Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

OBJECTIVETo observe the effects and duration of electroacupuncture on the mechanical pain threshold induced by paclitaxel and explore its analgesic mechanism.

METHODSSixty-four C57BL/6J male mice were randomly divided into 4 groups, a normal+sham EA group, a normal+EA group, a medicine+sham EA(Med+ sham EA) group, a medicine + EA (Med + EA) group, 16 cases in each group. The model of chemotherapy-induced peripheral neuropathy was established with paclitaxel intraperitoneal injection on the 1st, 3rd, 5th, 7th day in the Med + sham EA group and the Med + EA group. EA of 30 min was used on bilateral "Zusanli (ST 36)" on the 9th, 11th, 13th, 16th, 18th, 20th, 23rd, 25th, 27th, 30th day in the EA groups, 2 Hz/100 Hz and 1~ 1.5 mA. Acupuncture was applied on the same acupoint at the same times in the sham EA groups. Mechanical pain thresholds were tested by VonFrey before and after model establishment, namely on the 8th, 14th; 21st and, 28th day. The heart blood of 8 mice was drawn quickly to collect serum in every group on the 31st day, and the contents of tumor necrosis factor α (TNF-α), interleukin-1α (IL-1α), interleukin-1β (IL-1β) in proinflammatory cytokine were examined by ELISA. Mechanical pain thresholds were tested by VonFrey for the rest 8 mice of each group until there was no apparent difference in the two paclitaxel groups once a week,namely on the 35th, 42nd, 49th day.

RESULTSThe pain thresholds of each group were not statistically different before model establishment (P > 0.05). After model establishment (on the 8th day), thresholds of the paclitaxel groups were lower than those of the normal groups (all P < 0.05). After EA, the mechanical pain thresholds of the Med + EA group were higher than those of the Med + sham EA group at all the time points, and there was statistical difference on the 14th, 21st and 28th day (all P < 0.05). The analgesic effect was lasting to the 49th day. The contents of TNF-α, IL-1α, IL-1β of the Med + EA group were decreased than those of the Med+sham EA group in different degree, with statistical significance of IL-1α (P < 0.05).

CONCLUSIONEA can effectively treat paclitaxel-induced peripheral neuropathy,and the analgesic mechanism is probably related to decreasing the proinflammatory cytokine.

Acupuncture Points ; Animals ; Antineoplastic Agents ; administration & dosage ; adverse effects ; Electroacupuncture ; Humans ; Interleukin-1beta ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasms ; drug therapy ; Peripheral Nervous System Diseases ; etiology ; genetics ; metabolism ; therapy ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

The quantitative sudomotor axon reflex testing (QSART) is a classic test of routine postganglionic sudomotor function. We investigated sudomotor function by QSART after summer (July 2012) and winter (January 2013) seasonal acclimation (SA) in the Republic of Korea. QSART with acetylcholine (ACh) iontophoresis were performed to determine directly activated (DIR) and axon reflex-mediated (AXR1, 2) sweating rate. Onset time of axon reflex, activated sweat gland density (ASGD), activated sweat gland output (ASGO), tympanic and skin temperatures (T(ty), T(sk)), basal metabolic rate (BMR), and evaporative loss volume changes were measured. Tympanic and mean body temperature (T(b); calculated from T(ty), T(sk)) were significantly lower after summer-SA than that of winter-SA. Sweat onset time was delayed during winter-SA compared to that after summer-SA. BMR, AXR(1), AXR(2), and DIR sweat rates, ASGD and ASGO, and evaporative loss volume were significantly diminished after winter-SA relative to after summer-SA. In conclusion, changes in sweating activity measured by QSART confirmed the involvement of the peripheral nervous system in variation of sudomotor activity in seasonal acclimation.
Acclimatization* ; Acetylcholine ; Axons ; Basal Metabolism ; Body Temperature ; Humans* ; Iontophoresis ; Peripheral Nervous System ; Reflex ; Republic of Korea ; Seasons* ; Skin Temperature ; Sweat ; Sweat Glands ; Sweating

The purpose of this study was to study the role of neurofilament (NF) mRNA and calpain in NF reduction of acrylamide (ACR) neuropathy. Male Wistar adult rats were injected i.p. every other day with ACR (20 mg/kg·bW or 40 mg/kg·bW) for 8 weeks. NF mRNA expression was detected using RT-PCR and the calpain concentration was determined using western blot analysis. The NF mRNA expression significantly decreased while the level of m-calpain and μ-calpain significantly increased in two ACR-treated rats groups regardless of the ACR dose. The light NF (NF-L) protein expression was significantly correlated with NF-L mRNA expression. Combined with previous data, the concentrations of three NF subunits were negatively correlated with the calpain levels. These findings suggest that NF-L mRNA and calpain mediated the reduction in NF of ACR neuropathy.
Acrylamide ; toxicity ; Animals ; Calpain ; metabolism ; Gene Expression Regulation ; drug effects ; Intermediate Filaments ; genetics ; Male ; Peripheral Nervous System Diseases ; chemically induced ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Rats

OBJECTIVETo study the changes in microtubule motor protein expression in the spinal cord and sciatic nerve of rats exposed to carbon disulfide, and to investigate the possible molecular mechanism of changes in axonal transport in carbon disulfide-induced peripheral neuropathy.

METHODSHealthy adult male Wistar rats were randomly divided into one control group and three experimental groups (10 rats per group). The rats in experimental groups were intoxicated by gavage of carbon disulfide at a dose of 200, 400, or 600 mg/kg 6 times a week for 6 consecutive weeks, while the rats in control group were given the same volume of corn oil by gavage. Animals were sacrificed after exposure, with nerve tissue separated. The levels of dynein, dynactin, and kinesin in the spinal cord and sciatic nerve were determined by Western blot.

RESULTSThe content of dynein, dynactin, and kinesin in the sciatic nerve decreased significantly under exposure to carbon disulfide. The levels of dynein in the sciatic nerve were reduced by 23.47% and 33.34% at exposure doses of 400 and 600 mg/kg, respectively. The levels of dynactin in the sciatic nerve of the three experimental groups were reduced by 19.91%, 24.23%, and 41.30%, respectively. The level of kinesin was reduced by 25.98%under exposure to 600 mg/kg carbon disulfide. All the differences were statistically significant (P < 0.01). As compared with the control group, the 600 mg/kg group experienced a 28.24% decrease in level of dynactin in the spinal cord (P < 0.01), but no significant change was observed in the level of dynein or kinesin.

CONCLUSIONCarbon disulfide has an impact on microtubule motor protein expression in nerve tissues, which might be involved in the development of carbon disulfide-induced peripheral neuropathy.

Animals ; Axonal Transport ; drug effects ; physiology ; Carbon Disulfide ; toxicity ; Dynactin Complex ; Male ; Microtubule-Associated Proteins ; metabolism ; Nerve Tissue ; metabolism ; Peripheral Nervous System Diseases ; chemically induced ; metabolism ; Rats, Wistar ; Sciatic Nerve ; metabolism ; Spinal Cord ; metabolism

OBJECTIVETo study clinicopathologic features, immunohistochemical profile, diagnosis and differential diagnosis of childhood central nervous system primitive neuroectodermal tumors (CNS PNETs) with the features of ependymoblastoma and neuroblastoma.

METHODSThe clinical data, morphologic and immunohistochemical features were analyzed in 4 cases of pediatric CNS PNETs with features of ependymoblastoma and neuroblastoma. EnVision method immunohistochemistry was applied.

RESULTSFour patients including three boys and one girl presented at the age from 12 month to 4 years and three tumors located in cerebrum, one in brain stem. All tumors showed typical combined histological patterns of ependymoblastoma and neuroblastoma, demonstrating zones of true rosettes, occasional pseudovascular rosettes, and undifferentiated neuroepithelial cells in a prominent background of mature neuropils. There was focal expression of glial fibrillary acidic protein (GFAP) consistent with glial differentiation and epithelial membrane antigen (EMA) consistent with ependymal differentiation. Necrosis was seen in three cases and calcification was present in one case. Immunohistochemically, the rosettes and undifferentiated neuroepithelial cells were positive for vimentin, partially positive for GFAP and EMA but negative for synaptophysin. The tumor cells were also positive for synaptophysin in neuropils. The Ki-67 label index ranged from 20% to 60%.

CONCLUSIONSCNS PNETs with the features of ependymoblastoma and neuroblastoma is a rare tumor with poor prognosis. The tumor primarily occurs in childhood, especially infant and belongs to the family of embryonal tumors of the CNS. The morphologic, immunohistochemical and genetic features are important in differential diagnosis from other tumors of the CNS.

Antigens, Neoplasm ; metabolism ; Central Nervous System ; pathology ; Child ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Humans ; Immunohistochemistry ; Infant ; Male ; Mucin-1 ; metabolism ; Neuroblastoma ; diagnosis ; pathology ; Neuroectodermal Tumors, Primitive ; diagnosis ; pathology ; Neuroectodermal Tumors, Primitive, Peripheral ; diagnosis ; pathology ; Synaptophysin ; metabolism ; Vimentin ; metabolism

OBJECTIVETo study the clinicopathologic characteristics of peripheral neuroblastic tumors and to evaluate the prognostic significance of these features.

METHODSThe clinical and pathologic findings were retrospectively reviewed in 121 cases of peripheral neuroblastic tumor. The clinical outcomes of patients were evaluated. The three-year event-free survival rate was analyzed, with respect to age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.

RESULTSThe median age at diagnosis was 2.7 years; and 96 cases (79.3%) occurred in patients younger than 5 years old. The number of cases in Evan's staging I, II, III, IV and IVs was 24, 39, 24, 29 and 5, respectively. There were 82 cases of neuroblastoma (NB) (including 2 cases of undifferentiated NB, 52 cases of poorly differentiated NB and 28 cases of differentiating NB), 9 cases of ganglioneuroblastoma, intermixed type (GNBi), 19 cases of ganglioneuroma, maturing type (GN) and 11 cases of ganglioneuroblastoma, nodular type (GNBn). Forty-nine cases were in the favorable histology subgroup and 72 cases in the unfavorable histology subgroup. The overall three-year event-free survival rate of the 121 cases was 73.0% ± 4.3%. The three-year event-free survival rates were associated with age (P = 0.002), Evan's staging (P = 0.000), histologic category (P = 0.000), mitosis-karyorrhexis index (P = 0.043), prognostic subgroup (P = 0.000).

CONCLUSIONSMost of the peripheral neuroblastic tumors occur in the children younger than 5 years old. It is composed of NB, GNBi, GN and GNBn. The three-year event-free survival rate is approximately 70%. Significant prognostic parameters include age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.

Age Factors ; Antigens, Nuclear ; metabolism ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Ganglioneuroblastoma ; metabolism ; pathology ; surgery ; Ganglioneuroma ; metabolism ; pathology ; surgery ; Humans ; Infant ; Infant, Newborn ; Male ; Neoplasm Staging ; Nerve Tissue Proteins ; metabolism ; Nestin ; metabolism ; Neuroblastoma ; metabolism ; pathology ; surgery ; Peripheral Nervous System Neoplasms ; metabolism ; pathology ; surgery ; Phosphopyruvate Hydratase ; metabolism ; Retrospective Studies ; S100 Proteins ; metabolism

Age Factors ; Child ; Child, Preschool ; Ganglioneuroblastoma ; genetics ; metabolism ; pathology ; ultrastructure ; Ganglioneuroma ; genetics ; metabolism ; pathology ; ultrastructure ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Humans ; Infant ; N-Myc Proto-Oncogene Protein ; Neoplasm Staging ; Neuroblastoma ; genetics ; metabolism ; pathology ; ultrastructure ; Nuclear Proteins ; genetics ; metabolism ; Oncogene Proteins ; genetics ; metabolism ; Peripheral Nervous System Neoplasms ; classification ; genetics ; metabolism ; pathology ; ultrastructure ; Prognosis ; Proto-Oncogene Proteins c-myc ; metabolism ; Receptor, trkA ; metabolism ; S100 Proteins ; metabolism

OBJECTIVETo study the mechanism of bortezomib inducing peripheral neuropathy and the reversing affection of reduced glutathione.

METHODSFemale Wistar rats were randomly divided into three groups. Group 1, treatment with bortezomib; Group 2, treatment with bortezomib and reduced glutathione; Group 3, saline control group. Drugs were administrated on the 1st, 4th, 7th and 11th day for the three groups. The amorphous of sciatic nerve and dorsal root ganglion (DRG) were observed by electron microscope on 14th and 42nd day. On 14th day, laser confocal microscopy was used to detect reactive oxygen species (ROS) of DRG neuron obtained from the rats by treated with DCFH-DA after primary culture.

RESULTSOn 14th day, morphology of sciatic nerve and DRG changed in both group 1 and 2. On 42nd day, the amorphous became normally in group 1. On 14th day, ROS releasing from DRG neuron was increased obviously in group 1 (P < 0.01), while decreased in both group 2 and 3, and the difference between the latter two groups had no statistical significance (P = 0.210).

CONCLUSIONReleasing ROS to injure mitochondrion and endoplasmic reticulum maybe involved in bortezomib induced peripheral neuropathy. Although reduced glutathione can inhibit ROS release, it has no obviously reversal effect for peripheral neuropathy.

Animals ; Boronic Acids ; adverse effects ; Bortezomib ; Female ; Glutathione ; therapeutic use ; Peripheral Nervous System Diseases ; chemically induced ; metabolism ; prevention & control ; Pyrazines ; adverse effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; metabolism

OBJECTIVETo analyze the relationship between cutaneous glycometabolic disorders and cutaneous neuropathy in diabetic rats, and to look for the mechanism of neuropathy and impaired wound healing.

METHODSEighty male SD rats were randomly divided into the normal control group (NC, n = 20), diabetic group (D, n = 20), aminoguanidine-interfered group (AI, n = 20), and insulin-interfered group (II, n = 20) by drawing lots. Diabetes was reproduced in rats of D, AI, and II groups with intraperitoneal injection of streptozotocin (STZ). Then, rats in AI group were fed with 100 mg×kg(-1)×d(-1) aminoguanidine, while rats in II group were subcutaneously injected with insulin for satisfactory control of blood glucose. Changes in mechanical and heat pain thresholds of pad of hind limb were measured at post injection week (PIW) 2, 4, 8. Skin specimens were collected during PIW 2-8 from pads for determination of contents of glucose, advanced glycation end product (AGE), substance P (SP), calcitonin gene-related peptide (CGRP), and observation of distribution and ultrastructure of skin nerve fibers. Data were processed with t test.

RESULTSThe mechanical and heat pain thresholds in D group at PIW 2 [(6.3 ± 1.5) g, (6.0 ± 0.9) s, respectively ] were obviously lower than those in NC group [(13.0 ± 3.2) g, (10.3 ± 1.2) s, with t value respectively 2.71, 3.42, P values all below 0.05]. Contents of glucose and AGE in skin tissue in D group were significantly increased when compared with those in NC group, especially at PIW 8 [(2.85 ± 0.33) mg/g, (31.7 ± 3.2) U/mg of hydroxyproline vs. (0.82 ± 0.22) mg/g, (22.2 ± 1.9) U/mg of hydroxyproline, with t value respectively 1.65, 6.47, P values all below 0.01]. The myelinated nerve fibers were edematous and degenerated, with axons compressed, while the unmyelinated nerve fibers were vacuolated, with microfilament and microtubule disorderly arranged. Content of SP in skin tissue in D group was lower as compared with that in NC group, especially at PIW 2 [(16.8 ± 3.4) pg/g vs. (28.5 ± 5.0) pg/g, t = 2.42, P < 0.01]. There was no obvious difference in content of CGRP between NC and D groups, and also in content of glucose in skin between D and AI groups. Compared with those in D group, content of AGE in AI group at PIW 8 was decreased markedly [(27.2 ± 1.4) U/mg of hydroxyproline, t = 3.38, P < 0.05]; contents of glucose and AGE in II group at PIW 8 were significantly decreased [(1.42 ± 0.38) mg/g, (23.6 ± 1.3) U/mg of hydroxyproline, with t value respectively 1.74, 8.17, P < 0.05 or P < 0.01]. Compared with that in D group, contents of SP in AI and II groups were increased, with a delay in time of trough value. Content of CGRP showed no obvious difference among D, AI, and II groups.

CONCLUSIONSHigh glucose and accumulation of AGE are key mediators of cutaneous neuropathy and impaired wound healing in diabetes mellitus, which confirms that diabetic wound takes an atypical footing during wound repairing. Aminoguanidine and insulin can reduce contents of glucose and AGE in diabetic skin tissue, and ameliorate diabetic cutaneous neuropathy.

Animals ; Diabetes Mellitus, Experimental ; complications ; metabolism ; Glucose ; metabolism ; Glycation End Products, Advanced ; metabolism ; Male ; Peripheral Nervous System Diseases ; etiology ; Rats ; Rats, Sprague-Dawley ; Skin ; metabolism ; pathology ; Skin Diseases ; etiology ; Wound Healing