Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy.

AIM: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). PATIENTS-METHODS: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. RESULTS: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. CONCLUSIONS: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.

Peripheral Nerve Stimulation for Neuropathic Pain Management: A Narrative Review.

This narrative review examines the therapeutic efficacy of peripheral nerve stimulation (PNS) in the treatment of neuropathic pain (NP), a type of pain arising from lesions or diseases of the somatosensory system with a global prevalence ranging from 6.90% to 10.00%. Traditional pharmacological interventions often fall short for many persons, highlighting the need for alternative treatments such as PNS, which has demonstrated significant promise with minimal side effects. The review summarizes the effectiveness of PNS in various NP conditions, including trigeminal neuralgia and postherpetic neuralgia, and underscores the need for further research to refine treatment approaches. The mechanism of PNS is discussed, involving the activation of non-nociceptive Aß fibers and modulation of neurotransmitters, and offering pain relief through both peripheral and central pathways. Despite the proven efficacy of PNS, challenges remain, including the need for randomized controlled trials and the optimization of stimulation parameters. The review concludes that PNS is a promising treatment modality for NP, warranting additional high-quality trials to solidify its role in clinical practice.

Liquiritin ameliorates painful diabetic neuropathy in SD rats by inhibiting NLRP3-MMP-9-mediated reversal of aquaporin-4 polarity in the glymphatic system.

Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.

Treatment of Painful Diabetic Neuropathy with 10 kHz Spinal Cord Stimulation: Long-Term Improvements in Hemoglobin A1c, Weight, and Sleep Accompany Pain Relief for People with Type 2 Diabetes.

Purpose: The recent SENZA-PDN study showed that high-frequency (10kHz) spinal cord stimulation (SCS) provided significant, durable pain relief for individuals with painful diabetic neuropathy (PDN), along with secondary benefits, including improved sleep quality and HRQoL. Given that metabolic factors and chronic neuropathic pain are related, we evaluated potential secondary effects of 10kHz SCS on hemoglobin A1c (HbA1c) and weight in SENZA-PDN participants with type 2 diabetes (T2D). Patients and Methods: This analysis included 144 participants with T2D and lower limb pain due to PDN who received 10kHz SCS during the SENZA-PDN study. Changes in HbA1c, weight, pain intensity, and sleep were evaluated over 24 months, with participants stratified according to preimplantation HbA1c (>7% and >8%) and body mass index (BMI; ≥30 and ≥35 kg/m2). Results: At 24 months, participants with preimplantation HbA1c >7% and >8% achieved clinically meaningful and statistically significant mean reductions in HbA1c of 0.5% (P = 0.031) and 1.1% (P = 0.004), respectively. Additionally, we observed a significant mean weight loss of 3.1 kg (P = 0.003) across all study participants. In subgroups with BMI ≥30 and ≥35 kg/m2, weight reductions at 24 months were 4.1 kg (P = 0.001) and 5.4 kg (P = 0.005), respectively. These reductions were accompanied by a mean pain reduction of 79.8% and a mean decrease in pain interference with sleep of 65.2% at 24 months across all cohorts. Conclusion: This is the first study of SCS to demonstrate long-term, significant, and clinically meaningful reductions in HbA1c and weight in study participants with PDN and T2D, particularly among those with elevated preimplantation HbA1c and BMI. Although the mechanism for these improvements has yet to be established, the results suggest possible direct and indirect metabolic benefits with 10kHz SCS in addition to durable pain relief. Trial Registration: ClincalTrials.gov Identifier, NCT03228420.

Diabetic Neuropathy: A Guide to Pain Management.

PURPOSE OF REVIEW: Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. RECENT FINDINGS: Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

Metabolomic and lipidomic profiling of the spinal cord in type 2 diabetes mellitus rats with painful neuropathy.

In this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN.

Targeting TANK-binding kinase 1 attenuates painful diabetic neuropathy via inhibiting microglia pyroptosis.

BACKGROUND: Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. METHODS: PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. RESULTS: In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. CONCLUSIONS: Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.

Efficacy and safety of acupuncture for painful diabetic neuropathy: a systematic review and meta-analysis.

Background: Painful diabetic neuropathy (PDN) is a common chronic neurological complication of diabetes mellitus. Medications are often used to relieve pain, but with significant side effects. Acupuncture is now a component of pragmatic and integrative treatment for PDN. An increasing number of relevant randomized controlled trials have been published in recent years, but a comprehensive meta-analysis has not yet been performed. The aim of this paper is to verify the effectiveness and safety of acupuncture for PDN by meta-analysis and trial sequential analysis (TSA). Methods: All participants in this study should have had a PDN diagnosis and the trial group was treated with acupuncture. Eight databases, including EMbase, PubMed, Web of science, Cochrane Library, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to 5 April 2023. Meta-analysis was conducted utilizing RevMan 5.3 and Stata 15.0. TSA was performed to assess the adequacy of sample size for the outcomes. Results: A total of 36 studies, comprising 2,739 PDN patients, were included. Among them, 1,393 patients were assigned to the trial group and 1,346 patients were treated in the control group. Outcomes covers the primary indicator Total effective rate (RR = 1.42, 95%CI [1.34, 1.52], p < 0.00001), with 21 studies reported, Pain intensity (SMD = -1.27, 95%CI [-1.58, -0.95], p < 0.00001), with 23 studies reported, and other outcomes, including motor nerve conduction velocity (MCV; MD = 3.58, 95%CI [2.77, 4.38], p < 0.00001), sensory nerve conduction velocity (SCV; MD = 3.62, 95%CI [2.75, 4.49], p < 0.00001), Depression score (SMD = -1.02, 95%CI [1.58, 0.46]), Toronto clinical scoring system (TCSS; MD = -2.41, 95%CI [-3.37, -1.45], p < 0.00001), Quality of life (SMD = 1.06, 95%CI [0.66, 1.46]), traditional Chinese medicine (TCM) syndrome score (MD = -4.99, 95%CI [-6.79, -3.18], p < 0.00001), suggesting that acupuncture have an ameliorating effect on PDN in various respect. Egger's test revealed publication bias for four outcomes. TSA showed that as for Total effective rate, Pain Intensity, MCV and SCV, the number of included studies was sufficient to support the conclusions. Conclusion: Acupuncture demonstrates significant effectiveness in improving PDN outcomes, including Total effective rate, Pain intensity, MCV, SCV, Depression score, TCSS, Quality of life, TCM syndrome score. But the Adverse events rate is no different in trail group and control group. The publication bias presented in Total effective rate, Pain intensity, MCV and SCV can be remedied by Trim and filling method. Systematic review registration: Prospero, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=477295.

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study.

INTRODUCTION: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. METHODS: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. RESULTS: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. CONCLUSIONS: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. CLINICAL TRIAL REGISTRATION: NCT03749642.

Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.

OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN. METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study. RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC. DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects. TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET.

Introduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN. Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN. Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process. Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria. Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.

Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a-PINK1-Parkin signaling pathway to activate mitophagy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated. METHODS: In this study, we used high-fat diet/low-dose streptozotocin-induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real-time PCR, western blot, and immunofluorescence were performed to investigate the mechanism. RESULTS: We found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+-dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV-SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a-PINK1-Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected. CONCLUSION: These results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a-PINK1-Parkin-mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN.

Painful diabetic neuropathy: The role of ion channels.

Painful diabetic neuropathy (PDN) is a common chronic complication of diabetes that causes neuropathic pain and negatively affects the quality of life. The management of PDN is far from satisfactory. At present, interventions are primarily focused on symptomatic treatment. Ion channel disorders are a major cause of PDN, and a complete understanding of their roles and mechanisms may provide better options for the clinical treatment of PDN. Therefore, this review summarizes the important role of ion channels in PDN and the current drug development targeting these ion channels.

Ginkgolide B can alleviate spinal cord glymphatic system dysfunction and provide neuroprotection in painful diabetic neuropathy rats by inhibiting matrix metalloproteinase-9.

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. ß-Dystroglycan (ß-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated ß-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, ß-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased ß-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.

J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine.

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

New concepts drive the development of delivery tools for sustainable treatment of diabetic complications.

Diabetic complications, especially diabetic retinopathy, diabetic nephropathy and painful diabetic neuropathy, account for a large portion of patients with diabetes and display rising global prevalence. They are the leading causes of blindness, kidney failure and hypersensitivity to pain caused by diabetes. Current approved therapeutics against the diabetic complications are few and exhibit limited efficacy. The enhanced cell-specificity, stability, biocompatibility, and loading capacity of drugs are essential for the mitigation of diabetic complications. In the article, we have critically discussed the recent studies over the past two years in material sciences and biochemistry. The insightful concepts in these studies drive the development of novel nanoparticles and mesenchymal stem cells-derived extracellular vesicles to meet the need for treatment of diabetic complications. Their underlying biochemical principles, advantages and limitations have been in-depth analyzed. The nanoparticles discussed in the article include double-headed nanodelivery system, nanozyme, ESC-HCM-B system, soft polymer nanostars, tetrahedral DNA nanostructures and hydrogels. They ameliorate the diabetic complication through attenuation of inflammation, apoptosis and restoration of metabolic homeostasis. Moreover, mesenchymal stem cell-derived extracellular vesicles efficiently deliver therapeutic proteins to the retinal cells to suppress the angiogenesis, inflammation, apoptosis and oxidative stress to reverse diabetic retinopathy. Collectively, we provide a critical discussion on the concept, mechanism and therapeutic applicability of new delivery tools to treat these three devastating diabetic complications.

Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

Peripheral mechanisms of peripheral neuropathic pain.

Peripheral neuropathic pain (PNP), neuropathic pain that arises from a damage or disease affecting the peripheral nervous system, is associated with an extremely large disease burden, and there is an increasing and urgent need for new therapies for treating this disorder. In this review we have highlighted therapeutic targets that may be translated into disease modifying therapies for PNP associated with peripheral neuropathy. We have also discussed how genetic studies and novel technologies, such as optogenetics, chemogenetics and single-cell RNA-sequencing, have been increasingly successful in revealing novel mechanisms underlying PNP. Additionally, consideration of the role of non-neuronal cells and communication between the skin and sensory afferents is presented to highlight the potential use of drug treatment that could be applied topically, bypassing drug side effects. We conclude by discussing the current difficulties to the development of effective new therapies and, most importantly, how we might improve the translation of targets for peripheral neuropathic pain identified from studies in animal models to the clinic.