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Yamaguchi M, Noda-Asano S, Inoue R, Himeno T, Motegi M, Hayami T, Nakai-Shimoda H, Kono A, Sasajima S, Miura-Yura E, Morishita Y, Kondo M, Tsunekawa S, Kato Y, Kato K, Naruse K, Nakamura J, Kamiya H. Dipeptidyl Peptidase (DPP)-4 Inhibitors and Pituitary Adenylate Cyclase-Activating Polypeptide, a DPP-4 Substrate, Extend Neurite Outgrowth of Mouse Dorsal Root Ganglia Neurons: A Promising Approach in Diabetic Polyneuropathy Treatment. Int J Mol Sci 2024; 25:8881. [PMID: 39201570 PMCID: PMC11354620 DOI: 10.3390/ijms25168881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.
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Affiliation(s)
- Masahiro Yamaguchi
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Saeko Noda-Asano
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Rieko Inoue
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Tatsuhito Himeno
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
- Department of Innovative Diabetes Therapy, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Mikio Motegi
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Tomohide Hayami
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Hiromi Nakai-Shimoda
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Ayumi Kono
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Sachiko Sasajima
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Emiri Miura-Yura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Yoshiaki Morishita
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Masaki Kondo
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Shin Tsunekawa
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Yoshiro Kato
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Koichi Kato
- Department of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya 464-8650, Japan
| | - Keiko Naruse
- Department of Internal Medicine, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan
| | - Jiro Nakamura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
- Department of Innovative Diabetes Therapy, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1185, Japan
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Altaf N, Rehman NU, Karim N, Khan I, Halim SA, Alotaibi BS, Hamad RS, Batiha GES, Tayyeb JZ, Turkistani A, Khan A, Al-Harrasi A. Attenuation of Streptozotocin-Induced Diabetic Neuropathic Allodynia by Flavone Derivative Through Modulation of GABA-ergic Mechanisms and Endogenous Biomarkers. Neurochem Res 2024; 49:980-997. [PMID: 38170385 DOI: 10.1007/s11064-023-04078-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 11/19/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024]
Abstract
Diabetic neuropathic pain is one of the most devasting disorders of peripheral nervous system. The loss of GABAergic inhibition is associated with the development of painful diabetic neuropathy. The current study evaluated the potential of 3-Hydroxy-2-methoxy-6-methyl flavone (3-OH-2'MeO6MF), to ameliorate peripheral neuropathic pain using an STZ-induced hyperglycemia rat model. The pain threshold was assessed by tail flick, cold, mechanical allodynia, and formalin test on days 0, 14, 21, and 28 after STZ administration accompanied by evaluation of several biochemical parameters. Administration of 3-OH-2'-MeO6MF (1,10, 30, and 100 mg/kg, i.p) significantly enhanced the tail withdrawal threshold in tail-flick and tail cold allodynia tests. 3-OH-2'-MeO6MF also increased the paw withdrawal threshold in mechanical allodynia and decreased paw licking time in the formalin test. Additionally, 3-OH-2'-MeO6MF also attenuated the increase in concentrations of myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), nitrite, TNF-α, and IL 6 along with increases in glutathione (GSH). Pretreatment of pentylenetetrazole (PTZ) (40 mg/kg, i.p.) abolished the antinociceptive effect of 3-OH-2'-MeO6MF in mechanical allodynia. Besides, the STZ-induced alterations in the GABA concentration and GABA transaminase activity attenuated by 3-OH-2'-MeO6MF treatment suggest GABAergic mechanisms. Molecular docking also authenticates the involvement of α2β2γ2L GABA-A receptors and GABA-T enzyme in the antinociceptive activities of 3-OH-2'-MeO6MF.
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Affiliation(s)
- Nouman Altaf
- Department of Pharmacy, University of Malakand, Chakdara, Lower Dir, KPK, Pakistan
| | - Najeeb Ur Rehman
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat al Mouz, Initial Campus, 616, Nizwa, Sultanate of Oman
| | - Nasiara Karim
- Department of Pharmacy, University of Malakand, Chakdara, Lower Dir, KPK, Pakistan.
- Department of Pharmacy, University of Peshawar, Peshawar, KPK, Pakistan.
| | - Imran Khan
- Department of Pharmacy, University of Swabi, Swabi, KPK, Pakistan
| | - Sobia Ahsan Halim
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat al Mouz, Initial Campus, 616, Nizwa, Sultanate of Oman
| | - Badriyah S Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, 11671, Riyadh, Saudi Arabia
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, 31982, Al Ahsa, Saudi Arabia
- Central Laboratory, Theodor Bilharz Research Institute, Giza, 12411, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt
| | - Jehad Zuhair Tayyeb
- Department of Clinical Biochemistry, College of Medicine, University of Jeddah, 23890, Jeddah, Saudi Arabia
| | - Areej Turkistani
- Department of Pharmacology and Toxicology, College of Medicine, Taif University, 21944, Taif, Kingdom of Saudi Arabia
| | - Ajmal Khan
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat al Mouz, Initial Campus, 616, Nizwa, Sultanate of Oman.
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Center, University of Nizwa, Birkat al Mouz, Initial Campus, 616, Nizwa, Sultanate of Oman.
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Abdelhamid S, Shabani M, Russjan A, Tarnutzer AA. Treatment-induced neuropathy of diabetes: challenges in diagnosing neuropathic pain, value of sudomotor function testing. BMJ Case Rep 2023; 16:e256340. [PMID: 37967926 PMCID: PMC10661014 DOI: 10.1136/bcr-2023-256340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2023] Open
Abstract
A patient in his 60s was admitted for an extensive neurological work-up due to progressive asymmetrical, distally pronounced pain in both feet and legs. Conventional pain relievers did not help in pain reduction. A Sudoscan revealed small fibre damage in all extremities indicating an underlying neuropathy. The patient had started insulin treatment around 6 months prior to hospitalisation because of a newly diagnosed late-onset diabetes. Due to a rapid drop in glycated haemoglobin (from over 14% to 6% in 4 months), treatment-induced neuropathy of diabetes (TIND) was hypothesised. On increasing the dose of pregabalin and adding duloxetine, the patient reported improvement of symptoms, which further underlined the suspected diagnosis. Hence, in patients with severe hyperglycaemia, changes in glycaemic control should be stepwise and not rapid; however, to date, no guidelines exist how to avoid TIND.
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Affiliation(s)
| | | | - Arkadiusz Russjan
- Department of Neurology and Neurorehabilitation, Zurzach Care AG, Bad Zurzach, Switzerland
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Yang Y, Wang Q. Three genes expressed in relation to lipid metabolism considered as potential biomarkers for the diagnosis and treatment of diabetic peripheral neuropathy. Sci Rep 2023; 13:8679. [PMID: 37248406 PMCID: PMC10227002 DOI: 10.1038/s41598-023-35908-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 05/25/2023] [Indexed: 05/31/2023] Open
Abstract
Diabetic neuropathy is one of the most common chronic complications and is present in approximately 50% of diabetic patients. A bioinformatic approach was used to analyze candidate genes involved in diabetic distal symmetric polyneuropathy and their potential mechanisms. GSE95849 was downloaded from the Gene Expression Omnibus database for differential analysis, together with the identified diabetic peripheral neuropathy-associated genes and the three major metabolism-associated genes in the CTD database to obtain overlapping Differentially Expressed Genes (DEGs). Gene Set Enrichment Analysis and Functional Enrichment Analysis were performed. Protein-Protein Interaction and hub gene networks were constructed using the STRING database and Cytoscape software. The expression levels of target genes were evaluated using GSE24290 samples, followed by Receiver operating characteristic, curve analysis. And Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the target genes. Finally, mRNA-miRNA networks were constructed. A total of 442 co-expressed DEGs were obtained through differential analysis, of which 353 expressed up-regulated genes and 89 expressed down-regulated genes. The up-regulated DEGs were involved in 742 GOs and 10 KEGG enrichment results, mainly associated with lipid metabolism-related pathways, TGF-β receptor signaling pathway, lipid transport, and PPAR signaling pathway. A total of 4 target genes (CREBBP, EP300, ME1, CD36) were identified. Analysis of subject operating characteristic curves indicated that CREBBP (AUC = 1), EP300 (AUC = 0.917), ME1 (AUC = 0.944) and CD36 (AUC = 1) may be candidate serum biomarkers for DPN. Conclusion: Diabetic peripheral neuropathy pathogenesis and progression is caused by multiple pathways, which also provides clinicians with potential therapeutic tools.
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Affiliation(s)
- Ye Yang
- Department of Geriatrics and Cadre Ward, Second Affiliated Hospital of Xinjiang Medical University, Ürümqi, 830063, Xinjiang, China
| | - Qin Wang
- Department of Geriatrics and Cadre Ward, Second Affiliated Hospital of Xinjiang Medical University, Ürümqi, 830063, Xinjiang, China.
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Tóth M, Szőke A, Arányi Z. Nerve ultrasonographic findings in diabetes mellitus are determined by anatomical location and type of diabetes. Clin Neurophysiol Pract 2023; 8:115-122. [PMID: 38152244 PMCID: PMC10751747 DOI: 10.1016/j.cnp.2023.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 12/29/2023] Open
Abstract
Objective A prospective ultrasound study to analyze nerve size and its modifying factors in type 1 and type 2 diabetes mellitus. Methods The cross-sectional areas (CSAs) of motor and sensory nerves in both upper and lower limbs were measured at 14 measurement points, using high resolution ultrasound in 26 patients with type 1 and 76 patients with type 2 diabetes, and in 50 control subjects. All diabetic patients underwent electrophysiological assessment to check for the presence of polyneuropathy. Results Significant mild/moderate diffuse nerve enlargement was demonstrated in type 2 diabetes, more pronounced at compression sites versus non-compression sites, and on the upper limbs versus lower limbs (p value for pooled DM2 v. control group: <0.001). In type 1 diabetes, nerve enlargement was found only at one compression site (median nerve wrist; p = 0.002). No significant difference was found between patients with or without polyneuropathy. Conclusions The primary predictors of nerve size in diabetes are anatomical location (i.e. compression sites versus non-compression sites, upper versus lower limbs) and type of diabetes. Changes occur before the electrophysiological signs of polyneuropathy are detected. Significance Nerve ultrasound may contribute to early recognition of the neuropathic complications of diabetes.
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Affiliation(s)
- Marianna Tóth
- Dept. of Neurology, Vaszary Kolos Hospital, Esztergom, Hungary
| | - Annamária Szőke
- Dept. of Neurology, Vaszary Kolos Hospital, Esztergom, Hungary
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Miyashita A, Kobayashi M, Yokota T, Zochodne DW. Diabetic Polyneuropathy: New Strategies to Target Sensory Neurons in Dorsal Root Ganglia. Int J Mol Sci 2023; 24:ijms24065977. [PMID: 36983051 PMCID: PMC10051459 DOI: 10.3390/ijms24065977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/10/2023] [Accepted: 03/11/2023] [Indexed: 03/29/2023] Open
Abstract
Diabetic polyneuropathy (DPN) is the most common type of diabetic neuropathy, rendering a slowly progressive, symmetrical, and length-dependent dying-back axonopathy with preferential sensory involvement. Although the pathogenesis of DPN is complex, this review emphasizes the concept that hyperglycemia and metabolic stressors directly target sensory neurons in the dorsal root ganglia (DRG), leading to distal axonal degeneration. In this context, we discuss the role for DRG-targeting gene delivery, specifically oligonucleotide therapeutics for DPN. Molecules including insulin, GLP-1, PTEN, HSP27, RAGE, CWC22, and DUSP1 that impact neurotrophic signal transduction (for example, phosphatidylinositol-3 kinase/phosphorylated protein kinase B [PI3/pAkt] signaling) and other cellular networks may promote regeneration. Regenerative strategies may be essential in maintaining axon integrity during ongoing degeneration in diabetes mellitus (DM). We discuss specific new findings that relate to sensory neuron function in DM associated with abnormal dynamics of nuclear bodies such as Cajal bodies and nuclear speckles in which mRNA transcription and post-transcriptional processing occur. Manipulating noncoding RNAs such as microRNA and long-noncoding RNA (specifically MALAT1) that regulate gene expression through post-transcriptional modification are interesting avenues to consider in supporting neurons during DM. Finally, we present therapeutic possibilities around the use of a novel DNA/RNA heteroduplex oligonucleotide that provides more efficient gene knockdown in DRG than the single-stranded antisense oligonucleotide.
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Affiliation(s)
- Akiko Miyashita
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Masaki Kobayashi
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Department of Neurology, Nissan Tamagawa Hospital, Tokyo 158-0095, Japan
| | - Takanori Yokota
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Douglas W. Zochodne
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, The Neuroscience and Mental Health Institute and The Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2G3, Canada
- Correspondence: ; Tel.: +1-780-248-1928; Fax: +1-780-248-1807
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Mandali PK, Prabakaran A, Annadurai K, Krishnan UM. Trends in Quantification of HbA1c Using Electrochemical and Point-of-Care Analyzers. SENSORS (BASEL, SWITZERLAND) 2023; 23:1901. [PMID: 36850502 PMCID: PMC9965793 DOI: 10.3390/s23041901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 01/30/2023] [Accepted: 02/03/2023] [Indexed: 06/18/2023]
Abstract
Glycated hemoglobin (HbA1c), one of the many variants of hemoglobin (Hb), serves as a standard biomarker of diabetes, as it assesses the long-term glycemic status of the individual for the previous 90-120 days. HbA1c levels in blood are stable and do not fluctuate when compared to the random blood glucose levels. The normal level of HbA1c is 4-6.0%, while concentrations > 6.5% denote diabetes. Conventionally, HbA1c is measured using techniques such as chromatography, spectroscopy, immunoassays, capillary electrophoresis, fluorometry, etc., that are time-consuming, expensive, and involve complex procedures and skilled personnel. These limitations have spurred development of sensors incorporating nanostructured materials that can aid in specific and accurate quantification of HbA1c. Various chemical and biological sensing elements with and without nanoparticle interfaces have been explored for HbA1c detection. Attempts are underway to improve the detection speed, increase accuracy, and reduce sample volumes and detection costs through different combinations of nanomaterials, interfaces, capture elements, and measurement techniques. This review elaborates on the recent advances in the realm of electrochemical detection for HbA1c detection. It also discusses the emerging trends and challenges in the fabrication of effective, accurate, and cost-effective point-of-care (PoC) devices for HbA1c and the potential way forward.
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Affiliation(s)
- Pavan Kumar Mandali
- Centre for Nanotechnology& Advanced Biomaterials, SASTRA Deemed University, Thanjavur 613 401, India
- School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
| | - Amrish Prabakaran
- Centre for Nanotechnology& Advanced Biomaterials, SASTRA Deemed University, Thanjavur 613 401, India
- School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
| | - Kasthuri Annadurai
- Centre for Nanotechnology& Advanced Biomaterials, SASTRA Deemed University, Thanjavur 613 401, India
- School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
- School of Arts, Sciences, Humanities & Education, SASTRA Deemed University, Thanjavur 613 401, India
| | - Uma Maheswari Krishnan
- Centre for Nanotechnology& Advanced Biomaterials, SASTRA Deemed University, Thanjavur 613 401, India
- School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613 401, India
- School of Arts, Sciences, Humanities & Education, SASTRA Deemed University, Thanjavur 613 401, India
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Jiang J, Sun K, Lin F, Lu M, Huan L, Xu X, Sun J, Shi J, Guo Y. The Effect of Diabetes Mellitus on the Neurological Function of Patients with Cervical Spondylotic Myelopathy. Orthop Surg 2022; 14:3242-3250. [PMID: 36259631 PMCID: PMC9732620 DOI: 10.1111/os.13542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 08/08/2022] [Accepted: 08/24/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE To evaluate the clinical value of diabetes mellitus for diagnosis and postoperative prognosis in patients with cervical spondylotic myelopathy undergoing anterior decompression and fusion. METHODS A total of 84 Patients (50 males and 34 females) who underwent anterior decompression and fusion were reviewed in this single-center retrospective study. The patients were divided into two groups (44 patients in the diabetes mellitus group and 40 in the non-diabetic group). Clinical manifestations were evaluated, including characteristics baseline, clinical tests, MRI information, clinical scores, and complications. The predictive effect of diabetes mellitus on clinical scores were assessed via the receiver operating characteristic curve. The correlation between the severity of diabetes mellitus and neurological function recovery was estimated using the Pearson correlation coefficient. RESULTS Patients with diabetes mellitus exhibited a higher ratio of hyperintensity of the spinal cord (P < 0.05) and worse preoperative clinical scores and neurological recovery (all P < 0.05). Receiver operating characteristic curve results indicated that diabetes mellitus could serve as a good indicator for preoperative evaluation of the Japanese Orthopedic Association (JOA) score (area under curve [AUC] = 0.639), visual analogue score (AUC = 0.642), and Nurick score (AUC = 0.740). In addition, analysis of JOA in isolation suggested that diabetes mellitus correlated closely with the sensory function in the upper and lower limbs (both P < 0.01). The Receiver operating characteristic curve also demonstrated that diabetes mellitus as a clinical test had a reasonable specificity for sensory function in the upper (AUC = 0.654) and lower limbs (AUC = 0.671). Both the level of HbA1c and the duration of diabetes mellitus were negatively correlated with the recovery rate of the JOA score. There was no significant difference between the perioperative complications between the two groups (P > 0.05). CONCLUSION This present study revealed that the neurological impairment caused by diabetes mellitus in patients undergoing anterior decompression and fusion does not only affect postoperative functional recovery but also interferes with the preoperative clinical manifestations, especially the sensory function in the upper and lower limbs.
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Affiliation(s)
- Jialin Jiang
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Kaiqiang Sun
- Department of Orthopaedic SurgeryNaval Medical CenterShanghaiShanghaiChina
| | - Feng Lin
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina,Department of Orthopedic SurgeryThe Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityQingdaoShandongChina
| | - Mincheng Lu
- Department of Orthopaedics, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
| | - Le Huan
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Ximing Xu
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Jiangang Shi
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Yongfei Guo
- Department of Orthopedic Surgery, Spine Center, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
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Zanelli S, Ammi M, Hallab M, El Yacoubi MA. Diabetes Detection and Management through Photoplethysmographic and Electrocardiographic Signals Analysis: A Systematic Review. SENSORS (BASEL, SWITZERLAND) 2022; 22:4890. [PMID: 35808386 PMCID: PMC9269150 DOI: 10.3390/s22134890] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 06/15/2023]
Abstract
(1) Background: Diabetes mellitus (DM) is a chronic, metabolic disease characterized by elevated levels of blood glucose. Recently, some studies approached the diabetes care domain through the analysis of the modifications of cardiovascular system parameters. In fact, cardiovascular diseases are the first leading cause of death in diabetic subjects. Thanks to their cost effectiveness and their ease of use, electrocardiographic (ECG) and photoplethysmographic (PPG) signals have recently been used in diabetes detection, blood glucose estimation and diabetes-related complication detection. This review's aim is to provide a detailed overview of all the published methods, from the traditional (non machine learning) to the deep learning approaches, to detect and manage diabetes using PPG and ECG signals. This review will allow researchers to compare and understand the differences, in terms of results, amount of data and complexity that each type of approach provides and requires. (2) Method: We performed a systematic review based on articles that focus on the use of ECG and PPG signals in diabetes care. The search was focused on keywords related to the topic, such as "Diabetes", "ECG", "PPG", "Machine Learning", etc. This was performed using databases, such as PubMed, Google Scholar, Semantic Scholar and IEEE Xplore. This review's aim is to provide a detailed overview of all the published methods, from the traditional (non machine learning) to the deep learning approaches, to detect and manage diabetes using PPG and ECG signals. This review will allow researchers to compare and understand the differences, in terms of results, amount of data and complexity that each type of approach provides and requires. (3) Results: A total of 78 studies were included. The majority of the selected studies focused on blood glucose estimation (41) and diabetes detection (31). Only 7 studies focused on diabetes complications detection. We present these studies by approach: traditional, machine learning and deep learning approaches. (4) Conclusions: ECG and PPG analysis in diabetes care showed to be very promising. Clinical validation and data processing standardization need to be improved in order to employ these techniques in a clinical environment.
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Affiliation(s)
- Serena Zanelli
- University of Paris 8, LAGA, CNRS, Institut Galilée, 93200 Saint Denis, France;
- SAMOVAR Telecom SudParis, CNRS, Institut Polytechnique de Paris, 91764 Paris, France;
| | - Mehdi Ammi
- University of Paris 8, LAGA, CNRS, Institut Galilée, 93200 Saint Denis, France;
| | | | - Mounim A. El Yacoubi
- SAMOVAR Telecom SudParis, CNRS, Institut Polytechnique de Paris, 91764 Paris, France;
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Miyashita A, Kobayashi M, Ishibashi S, Nagata T, Chandrasekhar A, Zochodne DW, Yokota T. The Role of Long Noncoding RNA MALAT1 in Diabetic Polyneuropathy and the Impact of Its Silencing in the Dorsal Root Ganglion by a DNA/RNA Heteroduplex Oligonucleotide. Diabetes 2022; 71:1299-1312. [PMID: 35276003 DOI: 10.2337/db21-0918] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 03/06/2022] [Indexed: 11/13/2022]
Abstract
Diabetic polyneuropathy (DPN) is the most common complication of diabetes, yet its pathophysiology has not been established. Accumulating evidence suggests that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays pivotal roles in the regulation of cell growth and survival during diabetic complications. This study aimed to investigate the impact of MALAT1 silencing in dorsal root ganglion (DRG) sensory neurons, using an α-tocopherol-conjugated DNA/RNA heteroduplex oligonucleotide (Toc-HDO), on the peripheral nervous system of diabetic mice. We identified MALAT1 upregulation in the DRG of chronic diabetic mice that suggested either a pathological change or one that might be protective, and systemic intravenous injection of Toc-HDO effectively inhibited its gene expression. However, we unexpectedly noted that this intervention paradoxically exacerbated disease with increased thermal and mechanical nociceptive thresholds, indicating further sensory loss, greater sciatic-tibial nerve conduction slowing, and additional declines of intraepidermal nerve fiber density in the hind paw footpads. Serine/arginine-rich splicing factors, which are involved in pre-mRNA splicing by interacting with MALAT1, reside in nuclear speckles in wild-type and diabetic DRG neurons; MALAT1 silencing was associated with their disruption. The findings provide evidence for an important role that MALAT1 plays in DPN, suggesting neuroprotection and regulation of pre-mRNA splicing in nuclear speckles. This is also the first example in which a systemically delivered nucleotide therapy had a direct impact on DRG diabetic neurons and their axons.
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Affiliation(s)
- Akiko Miyashita
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaki Kobayashi
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Neurology, Nissan Tamagawa Hospital, Tokyo, Japan
| | - Satoru Ishibashi
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuya Nagata
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ambika Chandrasekhar
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas W Zochodne
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Takanori Yokota
- Department of Neurology, Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan
- Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan
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11
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Bhimavarapu U, Battineni G. Automatic Microaneurysms Detection for Early Diagnosis of Diabetic Retinopathy Using Improved Discrete Particle Swarm Optimization. J Pers Med 2022; 12:317. [PMID: 35207805 PMCID: PMC8878235 DOI: 10.3390/jpm12020317] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinopathy (DR) is one of the most important microvascular complications associated with diabetes mellitus. The early signs of DR are microaneurysms, which can lead to complete vision loss. The detection of DR at an early stage can help to avoid non-reversible blindness. To do this, we incorporated fuzzy logic techniques into digital image processing to conduct effective detection. The digital fundus images were segmented using particle swarm optimization to identify microaneurysms. The particle swarm optimization clustering combined the membership functions by grouping the high similarity data into clusters. Model testing was conducted on the publicly available dataset called DIARETDB0, and image segmentation was done by probability-based (PBPSO) clustering algorithms. Different fuzzy models were applied and the outcomes were compared with our probability discrete particle swarm optimization algorithm. The results revealed that the proposed PSO algorithm achieved an accuracy of 99.9% in the early detection of DR.
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Affiliation(s)
- Usharani Bhimavarapu
- Department of Computer Science and Engineering, Koneru Lakshmaiah Education Foundation, Vaddeswaram 522502, Andhra Pradesh, India;
| | - Gopi Battineni
- Clinical Research Center, School of Medicinal and Health Products Sciences, University of Camerino, 62032 Camerino, Italy
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12
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Harrington D, Henson J. Physical activity and exercise in the management of type 2 diabetes: where to start? PRACTICAL DIABETES 2021. [DOI: 10.1002/pdi.2361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Deirdre Harrington
- Diabetes Research Centre University of Leicester UK
- Psychological Sciences and Health University of Strathclyde Glasgow UK
| | - Joe Henson
- Diabetes Research Centre University of Leicester UK
- NIHR Leicester Biomedical Research Centre Leicester UK
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13
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Onyibe PN, Edo GI, Nwosu LC, Ozgor E. Effects of vernonia amygdalina fractionate on glutathione reductase and glutathione-S-transferase on alloxan induced diabetes wistar rat. BIOCATALYSIS AND AGRICULTURAL BIOTECHNOLOGY 2021. [DOI: 10.1016/j.bcab.2021.102118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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14
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Bak MS, Park H, Kim SK. Neural Plasticity in the Brain during Neuropathic Pain. Biomedicines 2021; 9:624. [PMID: 34072638 PMCID: PMC8228570 DOI: 10.3390/biomedicines9060624] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 01/02/2023] Open
Abstract
Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. Besides abnormal sensitization in the periphery and spinal cord, accumulating evidence suggests that neural plasticity in the brain is also critical for the development and maintenance of this pain. Recent technological advances in the measurement and manipulation of neuronal activity allow us to understand maladaptive plastic changes in the brain during neuropathic pain more precisely and modulate brain activity to reverse pain states at the preclinical and clinical levels. In this review paper, we discuss the current understanding of pathological neural plasticity in the four pain-related brain areas: the primary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray, and the basal ganglia. We also discuss potential treatments for neuropathic pain based on the modulation of neural plasticity in these brain areas.
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Affiliation(s)
- Myeong Seong Bak
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea; (M.S.B.); (H.P.)
| | - Haney Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea; (M.S.B.); (H.P.)
| | - Sun Kwang Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea; (M.S.B.); (H.P.)
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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15
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Zhu C, Liu N, Tian M, Ma L, Yang J, Lan X, Ma H, Niu J, Yu J. Effects of alkaloids on peripheral neuropathic pain: a review. Chin Med 2020; 15:106. [PMID: 33024448 PMCID: PMC7532100 DOI: 10.1186/s13020-020-00387-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/20/2020] [Indexed: 12/16/2022] Open
Abstract
Neuropathic pain is a debilitating pathological pain condition with a great therapeutic challenge in clinical practice. Currently used analgesics produce deleterious side effects. Therefore, it is necessary to investigate alternative medicines for neuropathic pain. Chinese herbal medicines have been widely used in treating intractable pain. Compelling evidence revealed that the bioactive alkaloids of Chinese herbal medicines stand out in developing novel drugs for neuropathic pain due to multiple targets and satisfactory efficacy. In this review, we summarize the recent progress in the research of analgesic effects of 20 alkaloids components for peripheral neuropathic pain and highlight the potential underlying molecular mechanisms. We also point out the opportunities and challenges of the current studies and shed light on further in-depth pharmacological and toxicological studies of these bioactive alkaloids. In conclusion, the alkaloids hold broad prospects and have the potentials to be novel drugs for treating neuropathic pain. This review provides a theoretical basis for further applying some alkaloids in clinical trials and developing new drugs of neuropathic pain.
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Affiliation(s)
- Chunhao Zhu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Ning Liu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China.,Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, No. 692 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Miaomiao Tian
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Lin Ma
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Jiamei Yang
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China.,Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, No. 692 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Xiaobing Lan
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China.,Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, No. 692 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Hanxiang Ma
- Department of Anesthesiology, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Yinchuan, Ningxia Hui Autonomous Region, 750004 Ningxia China
| | - Jianguo Niu
- Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China
| | - Jianqiang Yu
- Department of Pharmacology, College of Pharmacy, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China.,Ningxia Collaborative Innovation Center of Regional Characteristic Traditional Chinese Medicine, Ningxia Medical University, No. 692 Shengli Street, Yinchuan, 750004 Ningxia China.,Ningxia Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 Ningxia China
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16
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Polyphenols of marine red macroalga Symphyocladia latiuscula ameliorate diabetic peripheral neuropathy in experimental animals. Heliyon 2019; 5:e01781. [PMID: 31193485 PMCID: PMC6529741 DOI: 10.1016/j.heliyon.2019.e01781] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/24/2019] [Accepted: 05/17/2019] [Indexed: 12/29/2022] Open
Abstract
Aims Chronic hyperglycaemia activates the polyol pathway of glucose metabolism thereby stimulating the activation aldose reductase enzyme that in turn initiates a cascade of deleterious events, eventually, leading to nerve damage or neuropathy. Marine macroalgae and their isolated chemical constituents have been found to possess potential antidiabetic activity and have proved beneficial in the treatment of diabetes. In this study the neuroprotective effect of polyphenols isolated from the red macroalga Symphyocladia latiuscula was evaluated in experimental diabetic peripheral neuropathy. Main methods The polyphenolic fraction from Symphyocladia latiuscula was isolated. Diabetic peripheral neuropathy (DPN) was induced in animals by intraperitoneal injection of streptozotocin (45 mg/kg, b. w) and maintained for 6 weeks followed by treatment with SLPP or epalrestat. Nerve Conduction Velocity (NCV) and Compound Muscle Action Potential (CMAP) were measured using a non-invasive method followed by muscular grip strength test. Sciatic nerve aldose reductase activity, sorbitol accumulation, Na+K+-ATPase activity, production of pro-inflammatory cytokines and expression of AR and PKC were assessed. Key findings The Symphyocladia latiuscula polyphenols (SLPP) were found to inhibit aldose reductase activity as well as their expression in diabetic animals thereby improving the NCV, CMAP and muscle grip strength. Improvements in the sciatic nerve Na+K+-ATPase activity and intraneural accumulation of sorbitol, an index of aldose reductase overactivity, were evident with SLPP treatment. The production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and expression of protein kinase C (PKC) were also diminished. Significance The data suggest that the polyphenols of Symphyocladia latiuscula have neuroprotective potential against experimental DPN.
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17
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Samaddar S, Koneri R. Neuroprotective efficacy of polyphenols of marine brown macroalga Ecklonia cava in diabetic peripheral neuropathy. Pharmacogn Mag 2019. [DOI: 10.4103/pm.pm_212_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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18
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Shiri S, Abbasi N, Alizadeh K, Karimi E. Novel and green synthesis of a nanopolymer and its use as a drug delivery system of silibinin and silymarin extracts in the olfactory ensheathing cells of rats in normal and high-glucose conditions. RSC Adv 2019; 9:38912-38927. [PMID: 35540667 PMCID: PMC9075964 DOI: 10.1039/c9ra05608d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 10/27/2019] [Indexed: 01/03/2023] Open
Abstract
Drug delivery systems have been of interest to researchers. The effects of synthesized nano-polymers as silibinin and silymarin extract drug delivery systems on olfactory ensheathing cells under normal and high-glucose conditions were studied. The structure of the nanopolymer was characterized by IR, HNMR, GPC, DLS, and AFM. The toxicity was evaluated by an MTT assay. The production of ROS and the generation of NO were evaluated by a probe of fluorescein diacetate and Griess methods, respectively. The expressions of the protein levels of ILK, VEGF, BDNF, and NGF were investigated by western blotting. The polymer size was between 50 and 150 nm. The loading capacities for silibinin and silymarin were 68.5% and 56.4%, respectively, and the drug release for them was estimated at 54.1% and 50.8%, respectively. In high-glucose conditions, the cells were protected (EC50 = 4.88 ± 0.5 μM) by silibinin and nanopolymer in low concentrations by reducing the amount of ROS and NO, maintaining ILK, reducing VEGF and increasing NGF and BDNF. Incubation with silibinin and nanopolymer at high concentrations increased cell death with LC50 = 57.36 ± 2.5 and 43.18 ± 1.8 μM, respectively, in high-glucose states. Thus, the cells were protected by silibinin and nanopolymer in protective concentrations by reducing the amount of ROS and NO, maintaining ILK, reducing VEGF, and increasing BDNF and NGF. The mentioned mechanisms were totally reversed at high concentrations. A schematic of a new synthesized nanopolymer (CGONP) and its use as a drug delivery system of silibinin and silymarin extract in the olfactory ensheathing cells (OECs) of rats in normal and high-glucose conditions.![]()
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Affiliation(s)
- Sabah Shiri
- Department of Chemistry
- Lorestan University
- Khorramabad
- Iran
- Biotechnology and Medicinal Plants Research Center
| | - Naser Abbasi
- Biotechnology and Medicinal Plants Research Center
- Ilam University of Medical Sciences
- Ilam
- Iran
- Department of Pharmacology
| | - Kamal Alizadeh
- Department of Chemistry
- Lorestan University
- Khorramabad
- Iran
| | - Elahe Karimi
- Biotechnology and Medicinal Plants Research Center
- Ilam University of Medical Sciences
- Ilam
- Iran
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19
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Kobayashi M, Zochodne DW. Diabetic neuropathy and the sensory neuron: New aspects of pathogenesis and their treatment implications. J Diabetes Investig 2018; 9:1239-1254. [PMID: 29533535 PMCID: PMC6215951 DOI: 10.1111/jdi.12833] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/20/2018] [Accepted: 03/03/2018] [Indexed: 12/17/2022] Open
Abstract
Diabetic polyneuropathy (DPN) continues to be generally considered as a "microvascular" complication of diabetes mellitus alongside nephropathy and retinopathy. The microvascular hypothesis, however, might be tempered by the concept that diabetes directly targets dorsal root ganglion sensory neurons. This neuron-specific concept, supported by accumulating evidence, might account for important features of DPN, such as its early sensory neuron degeneration. Diabetic sensory neurons develop neuronal atrophy alongside a series of messenger ribonucleic acid (RNA) changes related to declines in structural proteins, increases in heat shock protein, increases in the receptor for advanced glycation end-products, declines in growth factor signaling and other changes. Insulin is recognized as a potent neurotrophic factor, and insulin ligation enhances neurite outgrowth through activation of the phosphoinositide 3-kinase-protein kinase B pathway within sensory neurons and attenuates phenotypic features of experimental DPN. Several interventions, including glucagon-like peptide-1 agonism, and phosphatase and tensin homolog inhibition to activate growth signals in sensory neurons, or heat shock protein overexpression, prevent or reverse neuropathic abnormalities in experimental DPN. Diabetic sensory neurons show a unique pattern of microRNA alterations, a key element of messenger RNA silencing. For example, let-7i is widely expressed in sensory neurons, supports their growth and is depleted in experimental DPN; its replenishment improves features of DPN models. Finally, impairment of pre-messenger RNA splicing in diabetic sensory neurons including abnormal nuclear RNA metabolism and structure with loss of survival motor neuron protein, a neuron survival molecule, and overexpression of CWC22, a splicing factor, offer further novel insights. The present review addresses these new aspects of DPN sensory neurodegeneration.
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Affiliation(s)
- Masaki Kobayashi
- Department of Neurology and Neurological ScienceGraduate School of MedicineTokyo Medical and Dental UniversityTokyoJapan
- Department of NeurologyYokufukai Geriatric HospitalTokyoJapan
| | - Douglas W Zochodne
- Division of Neurology and Department of MedicineNeuroscience and Mental Health InstituteFaculty of Medicine and DentistryUniversity of AlbertaEdmontonAlbertaCanada
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20
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Krieger SM, Reimann M, Haase R, Henkel E, Hanefeld M, Ziemssen T. Sudomotor Testing of Diabetes Polyneuropathy. Front Neurol 2018; 9:803. [PMID: 30319533 PMCID: PMC6168653 DOI: 10.3389/fneur.2018.00803] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 09/06/2018] [Indexed: 12/20/2022] Open
Abstract
Objective: The performance of the Sudoscan technology for diagnosing diabetic polyneuropathy (DPN) was evaluated against the quantitative sudomotor axon reflex test (QSART). Furthermore, the association of Sudoscan with two clinical neuropathy scoring systems was evaluated. Methods: Forty-seven patients with type 2 diabetes (20 without DPN, 27 with DPN) and 16 matched controls were examined for neuropathic symptoms and for the extent of sensory deficits. Sweat latency and volume by QSART and the skin electrochemical conductance (ESC) by Sudoscan were measured. Results: The feet and hand ESC was significantly lower in patients with DPN as compared to controls. Patients with DPN had also lower hand ESC than patients without DPN. Sensitivity and specificity of feet and hand ESC for detecting DPN were 70/85% and 53/50% respectively. QSART could not differentiate between the three groups. ESC was inversely related to neuropathic symptoms and sensory impairment. ESC was significantly correlated with sensory impairment and pain. Conclusions: Sudoscan shows a good performance in detecting subjects with DPN and it correlates well with clinical signs and symptoms of neuropathy. Significance: This study provides evidence that Sudoscan has high potential to be used as screening tool for DPN and possibly also for small fiber neuropathy in diabetic patients. HIGHLIGHTS - The sudomotor function test Sudoscan shows a good performance to detect diabetes peripheral neuropathy.- Sudoscan measures significantly correlate with clinical signs and symptoms of neuropathy.- The Sudoscan technology may help to secure clinical diagnosis of small fiber neuropathy.
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Affiliation(s)
- Sarah-Maria Krieger
- Autonomic and Neuroendocrinological Laboratory Dresden, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Manja Reimann
- Autonomic and Neuroendocrinological Laboratory Dresden, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Rocco Haase
- Autonomic and Neuroendocrinological Laboratory Dresden, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Elena Henkel
- GWT-TUD mbH, Study Center Professor Hanefeld, Dresden, Germany
| | | | - Tjalf Ziemssen
- Autonomic and Neuroendocrinological Laboratory Dresden, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden, Germany
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21
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Krentz AJ. Acute Symptomatic Diabetic Neuropathy Associated with Normalization of Haemoglobin A1. J R Soc Med 2018; 82:767-8. [PMID: 2693716 PMCID: PMC1292431 DOI: 10.1177/014107688908201224] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- A J Krentz
- Diabetic Clinic, General Hospital, Birmingham
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22
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Kobayashi M, Chandrasekhar A, Cheng C, Martinez JA, Ng H, de la Hoz C, Zochodne DW. Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22. Dis Model Mech 2017; 10:215-224. [PMID: 28250049 PMCID: PMC5374325 DOI: 10.1242/dmm.028225] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 12/23/2016] [Indexed: 12/31/2022] Open
Abstract
Unique deficits in the function of adult sensory neurons as part of their early neurodegeneration might account for progressive polyneuropathy during chronic diabetes mellitus. Here, we provide structural and functional evidence for aberrant pre-mRNA splicing in a chronic type 1 model of experimental diabetic polyneuropathy (DPN). Cajal bodies (CBs), unique nuclear substructures involved in RNA splicing, increased in number in diabetic sensory neurons, but their expected colocalization with survival motor neuron (SMN) proteins was reduced - a mislocalization described in motor neurons of spinal muscular atrophy. Small nuclear ribonucleoprotein particles (snRNPs), also participants in the spliceosome, had abnormal multiple nuclear foci unassociated with CBs, and their associated snRNAs were reduced. CWC22, a key spliceosome protein, was aberrantly upregulated in diabetic dorsal root ganglia (DRG), and impaired neuronal function. CWC22 attenuated sensory neuron plasticity, with knockdown in vitro enhancing their neurite outgrowth. Further, axonal delivery of CWC22 siRNA unilaterally to locally knock down the aberrant protein in diabetic nerves improved aspects of sensory function in diabetic mice. Collectively, our findings identify subtle but significant alterations in spliceosome structure and function, including dysregulated CBs and CWC22 overexpression, in diabetic sensory neurons that offer new ideas regarding diabetic sensory neurodegeneration in polyneuropathy.
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Affiliation(s)
- Masaki Kobayashi
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3
| | - Ambika Chandrasekhar
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3
| | - Chu Cheng
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1
| | - Jose A Martinez
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1
| | - Hilarie Ng
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1
| | - Cristiane de la Hoz
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1
| | - Douglas W Zochodne
- Division of Neurology and Department of Medicine, Faculty of Medicine and Dentistry, and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada, T6G 2G3 .,Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Canada, T2N 4N1
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23
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He XF, Wei JJ, Shou SY, Fang JQ, Jiang YL. Effects of electroacupuncture at 2 and 100 Hz on rat type 2 diabetic neuropathic pain and hyperalgesia-related protein expression in the dorsal root ganglion. J Zhejiang Univ Sci B 2017; 18:239-248. [PMID: 28271659 DOI: 10.1631/jzus.b1600247] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate the analgesic effects of electroacupuncture (EA) at 2 and 100 Hz on type 2 diabetic neuropathic pain (DNP) and on the expressions of the P2X3 receptor and calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG). METHODS Rat type 2 DNP was induced by a high calorie and high sugar diet fed for 7 weeks, plus a single intraperitoneal injection of streptozotocin (STZ) after 5 weeks. EA at 2 and 100 Hz was carried out once every day after 7 weeks for 7 consecutive days. Body weight, serum fasting insulin (FINS), fasting blood glucose (FBG), insulin sensitivity index (ISI), and paw withdrawal latency (PWL) were measured. The expressions of L4-L6 DRG P2X3 receptors and CGRP were assessed by immunofluorescence. RESULTS Type 2 DNP was successfully induced as shown by the increased body weight, FINS, and FBG, as well as the reduced ISI and PWL. Expressions of P2X3 receptors and CGRP in L4-L6 DRGs increased. EA at both 2 and 100 Hz relieved type 2 DNP, but the analgesic effect of EA was stronger at 2 Hz. P2X3 receptor expression decreased in L4-L6 DRGs following EA at 2 Hz and in L5 and L6 DRGs following EA at 100 Hz. EA at both 2 and 100 Hz down-regulated CGRP overexpression in L4-L6 DRGs. CONCLUSIONS These findings indicate that EA at 2 Hz is a good option for the management of type 2 DNP. The EA effect may be related to its down-regulation of the overexpressions of the DRG P2X3 receptors and CGRP in this condition.
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Affiliation(s)
- Xiao-Fen He
- Department of Neurobiology and Acupuncture Research, the Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jun-Jun Wei
- Department of Neurobiology and Acupuncture Research, the Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Sheng-Yun Shou
- Department of Neurobiology and Acupuncture Research, the Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jian-Qiao Fang
- Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yong-Liang Jiang
- Department of Neurobiology and Acupuncture Research, the Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
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Yakovleva OV, Zakharov AV, Zefirov AL, Sitdikova GF. Analysis of exo- and endocytosis in the mouse nerve ending in experimental diabetes mellitus. BIOCHEMISTRY (MOSCOW), SUPPLEMENT SERIES A: MEMBRANE AND CELL BIOLOGY 2017. [DOI: 10.1134/s199074781702009x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Physical Training and Activity in People With Diabetic Peripheral Neuropathy: Paradigm Shift. Phys Ther 2017; 97:31-43. [PMID: 27445060 PMCID: PMC6256941 DOI: 10.2522/ptj.20160124] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 07/11/2016] [Indexed: 12/31/2022]
Abstract
Diabetic peripheral neuropathy (DPN) occurs in more than 50% of people with diabetes and is an important risk factor for skin breakdown, amputation, and reduced physical mobility (ie, walking and stair climbing). Although many beneficial effects of exercise for people with diabetes have been well established, few studies have examined whether exercise provides comparable benefits to people with DPN. Until recently, DPN was considered to be a contraindication for walking or any weight-bearing exercise because of concerns about injuring a person's insensitive feet. These guidelines were recently adjusted, however, after research demonstrated that weight-bearing activities do not increase the risk of foot ulcers in people who have DPN but do not have severe foot deformity. Emerging research has revealed positive adaptations in response to overload stress in these people, including evidence for peripheral neuroplasticity in animal models and early clinical trials. This perspective article reviews the evidence for peripheral neuroplasticity in animal models and early clinical trials, as well as adaptations of the integumentary system and the musculoskeletal system in response to overload stress. These positive adaptations are proposed to promote improved function in people with DPN and to foster the paradigm shift to including weight-bearing exercise for people with DPN. This perspective article also provides specific assessment and treatment recommendations for this important, high-risk group.
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Yang L, Li Q, Liu X, Liu S. Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy. Int J Mol Sci 2016; 17:ijms17091479. [PMID: 27608006 PMCID: PMC5037757 DOI: 10.3390/ijms17091479] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 08/24/2016] [Accepted: 08/25/2016] [Indexed: 02/07/2023] Open
Abstract
Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause–effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy.
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Affiliation(s)
- Linlin Yang
- Department of Endocrinology, The General Hospital of the PLA Rocket Force, Beijing 100088, China.
| | - Quanmin Li
- Department of Endocrinology, The General Hospital of the PLA Rocket Force, Beijing 100088, China.
| | - Xinming Liu
- Department of Endocrinology, The General Hospital of the PLA Rocket Force, Beijing 100088, China.
| | - Shiguang Liu
- Department of Endocrinology, The General Hospital of the PLA Rocket Force, Beijing 100088, China.
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Abstract
Electrophysiologic studies provide objective data concerning nerve and muscle function. This information enables the diagnosis of disease states and monitoring of disease progression. This chapter describes the changes in electrophysiologic function in both prediabetes and diabetes and discusses the utility of this testing in patients with diabetes. Both the strengths and limitations of electrophysiology are discussed.
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Modeling long-term diabetes and related complications in rats. J Pharmacol Toxicol Methods 2016; 78:1-12. [DOI: 10.1016/j.vascn.2015.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 11/10/2015] [Accepted: 11/12/2015] [Indexed: 12/22/2022]
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Houten JK, Lenart C. Diabetes and cervical myelopathy. J Clin Neurosci 2015; 27:99-101. [PMID: 26747704 DOI: 10.1016/j.jocn.2015.07.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 06/12/2015] [Accepted: 07/01/2015] [Indexed: 11/29/2022]
Abstract
Diabetes may affect the typical physical findings associated with cervical spondylotic myelopathy, as coexisting diabetic neuropathy may dampen expected hyperreflexia and also produce non-dermatomal extremity numbness. Most large studies of surgically treated diabetic patients with cervical spondylotic myelopathy have focused upon infection rates rather than exploring any differences in the presenting physical signs. We conducted a retrospective study of the pattern of presenting neurological signs and symptoms and of the clinical outcomes in 438 patients surgically treated for cervical spondylotic myelopathy, 79 of whom had diabetes. Compared with non-diabetic patients, those with diabetes were slightly older and had lower preoperative modified Japanese Orthopaedic Association (mJOA) scores. Those with diabetes also had a significantly higher incidence of hyporeflexia and a higher incidence of a positive Babinski sign, but there was no difference in the appearance of the Hoffman sign. The magnitude of mJOA improvement after surgery was comparable. We conclude that diabetes may alter the typical signs and symptoms of cervical spondylotic myelopathy and suggest that knowledge of the differences may aid in securing a prompt and accurate diagnosis.
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Affiliation(s)
- John K Houten
- Marcus Neuroscience Institute at the Boca Raton Regional Hospital, Boca Raton, FL 33486, USA.
| | - Christopher Lenart
- Department of Neurosurgery, Montefiore Medical Center and Albert Einstein College of Medicine of Yeshiva University, 111 E. 210th Street Bronx, NY 10467, USA
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Schreiber AK, Nones CFM, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes 2015; 6:432-444. [PMID: 25897354 PMCID: PMC4398900 DOI: 10.4239/wjd.v6.i3.432] [Citation(s) in RCA: 278] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/26/2014] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, which affects over 90% of the diabetic patients. Although pain is one of the main symptoms of diabetic neuropathy, its pathophysiological mechanisms are not yet fully known. It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication, but several other hypotheses have been postulated. The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline. In addition, there is experimental and clinical evidence that opioids can be helpful in pain control, mainly if associated with first line drugs. Other agents, including for topical application, such as capsaicin cream and lidocaine patches, have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain, but the clinical evidence is insufficient to support their use. In conclusion, a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies, but also to the improvement of the guidelines to optimize pain control with the drugs currently available.
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The Combined Extract of Zingiber officinale and Zea mays (Purple Color) Improves Neuropathy, Oxidative Stress, and Axon Density in Streptozotocin Induced Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:301029. [PMID: 25969689 PMCID: PMC4410543 DOI: 10.1155/2015/301029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 03/10/2015] [Indexed: 01/01/2023]
Abstract
Based on the protective effect of the combined extract of purple waxy corn and ginger (PWCG) on oxidative stress related disorders in diabetic condition, we aimed to determine the effect of PWCG on the functional, biochemical, and structural change of the lesion nerve in streptozotocin- (STZ-) diabetic rats. PWCG at doses of 100, 200, and 300 mg·kg−1 BW were orally given to STZ-diabetic rats which were subjected to chronic constriction (CCI) at right sciatic nerve for 21 days. The blood sugar was assessed before and at the end of study whereas the sciatic function index (SFI), paw withdrawal threshold intensity (PWTI), and paw withdrawal latency (PWL) were assessed every 3 days until the end of study. At the end of study, the determination of nerve conduction velocity (NCV), axon density, oxidative stress status, and aldose reductase (AR) activity of the lesion nerve were performed. It was found that PWCG improved SFI, PWTI, PWL, and NCV together with the improved oxidative stress status and the axon density in the lesion nerve. No changes of AR activity or blood sugar level were observed. Therefore, PWCG might improve the functional and structural changes in STZ-diabetic rats plus CCI via the improved oxidative stress status.
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Schuelert N, Gorodetskaya N, Just S, Doods H, Corradini L. Electrophysiological characterization of spinal neurons in different models of diabetes type 1- and type 2-induced neuropathy in rats. Neuroscience 2015; 291:146-54. [PMID: 25686525 DOI: 10.1016/j.neuroscience.2015.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/15/2015] [Accepted: 02/03/2015] [Indexed: 10/24/2022]
Abstract
Diabetic polyneuropathy (DPN) is a devastating complication of diabetes. The underlying pathogenesis of DPN is still elusive and an effective treatment devoid of side effects presents a challenge. There is evidence that in type-1 and -2 diabetes, metabolic and morphological changes lead to peripheral nerve damage and altered central nociceptive transmission, which may contribute to neuropathic pain symptoms. We characterized the electrophysiological response properties of spinal wide dynamic range (WDR) neurons in three diabetic models. The streptozotocin (STZ) model was used as a drug-induced model of type-1 diabetes, and the BioBreeding/Worcester (BB/Wor) and Zucker diabetic fatty (ZDF) rat models were used for genetic DPN models. Data were compared to the respective control group (BB/Wor diabetic-resistant, Zucker lean (ZL) and saline-injected Wistar rat). Response properties of WDR neurons to mechanical stimulation and spontaneous activity were assessed. We found abnormal response properties of spinal WDR neurons in all diabetic rats but not controls. Profound differences between models were observed. In BB/Wor diabetic rats evoked responses were increased, while in ZDF rats spontaneous activity was increased and in STZ rats mainly after discharges were increased. The abnormal response properties of neurons might indicate differential pathological, diabetes-induced, changes in spinal neuronal transmission. This study shows for the first time that specific electrophysiological response properties are characteristic for certain models of DPN and that these might reflect the diverse and complex symptomatology of DPN in the clinic.
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Affiliation(s)
- N Schuelert
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany.
| | - N Gorodetskaya
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany
| | - S Just
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany
| | - H Doods
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany
| | - L Corradini
- Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach, Germany
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Haensch CA, Tosch M, Katona I, Weis J, Isenmann S. Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve 2014; 50:956-61. [PMID: 24647968 DOI: 10.1002/mus.24245] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2014] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. METHODS Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. RESULTS Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 ± 2.9/mm (normal ≥ 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r = 0.39, P = 0.001). CONCLUSIONS A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation.
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Affiliation(s)
- Carl-Albrecht Haensch
- Department of Neurology, Kliniken Maria Hilf Mönchengladbach, Faculty of Health, University of Witten/Herdecke, Viersenerstrasse 450, D-41063, Mönchengladbach, Germany
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Bai HP, Liu P, Wu YM, Guo WY, Guo YX, Wang XL. Activation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathy. J Neurol Sci 2014; 341:68-72. [PMID: 24787504 DOI: 10.1016/j.jns.2014.04.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 03/16/2014] [Accepted: 04/01/2014] [Indexed: 12/13/2022]
Abstract
N-methyl-D-aspartate receptor (NMDAR) activity is increased, while GABAB receptor is downregulated in the spinal cord dorsal horn in diabetic neuropathy. In this study, we determined the interaction of NMDARs and GABAB receptors in streptozotocin (STZ)-induced diabetic neuropathy. The paw withdrawal threshold (PWT) was significantly lower in STZ-treated rats than in vehicle-treated rats. Intrathecal injection of baclofen, a GABAB receptor agonist, significantly increased the PWT in STZ-treated rats, an effect that was abolished by pre-administration of the GABAB receptor specific antagonist CGP55845. Spinal NR2B, an NMDA receptor subunit, protein and mRNA expression levels were significantly higher in STZ-treated rats than in vehicle-treated rats. Intrathecal baclofen significantly reduced the NR2B protein and mRNA expression levels in STZ-treated rats. Intrathecal administration of CGP55845 eliminated baclofen-induced reduction of NR2B protein and mRNA levels in STZ-treated rats. In addition, the phosphorylated cAMP response element-binding (CREB) protein level was significantly higher in the spinal cord dorsal horn in STZ-treated rats compared with vehicle-treated rats. Intrathecal injection of baclofen significantly decreased phosphorylated CREB protein level in STZ-treated rats; an effect was blocked by CGP55845. These data suggest that activation of GABAB receptors in the spinal cord dorsal horn normalizes NMDAR expression level in diabetic neuropathic pain.
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Affiliation(s)
- Hui-Ping Bai
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, China
| | - Peng Liu
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, China
| | - Yu-Ming Wu
- Department of Physiology, Hebei Medical University, China
| | - Wen-Ya Guo
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, China
| | - Yue-Xian Guo
- Department of Urology, The Third Hospital of Hebei Medical University, China
| | - Xiu-Li Wang
- Department of Anesthesiology, The Third Hospital of Hebei Medical University, China.
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36
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Abstract
Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Symptoms usually include numbness, tingling, pain, and weakness. Dizziness with postural changes can be seen with autonomic neuropathy. Metabolic, vascular, and immune theories have been proposed for the pathogenesis of diabetic neuropathy. Axonal damage and segmental demyelination can be seen with diabetic neuropathies. Management of diabetic neuropathy should begin at the initial diagnosis of diabetes and mainly requires tight and stable glycemic control.
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Shabani M, Zangiabadi N, Asadi-Shekaari M. Evidence for Positive Effects of Date Extract That Attenuates Thermal Hyperalgesia in a Diabetic Rat Model of Neuropathic Pain. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/nm.2013.41003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Kim H, Kim JJ, Yoon YS. Emerging therapy for diabetic neuropathy: cell therapy targeting vessels and nerves. Endocr Metab Immune Disord Drug Targets 2012; 12:168-78. [PMID: 22236028 DOI: 10.2174/187153012800493486] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Accepted: 09/27/2011] [Indexed: 01/19/2023]
Abstract
Diabetic neuropathy (DN), the most common complication of diabetes, frequently leads to foot ulcers and may progress to limb amputations. Despite continuous increase in incidence, there is no clinical therapy to effectively treat DN. Pathogenetically, DN is characterized by reduced vascularity in peripheral nerves and deficiency in angiogenic and neurotrophic factors. We will briefly review the pathogenetic mechanism of DN and address the effects and the mechanisms of cell therapies for DN. To reverse the changes of DN, studies have attempted to deliver neurotrophic or angiogenic factors for treatment in the form of protein or gene therapy; however, the effects turned out to be very modest if not ineffective. Recent studies have demonstrated that bone marrow (BM)-derived cells such as mononuclear cells or endothelial progenitor cells (EPCs) can effectively treat various cardiovascular diseases through their paracrine effects. As BM-derived cells include multiple angiogenic and neurotrophic cytokines, these cells were used for treating experimental DN and found to reverse manifestations of DN. Particularly, EPCs were shown to exert favorable therapeutic effects through enhanced neural neovascularization and neuro-protective effects. These findings clearly indicate that DN is a complex disorder with pathogenetic involvement of both vascular and neural components. Studies have shown that cell therapies targeting both vascular and neural elements are shown to be advantageous in treating DN.
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Affiliation(s)
- Hyongbum Kim
- Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University, Seoul, Korea
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Kandhare AD, Raygude KS, Shiva Kumar V, Rajmane AR, Visnagri A, Ghule AE, Ghosh P, Badole SL, Bodhankar SL. Ameliorative effects quercetin against impaired motor nerve function, inflammatory mediators and apoptosis in neonatal streptozotocin-induced diabetic neuropathy in rats. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.biomag.2012.10.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes. Proc Natl Acad Sci U S A 2012; 109:11390-5. [PMID: 22733772 DOI: 10.1073/pnas.1208708109] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. The progressive damage to the peripheral nervous system is irreversible although strict control of hyperglycemia may prevent further damage. Current treatments include tricyclic antidepressants, anticonvulsants, and opioids, depending on the severity of the pain state. However, available therapeutics have drawbacks, arguing for the need to better understand the pathophysiology of neuropathic pain and develop novel treatments. Here we demonstrate that stabilization of a class of bioactive lipids, epoxygenated fatty acids (EpFAs), greatly reduces allodynia in rats caused by streptozocin-induced type I diabetes. Inhibitors of the soluble epoxide hydrolase (sEHI) elevated and stabilized the levels of plasma and spinal EpFAs, respectively, and generated dose-dependent antiallodynic effects more potently and efficaciously than gabapentin. In acute experiments, positive modulation of EpFAs did not display differences in insulin sensitivity, glucose tolerance, or insulin secretion, indicating the efficacy of sEHIs are not related to the glycemic status. Quantitative metabolomic analysis of a panel of 26 bioactive lipids demonstrated that sEHI-mediated antiallodynic effects coincided with a selective elevation of the levels of EpFAs in the plasma, and a decrease in degradation products coincided with the dihydroxy fatty acids in the spinal cord. Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain.
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Sun W, Miao B, Wang XC, Duan JH, Ye X, Han WJ, Wang WT, Luo C, Hu SJ. Gastrodin inhibits allodynia and hyperalgesia in painful diabetic neuropathy rats by decreasing excitability of nociceptive primary sensory neurons. PLoS One 2012; 7:e39647. [PMID: 22761855 PMCID: PMC3382466 DOI: 10.1371/journal.pone.0039647] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 05/24/2012] [Indexed: 01/29/2023] Open
Abstract
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus and adversely affects the patients' quality of life. Evidence has accumulated that PDN is associated with hyperexcitability of peripheral nociceptive primary sensory neurons. However, the precise cellular mechanism underlying PDN remains elusive. This may result in the lacking of effective therapies for the treatment of PDN. The phenolic glucoside, gastrodin, which is a main constituent of the Chinese herbal medicine Gastrodia elata Blume, has been widely used as an anticonvulsant, sedative, and analgesic since ancient times. However, the cellular mechanisms underlying its analgesic actions are not well understood. By utilizing a combination of behavioral surveys and electrophysiological recordings, the present study investigated the role of gastrodin in an experimental rat model of STZ-induced PDN and to further explore the underlying cellular mechanisms. Intraperitoneal administration of gastrodin effectively attenuated both the mechanical allodynia and thermal hyperalgesia induced by STZ injection. Whole-cell patch clamp recordings were obtained from nociceptive, capsaicin-sensitive small diameter neurons of the intact dorsal root ganglion (DRG). Recordings from diabetic rats revealed that the abnormal hyperexcitability of neurons was greatly abolished by application of GAS. To determine which currents were involved in the antinociceptive action of gastrodin, we examined the effects of gastrodin on transient sodium currents (I(NaT)) and potassium currents in diabetic small DRG neurons. Diabetes caused a prominent enhancement of I(NaT) and a decrease of potassium currents, especially slowly inactivating potassium currents (I(AS)); these effects were completely reversed by GAS in a dose-dependent manner. Furthermore, changes in activation and inactivation kinetics of I(NaT) and total potassium current as well as I(AS) currents induced by STZ were normalized by GAS. This study provides a clear cellular basis for the peripheral analgesic action of gastrodin for the treatment of chronic pain, including PDN.
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Affiliation(s)
- Wei Sun
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
- Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, the Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Bei Miao
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
- Jiangsu Province Key Laboratory of Anesthesiology and Center for Pain Research and Treatment, Xuzhou Medical College, Xuzhou, People’s Republic of China
| | - Xiu-Chao Wang
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Jian-Hong Duan
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Xin Ye
- Department of Endocrinology, The 451th Hospital of People’s Liberation Army, Xi’an, People’s Republic of China
| | - Wen-Juan Han
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Wen-Ting Wang
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Ceng Luo
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
| | - San-Jue Hu
- Institute of Neuroscience, The Fourth Military Medical University, Xi’an, People’s Republic of China
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Ohkawara S, Tanaka-Kagawa T, Furukawa Y, Jinno H. Methylglyoxal activates the human transient receptor potential ankyrin 1 channel. J Toxicol Sci 2012; 37:831-5. [DOI: 10.2131/jts.37.831] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
| | | | - Yoko Furukawa
- Division of Environmental Chemistry, National Institute of Health Sciences
| | - Hideto Jinno
- Division of Environmental Chemistry, National Institute of Health Sciences
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43
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Reagan LP. Diabetes as a chronic metabolic stressor: causes, consequences and clinical complications. Exp Neurol 2012; 233:68-78. [PMID: 21320489 PMCID: PMC3110581 DOI: 10.1016/j.expneurol.2011.02.004] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Revised: 01/04/2011] [Accepted: 02/06/2011] [Indexed: 12/30/2022]
Abstract
Diabetes mellitus is an endocrine disorder resulting from inadequate insulin release and/or reduced insulin sensitivity. The complications of diabetes are well characterized in peripheral tissues, but there is a growing appreciation that the complications of diabetes extend to the central nervous system (CNS). One of the potential neurological complications of diabetes is cognitive deficits. Interestingly, the structural, electrophysiological, neurochemical and anatomical underpinnings responsible for cognitive deficits in diabetes are strikingly similar to those observed in animals subjected to chronic stress, as well as in patients with stress-related psychiatric illnesses such as major depressive disorder. Since diabetes is a chronic metabolic stressor, this has led to the suggestion that common mechanistic mediators are responsible for neuroplasticity deficits in both diabetes and depression. Moreover, these common mechanistic mediators may be responsible for the increase in the risk of depressive illness in diabetes patients. In view of these observations, the aims of this review are (1) to describe the neuroplasticity deficits observed in diabetic rodents and patients; (2) to summarize the similarities in the clinical and preclinical studies of depression and diabetes; and (3) to highlight the diabetes-induced neuroplasticity deficits in those brain regions that have been implicated as important pathological centers in depressive illness, namely, the hippocampus, the amygdala and the prefrontal cortex.
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Affiliation(s)
- Lawrence P Reagan
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
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Xu GY, Li G, Liu N, Huang LYM. Mechanisms underlying purinergic P2X3 receptor-mediated mechanical allodynia induced in diabetic rats. Mol Pain 2011; 7:60. [PMID: 21851615 PMCID: PMC3168406 DOI: 10.1186/1744-8069-7-60] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Accepted: 08/18/2011] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Diabetic neuropathy is a common neuropathy associated with paresthaesia and pain. The mechanisms underlying the painful conditions are not well understood. The aim of this study is to investigate the participation of purinergic P2X3 receptors in painful diabetic neuropathy. RESULTS Diabetes was induced by an intraperitoneal injection of streptozotocin (STZ). We showed that mechanical allodynia was induced two weeks after a STZ injection and lasted for at least another seven weeks. The mechanical allodynia was significantly attenuated by peripheral administration of the P2X receptor antagonists, PPADS or TNP-ATP. DiI was subcutaneously injected into the rat hindpaw to label hindpaw-innervated dorsal root ganglion (DRG) neurons. ATP activated fast-inactivating P2X3 receptor-mediated currents in the labeled DRG neurons were studied. ATP responses in STZ-treated rats were ~2-fold larger than those in control rats. Furthermore, the expression of P2X3 receptor proteins in the plasma membrane of L4-6 DRGs of STZ rats was significantly enhanced while the total expression of P2X3 receptors remained unaltered. CONCLUSIONS These results indicate that a large enhancement of P2X3 receptor activity and an increase in the membrane expression of P2X3 receptors contribute to the development of chronic pain in STZ-induced diabetic rats and suggest a possible target for the treatment of diabetic neuropathic pain.
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Affiliation(s)
- Guang-Yin Xu
- Institute of Neuroscience and Department of Neurobiology and Psychology, Key lab of Pain Research and Therapy, Soochow University, Suzhou 215123, the People's Republic of China
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0655, USA
| | - Guangwen Li
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA
| | - Ningang Liu
- Institute of Neuroscience and Department of Neurobiology and Psychology, Key lab of Pain Research and Therapy, Soochow University, Suzhou 215123, the People's Republic of China
| | - Li-Yen Mae Huang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA
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Wang XL, Zhang Q, Zhang YZ, Liu YT, Dong R, Wang QJ, Guo YX. Downregulation of GABAB receptors in the spinal cord dorsal horn in diabetic neuropathy. Neurosci Lett 2011; 490:112-5. [PMID: 21184807 DOI: 10.1016/j.neulet.2010.12.038] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2010] [Revised: 12/13/2010] [Accepted: 12/15/2010] [Indexed: 11/23/2022]
Abstract
Diabetic neuropathic pain is a common clinical problem and remains difficult to treat with classic analgesics. Spinal dorsal horn neurons are important in mediating nociceptive signaling, and the hyperactivity of these neurons is critical in diabetic neuropathy. In this study, we determined the GABA(B) receptor expression level in dorsal horn neurons in streptozotocin (STZ)-induced diabetes in rats by using reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses. Mean blood glucose concentrations were significantly higher and the paw withdrawal threshold was significantly lower in STZ-treated rats than in saline-treated rats. Immunohistochemical staining showed that the GABA(B) receptor was extensively expressed in the spinal dorsal horn neurons. The GABA(B1) mRNA level decreased in a time-dependent manner in STZ-treated rats compared with saline-treated controls. Furthermore, the protein expression level revealed by western blot analysis was lower in STZ-treated rats than in saline-treated rats. These data suggest that GABA(B) receptors are downregulated in the spinal dorsal horn in this model of STZ-induced diabetic neuropathic pain. The reduction of GABA(B) expression may contribute to the hyperactivity of spinal dorsal horn neurons and diabetic neuropathic pain.
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Affiliation(s)
- Xiu-Li Wang
- Department of Anesthesiology, The Third Hospital of HeBei Medical University, Shijiazhuang, HeBei Province 050011, China.
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Abstract
Diabetes mellitus is generally treated with oral diabetic drugs and/or insulin. However, the morbidity and mortality associated with this condition increases over time, even in patients receiving intensive insulin treatment, and this is largely attributable to diabetic complications or the insulin therapy itself. Pancreas transplantation in humans was first conducted in 1966, since when there has been much debate regarding the legitimacy of this procedure. Technical refinements and the development of better immunosuppressants and better postoperative care have brought about marked improvements in patient and graft survival and a reduction in postoperative morbidity. Consequently, pancreas transplantation has become the curative treatment modality for diabetes, particularly for type I diabetes. An overview of pancreas transplantation is provided herein, covering the history of pancreas transplantation, indications for transplantation, cadaveric and living donors, surgical techniques, immunosuppressants, and outcome following pancreas transplantation. The impact of successful pancreas transplantation on the complications of diabetes will also be reviewed briefly.
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Affiliation(s)
- Duck Jong Han
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Ohsawa M, Aasato M, Hayashi SS, Kamei J. RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice. Pain 2010; 152:114-122. [PMID: 20980102 DOI: 10.1016/j.pain.2010.10.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Revised: 09/17/2010] [Accepted: 10/04/2010] [Indexed: 10/18/2022]
Abstract
Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies.
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Affiliation(s)
- Masahiro Ohsawa
- Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-Chome, Shinagawa-Ku, Tokyo 142-8501, Japan
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Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor. J Neurochem 2010; 114:1460-75. [PMID: 20557422 PMCID: PMC2923276 DOI: 10.1111/j.1471-4159.2010.06863.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.
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Affiliation(s)
- Xue-Hong Cao
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Hee-Sun Byun
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Shao-Rui Chen
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - You-Qing Cai
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Hui-Lin Pan
- Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Program in Neuroscience, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77225
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RhoA/Rho kinase signaling in the spinal cord and diabetic painful neuropathy. Eur J Pharmacol 2010; 644:1-4. [PMID: 20655903 DOI: 10.1016/j.ejphar.2010.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 07/05/2010] [Accepted: 07/11/2010] [Indexed: 11/20/2022]
Abstract
Diabetic neuropathy is one of the most common complications in diabetes, and hyperalgesia and allodynia are serious symptoms of diabetic neuropathy. There are few therapeutic options available for the treatment of such diabetic painful neuropathy. While several reports have indicated that an abnormality of intracellular signaling molecules is involved in the pathogenesis of diabetic painful neuropathy, agents that affect these intracellular signaling molecules have failed to deliver convincing results in clinical trials. Recently, the small molecular G-protein RhoA has been shown to be involved in the pathogenesis of diabetic nephropathy. RhoA and its downstream kinase Rho kinase (ROCK) have been shown to modulate nociceptive transmission in the spinal cord. In this report, we provide a brief overview of the role of the RhoA/ROCK pathway in diabetic complications. We especially focus on the role of the spinal RhoA/ROCK pathway in the pathogenesis of diabetic painful neuropathy. Findings on the association between the spinal RhoA/ROCK pathway and diabetic painful neuropathy may lead to new strategies for its treatment.
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Serafín A, Molín J, Márquez M, Blasco E, Vidal E, Foradada L, Añor S, Rabanal RM, Fondevila D, Bosch F, Pumarola M. Diabetic neuropathy: electrophysiological and morphological study of peripheral nerve degeneration and regeneration in transgenic mice that express IFNbeta in beta cells. Muscle Nerve 2010; 41:630-41. [PMID: 19918773 DOI: 10.1002/mus.21564] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Diabetic neuropathy is one of the most frequent complications in diabetes but there are no treatments beyond glucose control, due in part to the lack of an appropriate animal model to assess an effective therapy. This study was undertaken to characterize the degenerative and regenerative responses of peripheral nerves after induced sciatic nerve damage in transgenic rat insulin I promoter / human interferon beta (RIP/IFNbeta) mice made diabetic with a low dose of streptozotocin (STZ) as an animal model of diabetic complications. In vivo, histological and immunohistological studies of cutaneous and sciatic nerves were performed after left sciatic crush. Functional tests, cutaneous innervation, and sciatic nerve evaluation showed pronounced neurological reduction in all groups 2 weeks after crush. All animals showed a gradual recovery but this was markedly slower in diabetic animals in comparison with normoglycemic animals. The delay in regeneration in diabetic RIP/IFNbeta mice resulted in an increase in active Schwann cells and regenerating neurites 8 weeks after surgery. These findings indicate that diabetic-RIP/IFNbeta animals mimic human diabetic neuropathy. Moreover, when these animals are submitted to nerve crush they have substantial deficits in nerve regrowth, similar to that observed in diabetic patients. When wildtype animals were treated with the same dose of STZ, no differences were observed with respect to nontreated animals, indicating that low doses of STZ and the transgene are not implicated in development of the degenerative and regenerative events observed in our study. All these findings indicate that RIP/IFNbeta transgenic mice are a good model for diabetic neuropathy.
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Affiliation(s)
- Anna Serafín
- Centre de Biotecnologia Animal i Terapia Gènica (CBATEG), Universitat Autònoma de Barcelona, Edifici H, Campus UAB, 08193 Bellaterra (Cerdanyola del Vallès), Spain.
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