scholarly journals N-Acetylcysteine Attenuates Hyperalgesia in Rats with Diabetic Neuropathic Pain: Role of Oxidative Stress and Inflammatory Mediators and CXCR4

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Sisi Li ◽  
Xuying Li ◽  
Xiangbin Xie ◽  
Xiao Wei ◽  
Cong Yu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Prefrontal Cortex ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Diabetic Neuropathic Pain ◽  
Withdrawal Threshold ◽  
Sprague Dawley Rats ◽  
Therapeutic Value ◽  
Tnf Α

Objectives. CXCR4 plays critical roles in the development of diabetic neuropathic pain (DNP) in rats, and its mechanism is unknown. This study was aimed at evaluating the potential therapeutic value of the antioxidant N-acetylcysteine (NAC) against DNP in rats and how CXCR4 participates in the formation of DNP. Methods. Control or streptozotocin- (STZ-) induced diabetic Sprague-Dawley rats received vehicle or NAC for four weeks starting one week after STZ injection. Von Frey and Hargreaves Apparatus were used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia. CXCR4, p-CXCR4, interleukin- (IL-) 6, and tumor necrosis factor- (TNF-) α in the spinal cord and the prefrontal cortex were detected by western blotting. Plasma IL-6, TNF-α, superoxide dismutase- (SOD-) 1, SOD-2, and lipid peroxidation products malondialdehyde (MDA) and 15-F2t-Isoprostane were detected by ELISA. Results. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced in diabetic rats compared to control rats that were concomitant with significant increases of CXCR4, p-CXCR4, IL-6, and TNF-α protein expressions in the spinal cord and prefrontal cortex. The treatment with NAC decreased the IL-6 and TNF-α protein expression and further increased CXCR4 and p-CXCR4 in the spinal cord and the cortex of diabetic rats that were accompanied with enhancement of PWT and PWL. NAC also significantly attenuated or reverted the increases of plasma IL-6, TNF-α, SOD-1, SOD-2, MDA, and 15-F2t-Isoprostane in diabetic rats. Conclusion. It is concluded that NAC treatment could effectively alleviate DNP and that induction of CXCR4 and p-CXCR4 may represent a mechanism whereby NAC attenuates DNP.

scholarly journals EGCG Prevents the Loss of Pontine Noradrenergic Neurons Induced by Diabetes: A Role in Diabetic Neuropathic Pain

2012 ◽  
Vol 18 (S5) ◽  
pp. 5-6 ◽  
Author(s):  
Carla Morgado ◽  
João Silva ◽  
André Miranda ◽  
Patrícia Pereira-Terra ◽  
Diogo Raposo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Diabetic Rats ◽  
Pain Modulation ◽  
Diabetic Patients ◽  
Spontaneous Pain ◽  
Noradrenergic Neurons ◽  
Diabetic Neuropathic Pain ◽  
Descending Pain Modulation ◽  
Pain Responses

Diabetes is a major health problem with an alarming increasing prevalence, and is the most frequent cause of neuropathy worldwide. Neuropathy affects 50–60% of diabetic patients, being a major life-quality impairment for a quarter of these patients. Diabetic neuropathic pain (DNP) is characterized by spontaneous pain, mechanical hyperalgesia and tactile allodynia and is accompanied by functional and neurochemical changes at the peripheral nerves, spinal cord and supraspinal pain control areas. Regarding the effects of diabetic neuropathy in the central somatossensory system, it was shown that streptozotocin (STZ)-diabetic rats present spontaneous hyperactivity and hyperexcitability of spinal nociceptive neurons, which may be subserving the exacerbated pain responses. The spinal functional changes and pain may be due to increased peripheral input(2), changes in spinal nociceptive modulatory mechanisms and altered supraspinal descending pain modulation. Noradrenergic descending pain modulation seems to be impaired since STZ-diabetic rats present decreased numbers of noradrenergic neurons at the A5 and A7 pontine cell groups, along with lower levels of noradrenaline at the spinal cord and higher behavioral responses to pain. This is consistent with the strong noradrenergic projection from A5 and A7 neurons to the spinal dorsal horn and the modulation of nociceptive transmission by local release of noradrenaline. The mechanisms underlying the decrease in noradrenergic neurons in the brainstem during diabetes remain unclear. Our recent findings that diabetes induces oxidative stress damage in neurons from those areas, lead us to hypothesize that it may contribute to their loss. Thereafter, with the present study we aimed to evaluate the effects of Epigallocathechin Gallate (EGCG), a potent antioxidant present in green tea, on spinal noradrenaline levels, on A5 and A7 noradrenergic neurons and on behavioral pain responses of STZ-diabetic rats.

Pterostilbene Ameliorates Nephropathy Injury in Streptozotocin-Induced Diabetic Rats

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 71-80 ◽  
Author(s):  
Ying Zhang ◽  
Shaoyu Ren ◽  
Ying Ji ◽  
Yafeng Liang
Keyword(s):  
High Fat Diet ◽  
Nuclear Factor Κb ◽  
Diabetic Rats ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Necrosis Factor ◽  
Different Doses

Background: Our study investigated the therapeutic role and potential mechanisms of pterostilbene (PS) in diabetic nephropathy (DN) rats. Methods: DN models were established by high-fat diet after streptozotocin injection. A total of 50 Sprague-Dawley rats were randomly divided into control, DN, PS-treated groups (PS-H, PS-M, PS-L). PS was administered to rats by gavage for 8 weeks at 3 different doses (25, 10, and 5 mg/kg/day). The levels of oxidative stress activity (superoxide dismutase [SOD], malondialdehyde [MDA], glutathione peroxidase [GSH-PX]) and inflammatory factors (tumor necrosis factor [TNF]-α, interleukin (IL)-6, IL-1β, monocyte chemoattractant factor [MCP]-1) were detected by ­ELISA. TGF-β, Smad1, and fibronectin (FN) were measured through immunohistochemistry. The relative expressions of phospho-IκBα/IκBα, phospho-IκB kinases (IKK)β/IKKβ, phospho-nuclear factor-κB (NF-κB) p65/NF-κB p65 were detected by western blot. Results: Compared with DN group, the levels of TNF-α, IL-6, IL-1β, and MCP-1 were decreased in the PS-H group (p < 0.05). Meanwhile, the levels of SOD, MDA, GSH-PX improved in kidney and serum in PS-H groups (p< 0.05). PS also significantly decreased the level of phospho-NF-κB p65 and increased the levels of phospho- IKKβ and phospho-Iκ-Bα (p < 0.05). The results showed that PS treatment decreased TGF-β, Smad1, and FN expressions. Conclusion: PS had potential therapeutic effects on DN, which may be related to the regulation of NF-κB pathway.

scholarly journals Protective Effect ofAgaricus brasiliensison STZ-Induced Diabetic Neuropathic Pain in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Weifeng Ji ◽  
Haiying Huang ◽  
Ji Chao ◽  
Wuchao Lu ◽  
Jianyou Guo
Keyword(s):  
Body Weight ◽  
Neuropathic Pain ◽  
Neuroprotective Effect ◽  
Serum Glucose ◽  
Diabetic Rats ◽  
Dependent Manner ◽  
Diabetic Neuropathic Pain ◽  
Laboratory Rats ◽  
Withdrawal Threshold ◽  
Behavioral Parameters

Objective. The present investigation examined the neuroprotective effect ofAgaricus brasiliensis(AbS) against STZ-induced diabetic neuropathic pain in laboratory rats. STZ-induced diabetic rats were administered orally with AbS. Body weight, serum glucose, and behavioral parameters were measured before and at the end of the experiment to see the effect of AbS on these parameters. After 6 weeks of treatments, all animals were sacrificed to study various biochemical parameters. Treatment with AbS 80 mg/kg in diabetic animals showed significant increase in body weight, pain threshold, and paw withdrawal threshold and significant decrease in serum glucose, LPO and NO level, Na-K-ATPase level, and TNF-αand IL-1βlevel as compared to vehicle treated diabetic animals in dose and time dependent manner. AbS can offer pain relief in PDN. This may be of potential benefit in clinical practice for the management of diabetic neuropathy.

Peripheral Nerve Injury Sensitizes the Response to Visceral Distension but Not Its Inhibition by the Antidepressant Milnacipran

2004 ◽  
Vol 100 (3) ◽  
pp. 671-675 ◽  
Author(s):  
Sang-Wook Shin ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Visceral Pain ◽  
Spinal Nerve ◽  
Reflex Response ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Withdrawal Threshold ◽  
Sprague Dawley Rats ◽  
Lumbar Spinal

Background Manipulations that cause hypersensitivity to visceral stimuli have been shown to also result in hypersensitivity to somatic stimuli coming from convergent dermatomes, but the converse has not been examined. The authors tested whether lumbar spinal nerve ligation in rats, a common model of neuropathic pain that results in hypersensitivity to somatic stimuli, also leads to hypersensitivity to visceral stimuli coming from convergent dermatomes and whether pharmacology of inhibition differed between these two sensory modalities. Methods Female Sprague-Dawley rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Animals received either intrathecal saline or milnacipran (0.1-3 microg), and withdrawal thresholds to mechanical testing in the left hind paw, using von Frey filaments, and visceral testing, using balloon colorectal distension, were determined. Results Nerve ligation resulted in decreases in threshold to withdrawal to somatic mechanical stimulation (from 13 +/- 1.8 g to 2.7 +/- 0.7 g) and also in decreases in threshold to reflex response to visceral stimulation (from 60 mmHg to 40 mmHg). Intrathecal milnacipran increased withdrawal threshold to somatic stimulation in a dose-dependent manner but failed to alter the response to noxious visceral stimulation. Conclusions Injury of nerves innervating somatic structures enhances nociception from stimulation of viscera with convergent input from nearby dermatomes, suggesting that somatic neuropathic pain could be accompanied by an increased likelihood of visceral pain. Lack of efficacy of the antidepressant milnacipran against visceral stimuli suggests that visceral hypersensitivity may not share the same pharmacology of inhibition as somatic hypersensitivity after nerve injury.

scholarly journals Tetrahydropalmatinee alleviates diabetic neuropathic pain by inhibiting the inflammation via p38-MAPK signaling pathway in microglia

2021 ◽  
Author(s):  
Lianzhi Cheng ◽  
Junlong Ma ◽  
Aijuan Jiang ◽  
Kai Cheng ◽  
Fanjing Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Inflammatory Factors ◽  
Specific Marker ◽  
Diabetic Neuropathic Pain ◽  
Tnf Α

Abstract Object: Exploring the effect of Tetrahydropalmatine (THP) on diabetic neuropathic pain (DNP) and its possible mechanism. Methods: The type 2 diabetic (T2DM) rat models were prepared by high-fat and high-sugar feeding combined with a single small-dose intraperitoneal injection of streptozotocin (STZ). When the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) of T2DM model rats decreased to less than 85% which were judged as DNP-bearing rats. After treatment with or without THP, the protein expression of hypertonic glycerol reactive kinase (p38), phosphorylated hypertonic glycerol-responsive kinase (p-p38) and OX42 (a specific marker of microglia) were detected by Western Blot and and the mRNA content of p38 and OX42 were detected by qRT-PCR. The expression of pro-inflammatory factors IL-1β, IL-6, TNF-α, as well as chemotactic factors and their receptors including CXCL1, CXCR2, CCL2 and CCR2 in spinal tissues were detected by ELISA. Serum FINS and GSP content were also detected by ELISA. Double-label immunofluorescence were used to observe the expression of OX42 and p-p38 in the spinal dorsal horn. Results: Results showed that THP inhibited microglial activation of spinal in DNP rats. And after THP intervention, the MWT and TWL of DNP rats decreased, the expression of p38, p-p38 and OX42 in the spinal cord tissues of rats was significantly reduced while the mRNA of p38 and OX42 also reduced. The expression of IL-1β, IL-6, TNF-α, CXCL1, CXCR2, CCL2 and CCR2 in the spinal cord tissues of rats was significantly reduced (P < 0.01). At the same time, THP significantly proved FINS, but did not affect FBG and GSP in DNP rats. Conclusions: THP significantly alleviates pain symptoms in DNP rats, and this effect may be achieved by inhibiting the inflammatory response caused by the activation of microglia mediated by the p38-MAPK signaling pathway.

scholarly journals Sodium Hydrosulfide Relieves Neuropathic Pain in Chronic Constriction Injured Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jian-qing Lin ◽  
Hui-qin Luo ◽  
Cai-zhu Lin ◽  
Jin-zhuan Chen ◽  
Xian-zhong Lin
Keyword(s):  
Neuropathic Pain ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Sodium Hydrosulfide ◽  
Withdrawal Threshold ◽  
Molecular Events ◽  
Relieve Pain ◽  
Sprague Dawley Rats ◽  
Clinical Potential ◽  
Dose Dependent

Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain (NPP). Channel protein pCREB of that activity has been shown to mitigate the onset of associated molecular events in the nervous system, and sodium hydrosulfide (NaHS) could inhibit the expression of pCREB. However, whether NaHS could relieve the pain, it needs further experimental research. Furthermore, the clinical potential that NaHS was used to relieve pain was limited so it would be required. To address these issues, the rats of sciatic nerve chronic constriction injury (CCI) were given intraperitoneal injection of NaHS containing hydrogen sulfide (H2S). The experimental results showed that NaHS inhibited the reduction of paw withdrawal thermal latency (PWTL), mechanical withdrawal threshold (MWT), and the level of pCREB in CCI rats in a dose-dependent manner and they were greatly decreased in NaHSMgroup (P< 0.05). NaHS alleviates chronic neuropathic pain by inhibiting expression of pCREB in the spinal cord of Sprague-Dawley rats.

scholarly journals Acupuncture attenuates the development of diabetic peripheral neuralgia by regulating P2X4 expression and inflammation in rat spinal microglia

2020 ◽  
Vol 70 (1) ◽  
Author(s):  
He-yong Tang ◽  
Fan-jing Wang ◽  
Jun-long Ma ◽  
Hao Wang ◽  
Guo-ming Shen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Peripheral Neuropathy ◽  
Single Injection ◽  
Underlying Mechanism ◽  
Diabetic Rats ◽  
Inflammatory Factors ◽  
Once Daily ◽  
Withdrawal Threshold ◽  
Withdrawal Latency ◽  
Tnf Α

Abstract Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication of diabetes. The purpose of this study is to find the underlying mechanism for the effects of acupuncture in DPN rats. Rats were rendered diabetic with a single injection of 35 mg/kg streptozotocin (STZ). These STZ-diabetic rats were treated with acupuncture for 20 min once daily. The therapeutic efficacy of acupuncture was assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) evaluations. After 14 days treatment, acupuncture markedly reduced the pathological injury in STZ-diabetic rats. Moreover, it significantly down-regulated P2X4 and OX42 expression along with the reduced levels of inflammatory factors (CXCR3, TNF-α, IL-1β, IL-6), GSP and lipid metabolisms in the spinal cord of the DPN rats. Acupuncture could relieve DPN in rats by regulating P2X4 expression and inflammation in spinal microglia.

scholarly journals Hydrogen-Rich Saline Activated Autophagy via HIF-1α Pathways in Neuropathic Pain Model

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Huixing Wang ◽  
Xiaodong Huo ◽  
Hongguang Chen ◽  
Bo Li ◽  
Jingzhi Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Intractable Pain ◽  
Sprague Dawley ◽  
Pain Model ◽  
Withdrawal Threshold ◽  
Downstream Target ◽  
Cord Injury ◽  
Neuropathic Pain Model ◽  
Regulatory Effects

Background. Neuropathic pain is a chronic and intractable pain, with very few effective analgesics. It involves an impaired cell autophagy process. Hydrogen-rich saline (HRS) reportedly reduces allodynia and hyperalgesia in a neuropathic pain model; however, it is unknown whether these effects involve autophagy induction. Methods. We investigated the relationship between HRS and cell autophagy in a neuropathic pain model generated by chronic constriction injury (CCI) in Sprague–Dawley rats. Rats received an intraperitoneal injection of HRS (10 mL/kg daily, from 1 day before until 14 days after CCI), 3MA (autophagy inhibitor), 2ME2 (HIF-1α inhibitor), or EDHB (HIF-1α agonist). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were tested 1 day before and 1, 3, 7, 10, and 14 days after the operation. HIF-1α and cell autophagy markers in the spinal cord were evaluated by western blotting and real-time PCR assays at 14 days after CCI. Autophagosomes with double membranes were identified by transmission electron microscopy. Results. CCI caused behavioral hypersensitivity to mechanical and thermal stimulation in the hind-paw of the injured side. HRS improved MWT and TWL, activated autophagy, and increased autophagosomes and autolysosomes in CCI rats. 3-MA aggravated hyperalgesia and allodynia and suppressed autophagy, while EDHB attenuated hyperalgesia and activated the autophagy procedure and the HIF-1α downstream target gene BNIP3. HIF-1α inhibitors reversed the regulatory effects of HRS on autophagy in CCI rats at 14 days after spinal cord injury. Conclusion. HRS reduced mechanical hyperalgesia and activation of cell autophagy in neuropathic pain through a HIF1-dependent pathway.

scholarly journals TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats

2022 ◽  
Vol 23 (1) ◽  
pp. 506
Author(s):  
Jo Young Son ◽  
Jin Sook Ju ◽  
Yu Mi Kim ◽  
Dong Kuk Ahn
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Inflammatory Responses ◽  
Inferior Alveolar Nerve ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Factor Α ◽  
Inferior Alveolar Nerve Injury

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.

Modulation of Nerve Injury–induced HDAC4 Cytoplasmic Retention Contributes to Neuropathic Pain in Rats

2015 ◽  
Vol 123 (1) ◽  
pp. 199-212 ◽  
Author(s):  
Tzer-Bin Lin ◽  
Ming-Chun Hsieh ◽  
Cheng-Yuan Lai ◽  
Jen-Kun Cheng ◽  
Yat-Pang Chau ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Histone Deacetylases ◽  
Spinal Nerve ◽  
Sprague Dawley ◽  
Withdrawal Threshold ◽  
Dorsal Horn Neurons ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Interfering Rna

Abstract Background: The histone deacetylases (HDACs) have been implicated in pain hypersensitivity. This study investigated the potential involvement of an HDAC4-related mechanism in the spinal nerve ligation (SNL)-induced nociceptive hypersensitivity. Methods: The left L5 to L6 spinal nerves of 627 adult male Sprague–Dawley rats were surgically ligated. The withdrawal threshold of hind paws and the abundances, cellular location, and interactions of proteins in the dorsal horn were assayed before and after surgery. The 14-3-3β-targeting small-interfering RNA, a serum- and glucocorticoid-inducible kinase 1 (SGK1) antagonist, or an HDAC inhibitor was spinally injected to elucidate the role of 14-3-3β, SGK1, and HDAC4. Results: Without affecting the HDAC4 level, SNL provoked SGK1 phosphorylation (mean ± SEM from 0.24 ± 0.02 to 0.78 ± 0.06 at day 7, n = 6), HDAC4 phosphorylation (from 0.38 ± 0.03 to 0.72 ± 0.06 at day 7, n = 6), 14-3-3β expression (from 0.53 ± 0.09 to 0.88 ± 0.09 at day 7, n = 6), cytoplasmic HDAC4 retention (from 1.18 ± 0.16 to 1.92 ± 0.11 at day 7, n = 6), and HDAC4-14-3-3β coupling (approximately 2.4-fold) in the ipsilateral dorsal horn in association with behavioral allodynia. Knockdown of spinal 14-3-3β expression prevented the SNL-provoked HDAC4 retention (from 1.89 ± 0.15 to 1.32 ± 0.08 at day 7, n = 6), HDAC4-14-3-3β coupling (approximately 0.6-fold above SNL 7D), and behavioral allodynia (from 0.16 ± 0.3 to 6 ± 1.78 at day 7, n = 7), but not SGK1 (from 0.78 ± 0.06 to 0.71 ± 0.04 at day 7, n = 6) or HDAC4 (from 0.75 ± 0.15 to 0.68 ± 0.11 at day 7, n = 6) phosphorylation. Conclusion: Neuropathic pain maintenance involves the spinal SGK1 activation–dependent HDAC4 phosphorylation and its subsequent association with 14-3-3β that promotes cytoplasmic HDAC4 retention in dorsal horn neurons.

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