Development Of Painful Diabetic Neuropathy Research Articles

Attenuation of Streptozotocin-Induced Diabetic Neuropathic Allodynia by Flavone Derivative Through Modulation of GABA-ergic Mechanisms and Endogenous Biomarkers.

Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2β2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF.

18-LB: Histone Modifications and CXCR4 Chemokine Receptor Signaling in Hyperglycemic DRG Neurons

Diabetes is a global epidemic that affects many individuals throughout the world and presents a major health challenge to society. The state of chronic hyperglycemia can have many devastating secondary effects including neuropathy, nephropathy, retinopathy, and cardiovascular disease. The diabetes mediated neuropathic complications are a substantial burden to society due to a lack of therapies as well as decreased quality of life and increased mortality. Approximately 50% diabetic patients suffer from neuropathy which is described as alterations of pain sensation in the feet that leads to increased risk for infection, ulcers, non-traumatic amputations and ultimately death. Painful diabetic neuropathy (PDN) affects individuals within 20 years after the onset of disease, mediated by the gradual degeneration of axonal structures in sensory neurons. It is known that hyperglycemia is involved in the pathogenesis of this disease, but specific mechanisms are not well understood. Previous studies have shown that inflammation and epigenetic changes may play a role in the development of PDN. Specifically, it has been demonstrated that the chemokine receptor CXCR4 is involved in inflammation relating to PDN while the histone deacetylases HDAC4 and HDAC6 are involved in mediating the epigenetic changes in sensory neurons under hyperglycemic conditions. This study investigated the alterations in inflammatory mediators and epigenetic changes in sensory neurons under normal glucose and high glucose environments. Western blot and immunocytochemistry techniques were used to measure any differences in these two conditions. The results from this study demonstrated an upregulation of histone deacetylases and CXCR4 in hyperglycemic conditions, while histone acetyltransferases were shown to be down-regulated in high glucose environments. These findings may lead to potential therapeutic targets for PDN since it is a life altering condition with minimal treatment options available today. Disclosure N. Satterfield: None. V. Thakur: None. M. Chattopadhyay: None. Funding Texas Tech University Health Sciences Center El Paso (183381SEED)

Current Strategies for the Management of Painful Diabetic Neuropathy.

The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.

SIRT1 Activation by Polydatin Alleviates Oxidative Damage and Elevates Mitochondrial Biogenesis in Experimental Diabetic Neuropathy.

Mitochondrial dysfunction has been implicated as a one of the major factors linked to the development of painful diabetic neuropathy (DN). Several studies have demonstrated that sirtuin (SIRT1) activation recuperates nerve function by activating mitochondrial biogenesis. Polydatin, a resveratrol glycoside, has been explored to improve mitochondrial function via SIRT1 activation. However, the neuroprotective effects of polydatin in DN remain elusive. In this study, polydatin (25 and 50mg/kg, oral) was administered for last 2weeks of 8-week study to diabetic Sprague-Dawley rats weighing 250-300g (post 6-weeks of streptozotocin 55mg/kg, intraperitoneal). Treatment with polydatin significantly attenuated mechanical and thermal hyperalgesia in diabetic rats. Treated diabetic rats also showed improvement in motor/sensory nerve conduction velocities and nerve blood flow. For in vitro studies, Neuro2a cells were exposed to high-glucose (30mM) condition to simulate short-term hyperglycemia. Polydatin was evaluated for its role in SIRT1 and Nrf2 activation at a dose of 5, 10, and 20µM concentrations. Polydatin exposure normalized the mitochondrial superoxides, membrane potentials and improved neurite outgrowth in high-glucose-exposed Neuro2a cells. Increased SIRT1 activation by polydatin resulted in peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis. SIRT1 activation also facilitated Nrf2-directed antioxidant signaling. Study results inferred that decline in mitochondrial biogenesis and oxidative function in diabetic rats and high-glucose-exposed Neuro2a cells, could be counteracted by polydatin administration, postulated via enhancing SIRT1 and Nrf2 axis.

Diabetic neuropathy: A focus on small fibres.

Diabetic peripheral neuropathy (DPN) is diagnosed too late, which contrasts with our approach for diabetic retinopathy and nephropathy, where incipient disease is detected early enabling timely treatment. The 10-g monofilament and a foot exam are the commonly used methods for screening diabetic neuropathy, but this primarily identifies moderate to severe diabetic neuropathy. Small fibres are damaged early and are associated with the development of painful diabetic neuropathy, foot ulceration, and Charcot foot. Tests of small fibre damage include thermal thresholds, microneurography, evoked potentials, sudomotor function, laser Doppler flare, skin biopsy, and corneal confocal microscopy. Measures of small fibre damage and repair may be key to the assessment of efficacy in clinical trials of disease modifying therapies for diabetic neuropathy.

Increased Nociceptive Responses in Streptozotocin-Induced Diabetic Rats and the Related Expression of Spinal NR2B Subunit of N-Methyl-D-Aspartate Receptors.

BackgroundThis study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli.MethodsThirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed.ResultsDM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B.ConclusionWe suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

Quantitative sensory testing in type 1 diabetic patients with painful and painless diabetic neuropathy

The mechanism underlying the development of painful diabetic neuropathy (DN) is unknown. The aim of this study was to compare quantitative sensory testing (QST) characteristics of patients with painful and painless DN and to correlate QST measures with DN pain. Fifty type 1 diabetic patients with DN (30 with painful DN and 20 with painless DN) and 32 age-matched non-diabetic controls were included in this study. For all patients and controls, a detailed assessment of DN was performed which comprised McGill visual analogue scale (McGill VAS) for pain, neuropathy symptom profile and neuropathy disability score (NDS), quantitative sensory testing in form of cold, warm and vibration perception thresholds, nerve conduction studies (NCS), deep-breathing hear rate variability and Neuropad staining scores. Measures of QST, NCS and DB-HRV were correlated with McGill VAS for pain. There were no significant differences in cold, warm and vibration perception thresholds, NCS, DB-HRV and Neuropad scores between patients with painful and painless DN. Cold (r=-0.57, P=0.005), warm (r=0.47, P=0.026) and DB-HRV (r=0.50, P=0.023), however, correlated significantly with McGill VAS scores of pain. In conclusion, Quantitative sensory testing is a helpful tool to identify small nerve fibres damage of DN, correlates with pain intensity but cannot differentiate between painful and painless DN. Both central and peripheral neural injury could be implicated in the genesis of DN pain.

Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8 weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N6-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of painful diabetic neuropathy. Moreover, central and peripheral activation of A1R significantly improved mechanical sensitivity, warranting further investigation into this important antinociceptive pathway as a novel therapeutic option for the treatment of painful diabetic neuropathy.

Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia

BackgroundLangerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear.MethodsThe db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor.ResultsCD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-α-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-α expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia.ConclusionsOur data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN.

Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in ob/ob Mice

OBJECTIVEMorbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy.RESEARCH DESIGN AND METHODSIn vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice.RESULTSWe found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, α1H (Cav3.2), was most strongly affected. Moreover, (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice.CONCLUSIONSOur results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy.