, Yutaka; Nakamura, Jiro

doi:10.1371/journal.pone.0027458

Cited by 66 publications

(63 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Measurement of Nerve Conduction Velocity-The measurement of nerve conduction velocity (NCV) was performed as described previously (39,40). Briefly, mice were anesthetized with ketamine.…”

Section: Methodsmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.Painful neuropathy is one of the most common complications of diabetes. Patients with diabetes frequently exhibit a variety of aberrant sensations, including pain hypersensitivity (1, 2). Interrelation and mutual perpetuation of distinct aberrations of specific metabolic pathways cause painful diabetic neuropathy. Furthermore, painful diabetic neuropathy probably results from a combination of metabolic and immune factors (3, 4). Metabolic aberrations are thought to be early events in painful diabetic neuropathy, leading to biochemical, structural, and functional changes in the dorsal root ganglion (DRG) 3 and its nerve trunk (5, 6). Likewise, hyperglycemia-induced immune activation creates an inflammatory microenvironment surrounding the influenced nerves (7).The DRG is pathologically important in diabetes presenting with painful neuropathic states, which patients with early polyneuropathy commonly experience (8). Ganglionic sensory neurons are devoid of any special protection by the blood-brain or blood-nerve barrier and have higher metabolic requirements than the nerve trunk, which makes the ganglion a vulnerable site in the pathogenesis of diabetic neurop...

show abstract

“…Measurement of Nerve Conduction Velocity-The measurement of nerve conduction velocity (NCV) was performed as described previously (39,40). Briefly, mice were anesthetized with ketamine.…”

Section: Methodsmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…At the end of the experiment (day 14), rats were anesthetized and sciatic nerves were exposed for nerve blood flow detection using a laser Doppler flowmetry system (PeriFlux System 5000, Perimed AB, Sweden) according to procedure described by Naruse [24]. The blood flow was reported as arbitrary perfusion units.…”

Section: Nerve Blood Flow Detectionmentioning

confidence: 99%

Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway

Yao

Gong

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling pathway. Methods: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- γ/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT-qPCR) and Westernblot. Besides, PPAR-γ antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-γ and AMPK. Results: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-γ mediated the activation of AMPK and subsequent inhibition of ACC expression. Conclusion: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-γ/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN.

show abstract

“…However, recent studies have demonstrated that stem cells also have paracrine properties of angiogenic cytokines. For example, EPCs produce multiple angiogenic factors such as VEGF, insulin-like growth factor-1 (IGF-1), and fibroblast growth factor-2 (FGF-2) (40); other stem cells (e.g., BM-MNCs and MSCs) have also been shown to release angiogenic ligands (41,42). Angiogenic factors have been reported to play a crucial role in neovascularization (43).…”

Section: Painful Diabetic Peripheral Neuropathymentioning

confidence: 99%

Stem Cells for the Treatment of Neuropathic Pain

Xie¹,

Yue²,

Guan³

et al. 2017

J Anesth Perioper Med

View full text Add to dashboard Cite

Aim of review:Neuropathic pain induced by injury to the somatosensory system is a great clinical problem. Despite multiple therapeutic strategies, the medical community still faces a challenge to treat neuropathic pain in a complete and definitive way, since the pathogenesis of this hypersensitive state is very complex. Stem cell transplantation may be an important approach for the treatment of neuropathic pain. This article aimed to review important and illustrative results from recent stem cell studies under various neuropathic pain conditions and to interpret their clinical implications for stem cell transplantation. Methods: We reviewed recent articles and literatures about stem cells for the treatment of neuropathic pain, in order to identify the types of stem cells, delivery approaches and the advances of stem cells for the treatment of peripheral nerve injury induced neuropathic pain, painful diabetic peripheral neuropathy and spinal cord injury (SCI) induced chronic pain. Recent findings: Recently, the successful use of stem cell for the treatment of a diverse spectrum of diseases in animals has attracted more attentions from pain scientists. Accumulating evidence has shown that stem cell transplantation has a therapeutic effect on neuropathic pain. Stem cell transplantation can effectively relieve neuropathic pain under different pathological conditions. However, it is interesting to point out that peripheral neuropathic pain seems to be more responsive to stem cell therapy than SCI-induced chronic pain. Moreover, stem cell treatment does not always exert positive results in SCI-induced chronic pain (e.g. aggravating pain above the lesion spinal cord segment). Conclusion:The analgesic effect of stem cells depends on the capacity to offer a multipotent cellular source for replacing injured neural cells and delivering trophic factors to lesion sites. Stem cell researches should focus on both experimental and clinical studies of

show abstract

Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

Cited by 66 publications

References 50 publications

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway

Stem Cells for the Treatment of Neuropathic Pain

Contact Info

Product

Resources

About