Clinical Efficacy of Pentoxifylline Combined with Thioctic Acid in the Treatment of Painful Diabetic Peripheral Neuropathy

Objective:To observe the efficacy of pentoxifylline+thioctic acid in the treatment of patients with painful diabetic peripheral neuropathy(PDPN).Methods:70 patients with PDPN admitted from October 2019 to October 2022 were selected and randomly grouped,with pentoxifylline+thioctic acid treatment in Group A and thioctic acid treatment in Group B,and the treatment efficacy was compared.Results:The treatment efficacy in Group A was higher than that of Group B,P<0.05;the points of each symptom of PDPN in Group A were lower than that of Group B,P<0.05;the C-reactive protein and electromyography indexes of PDPN patients in Group A were better than that of Group B,P<0.05.Conclusion:PDPN patients treated with pentoxifylline+thioctic acid can optimize nerve function,inhibit inflammation progression,and reduce PDPN symptoms,which is an efficient and feasible treatment option.

Validation of neuropathic pain assessment tools among Chinese patients with painful diabetic peripheral neuropathy

Objective:This study aims to evaluate the reliability and validity of neuropathic pain assessment tools among Chinese patients with painful diabetic peripheral neuropathy(PDPN).Methods:One hundred patients with PDPN and 70 patients with non-neuropathic pain were recruited from five grade III general hospitals in Guangzhou.Pain was assessed using the Leeds Assessment of Neuropathic Symptoms and Signs(LANSS),Douleur Neuropathique 4 questionnaire(DN4),and Brief Pain Inventory for Painful Diabetic Peripheral Neuropathy(BPI-DPN).Reliability was evaluated by internal consistency of the Cronbach's a coefficient and Guttman split-half.Construct validity was analyzed by factor analysis and Spearman correlation coefficients.Sensitivity and specificity were also assessed.Results:The Cronbach's a coefficients of the LANSS,DN4,and BPI-DPN were 0.735,0.750,and 0.898,respectively.The Guttman split-half coefficients of the LANSS,DN4,and BPIDPN were 0.660,0.726,and 0.849,respectively.The cumulative contributions of the LANSS,DN4,and BPI-DPN to the total variance were 61.945%,57.010%,and 66.056%,respectively.The items of the LANSS,DN4,and BPI-DPN presented high factorial loads,ranging from 0.387 to 0.841,0.137 to 0.948,and 0.487 to 0.953,respectively.The LANSS and DN4 exhibited sensitivities of 58.0%and 82.7%,respectively,and specificity of 97.1%.Conclusions:The LANSS or DN4 can be used to detect neuropathic pain in Chinese patients with PDPN.The BPI-DPN can be employed to monitor the effectiveness of pain intervention.

Unique Traditional Chinese Medicine Therapy for Painful Diabetic Peripheral Neuropathy

Painful diabetic peripheral neuropathy is one of the common chronic complications of diabetes."Pain"is the most typical symptom in patients,which seriously affects their quality of life.Traditional Chinese medicine(TCM)treatment of the disease includes oral administration of Chinese medicine,TCM fumigation and acupuncture,etc.,which can significantly reduce the pain of patients and reduce the frequency of disease.Chinese decoctions regulate the imbalance of yin and yang in the human body through syndrome differentiation,so as to achieve the balance of yin and yang,which will then eliminate the disease.Chinese medicine fumigation make the medicine seep into the body from the skin to exert the medical effects,and nourish and dredge the meridians.There is no pain if the meridians are smooth flowing,there will be pain if the meridians are blocked,fumigation can be used alone or assisted by other treatment methods to enhance the efficacy.The characteristics of acupuncture are rapid painrelief,economic and convenient,and can quickly relieve pain for patients with low tolerance.

A randomized,controlled trial of Shutangluo fang in treating painful diabetic peripheral neuropathy

OBJECTIVE:To assess efficacy of Shutangluo fang on painful diabetic peripheral neuropathy(PDPN).METHODS:Adopting stratified randomized and controlled design,82 patients with PDPN were assigned to two groups.Both groups continued conventional therapy.Epalrestat was administered to patients in both groups,and Shutangluo fang was given to patients in the treatment group.The treatment course lasted for 3 months.The changes before and after treatment of symptoms and signs,electrophysiological assessments were observed.RESULTS:The efficacy of the treatment group was better than the control group.The sensory nerve conduction velocity was significantly improved in the treatment group than the control group.CONCLUSIONS:Shutangluo fang is effective on PDPN.

Puerarin ameliorates allodynia and hyperalgesia in rats with peripheral nerve injury

Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.

A double-network hydrogel for the dynamic compression of the lumbar nerve root

Current animal models of nerve root compression due to lumbar disc herniation only assess the mechanical compression of nerve roots and the inflammatory response. Moreover, the pressure applied in these models is static, meaning that the nerve root cannot be dynamically compressed. This is very different from the pathogenesis of lumbar disc herniation. In this study, a chitosan/polyacrylamide double-network hydrogel was prepared by a simple two-step method. The swelling ratio of the double-network hydrogel increased with prolonged time, reaching 140. The compressive strength and compressive modulus of the hydrogel reached 53.6 and 0.34 MPa, respectively. Scanning electron microscopy revealed the hydrogel's crosslinked structure with many interconnecting pores. An MTT assay demonstrated that the number of viable cells in contact with the hydrogel extracts did not significantly change relative to the control surface. Thus, the hydrogel had good biocompatibility. Finally, the double-network hydrogel was used to compress the L4 nerve root of male sand rats to simulate lumbar disc herniation nerve root compression. The hydrogel remained in its original position after compression, and swelled with increasing time. Edema appeared around the nerve root and disappeared 3 weeks after operation. This chitosan/polyacrylamide double-network hydrogel has potential as a new implant material for animal models of lumbar nerve root compression. All animal experiments were approved by the Animal Ethics Committee of Neurosurgical Institute of Beijing, Capital Medical University, China(approval No. 201601006) on July 29, 2016.

Evaluation of NR2B peptide as subunit vaccines against experimental neuropathic pain

Background NR2B containing N-methyI-D-aspartate （NMDA） receptor plays an important role in the facilitation and maintenance of neuropathic pain. The discrete distribution of NR2B subunit in the central nervous system （CNS） may support reduced side effects of agents that act selectively at this site. Therefore, we investigated the hypothesis that a humoral autoimmune response targeting the NR2B subunit of NMDA receptor relieves pain like behaviours produced by peripheral injury. Methods Rats were immunized subcutaneously with NR2B-Keyhole Limpet Hemocyanin （NR2B-KLH） three times at two-week intervals. NR2B specific IgG titres in sera and cerebrospinal fluid were determined by indirect ELISA. Seven days after the third immunization, 2 of the 3 terminal branches of the sciatic nerve （tibial and common peroneal nerves） were tightly ligated. Behavioural testing was carried out on every other day after surgery, until 7 days after surgery. The lumbar spinal cord （L4-6） was removed on day 7 after ligation. The expression of NR2B protein in the lumbar spinal cord was determined using Western blotting. Results After the second vaccination, NR2B specific IgG in sera was detected to be 〉0.5 μg/ml in six of nine rats. After the third vaccination, all the immunized rats had 〉2.2 μg/ml. Titres of NR2B specific IgG in sera peaked 42 days post initial immunization and persisted for over 70 days. No NR2B specific IgG was detected in sera from PBS or KLH group. The behavioural thresholds in NR2B group were significantly higher than those in PBS and KLH groups on day 7 after ligation. NR2B specific IgG in CSF in NR2B group could not be detected on day 1 before spinal dissection; but could be detected on day 7 after surgery. The expression of NR2B protein in group NR2B was significantly lower than in PBS and KLH groups on day 7 after surgery. Conclusion The NR2B peptide could be used as a vaccine against neuropathic pain, which could be associated with reduction of NR2B protein in the lumbar spinal cord.

Extracellular signal-regulated protein kinase activation in spinal cord contributes to pain hypersensitivity in a mouse model of type 2 diabetes

Painful peripheral neuropathy is a common complication of diabetes mellitus. The symptom of pain can become a major factor that decreases the quality of life of patients with diabetes, while effective treatment is lacking. In the present study, we aimed to investigate the changes of pain threshold in the early stage of diabetes in db/db mice, an animal model of type 2 diabetes mellitus, and the underlying molecular mechanisms. We found that （1） db/db mice （with a leptin receptor-null mutation and characterized by obesity and hyperglycemia） showed hypersensitivity to mechanical and thermal stimuli at the early stage of diabetes; （2） phosphorylated extracellular signal- regulated kinase （pERK）, but not total ERK in the spinal cord and dorsal root ganglia in db/db mice significantly increased compared with wild-type mice. The increased pERK immunoreactivity occurred in both NeuN-expressing neurons and GFAP- expressing astrocytes, but not in Iba-l-expressing microglia; （3） both single and consecutive （for 5 days） intrathecal injections of U0126 （2 nmol per day）, a selective MEK （an ERK kinase） inhibitor beginning at 8 weeks of age, attenuated the bilateral mechanical allodynia in the von-Frey test and heat hyperalgesia in Hargreave＇s test; and （4） db/db mice also displayed increased nocifensive behavior during the formalin test, and this was blocked by intrathecal injection of U0126. Also, the expression of pERK1 and pERK2 was upregulated following the formalin injection. Our results suggested that the activation of ERK in spinal neurons and astrocytes is correlated with pain hypersensitivity of the type 2 diabetes animal model. Inhibiting the ERK pathway may provide a new therapy for pain control in type 2 diabetes.

Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China

Background Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain （DPNP） in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain. Methods This double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory （BPI） 24-hour average pain severity ratings ≥4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator＇s judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol： 5 Dimensions, Athens Insomnia Scale, and safety measures. Results Of 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively,completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups （P=0.124）. Duloxetinetreated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1,2, and 4 （P=0.004, P=0.009, and P=0.006, respectively） but not at weeks 8 （P=0.125） and 12 （P=0.107）. Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now, and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction on the Brief Pain Inventory average pain score relative to placebo. Duloxetine-treated patients reported nausea, somnolence, anorexia, and dysuria significantly more than placebo. Conclusions Although the primary study endpoint was not achieved, the overall observed response pattern suggests the efficacy of duloxetine in the treatment of Chinese patients with diabetic peripheral neuropathic pain. The safety profile for duloxetine is similar to that reported in other global trials.

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity

Vincristine,a widely used chemotherapeutic agent for treating different cancer,often induces severe peripheral neuropathic pain.A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia.However,mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood.In the present study,we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity.Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting(RA)mechanically-activated(MA)currents in rat dorsal root ganglion(DRG)neurons.We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension(SPMT)of these cells following vincristine treatment.Reducing SPMT of DRG neurons by cytochalasin D(CD),a disruptor of the actin filament,abolishes vincristine-induced potentiation of PIEZO2 MA currents,and suppresses vincristine-induced mechanical hypersensitivity in rats.Collectively,enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristineinduced mechanical allodynia and hyperalgesia in rats.Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.