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Hamour HM, Marangoz AH, Altun G, Kaplan S. Neuroprotective effects of Garcinia kolaand curcumin on diabetic transected sciatic nerve. Biomed Mater 2025; 20:035025. [PMID: 40267944 DOI: 10.1088/1748-605x/adcfe3] [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: 12/21/2024] [Accepted: 04/23/2025] [Indexed: 04/25/2025]
Abstract
The growing interest in peripheral nerve regeneration and developing post-traumatic repair methods under diabetes was the impetus for this study, which aims to investigate the effect of curcumin andGarcinia kola(GK) on the transected and diabetic sciatic nerves. Thirty-five male Wistar albino rats were used. The animals were divided into five groups; each consisted of seven rats. The sciatic nerve was transected in all groups of rats except the control (Cont) group, which underwent no treatment. In the transected animals, a 10 mm nerve stump was removed from the 2 cm distal to the sciatic notch. The external jugular vein was used as a conduit to repair the gap between the two ends of the sciatic nerve. Diabetes was induced in the transected + diabetes mellitus (T + DM), the transected + diabetes mellitus + GK (T + DM + GK), and the transected + diabetes mellitus + Curcumin (T + DM + Cur) groups except for the sham group. A dose of 300 mg kg-1d-1of curcumin dissolved in olive oil was administered to the T + DM + Cur group (via oral gavage every day for 28 d) and 200 mg kg-1d-1of GK to the T + DM + GK group (via oral gavage every day for 7 d). All animals were sacrificed after three months. Stereological analysis and functional and microscopic evaluations were done to evaluate the sciatic nerve regeneration and function. In the T + DM + GK and the sham groups, the number of axons increased. A slight improvement in the axonal area in the T + DM + Cur and the sham groups was also observed, and an increase in the myelin sheath thickness was found in the T + DM + GK and the sham group. When the SFI test results were evaluated, it was seen that GK had a stronger effect than curcumin in terms of functional regeneration. Additionally, no significant difference was observed between T + DM and Cont groups when the electrophysiological results were examined. The study showed GK's efficiency in treating diabetic peripheral nerve regeneration.
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Affiliation(s)
- Hala Mahgoub Hamour
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun, Turkey
| | | | - Gamze Altun
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun, Turkey
| | - Süleyman Kaplan
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun, Turkey
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Silva GSDA, Santana TDCM, Velozo ACL, Macêdo APA, Gonçalves MDS, Couto RD, Soares MBP, Viana MDM, Villarreal CF. Green Tea Intake Reduces High-Fat Diet-Induced Sensory Neuropathy in Mice by Upregulating the Antioxidant Defense System in the Spinal Cord. Antioxidants (Basel) 2025; 14:452. [PMID: 40298836 PMCID: PMC12023980 DOI: 10.3390/antiox14040452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/04/2025] [Accepted: 04/07/2025] [Indexed: 04/30/2025] Open
Abstract
One of the most common complications of obesity is peripheral nerve damage, which progresses to sensory neuropathy. Green tea (GT) intake has been associated with weight loss and metabolic biomarkers modulation due to its antioxidant properties. The present work characterized the effects of GT in high-fat diet (HFD)-induced neuropathy and investigated the mechanisms involved. C57BL/6J male mice were fed an HFD or control diet, associated with GT or vehicle intake for 16 weeks. Weight, blood glucose, and nociceptive thresholds were assessed. Morphological and morphometric analyses of the sciatic nerves were performed. Activation of the cellular antioxidant system in the spinal cord was assessed by real-time PCR. GT intake reduced weight gain, hyperglycemia, and the development of sensory neuropathy. Furthermore, in HFD-fed mice that consumed GT, the morphology of the sciatic nerve was preserved. RT-qPCR analysis showed that HFD-fed mice ingesting GT had higher spinal levels of superoxide dismutase, catalase, glutathione peroxidase, and nuclear factor erythroid 2-related factor 2 (NRF2) mRNA compared to the HFD-fed mice ingesting vehicle, suggesting that the endogenous antioxidant system was more activated in response to GT consumption. In conclusion, the data suggest that GT intake reduces HFD-induced neuropathy, probably by upregulating antioxidant gene expression.
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Affiliation(s)
- Gessica Sabrina de Assis Silva
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Thalita da Cruz Monteiro Santana
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Ana Carolina Lucchese Velozo
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Ana Paula Azevêdo Macêdo
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Mariane dos Santos Gonçalves
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Ricardo David Couto
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296710, BA, Brazil;
- Institute of Advanced Systems in Health (ISI-SAS), Senai Cimatec, Salvador 41650010, BA, Brazil
| | - Max Denisson Maurício Viana
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
| | - Cristiane Flora Villarreal
- School of Pharmacy, Federal University of Bahia, Salvador 40170290, BA, Brazil; (G.S.d.A.S.); (T.d.C.M.S.); (A.C.L.V.); (A.P.A.M.); (M.d.S.G.); (R.D.C.); (M.D.M.V.)
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296710, BA, Brazil;
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Ivanova N, Hristov M, Gateva P. Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic. Int J Mol Sci 2025; 26:2094. [PMID: 40076715 PMCID: PMC11899846 DOI: 10.3390/ijms26052094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Diabetic neuropathy (DN) is characterized by nerve damage as a consequence of diabetes mellitus. Diabetes causes high blood glucose and triglyceride levels, which destroy the nerve blood vessels over time and trigger DN. Peripheral neuropathy is the most common type of DN, which encompasses a broad range of symptoms. One fourth of patients with diabetes suffer from neuropathic pain, which decreases their quality of life and puts them at high risk for emotional disturbances and depression. Finding an adequate therapy is an essential element in the cure of painful DN (PDN). Since the pathophysiology of this disease still needs to be elucidated, this has led to the development of various in vivo diabetic models. Animal models of DN not only provide insights into this disease but also are significant drivers for treatment assessment and improvement. In this review, we present the major features of the most commonly used chemically and diet-induced models of PDN in rodents and their progress to date, which are utilized for a better understanding of the disease mechanism for finding novel therapeutics. Considering the role of Ca2+ homeostasis in pain, we also review our recent research data on the Na+/Ca2+ exchanger blocker KB-R7943, which is a potential neuropathic pain reliever in a rodent model of DN.
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Affiliation(s)
- Natasha Ivanova
- Institute of Neurobiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria; (M.H.)
| | - Milen Hristov
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria; (M.H.)
| | - Pavlina Gateva
- Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria; (M.H.)
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Yuan CX, Wang X, Liu Y, Xu TC, Yu Z, Xu B. Electroacupuncture alleviates diabetic peripheral neuropathy through modulating mitochondrial biogenesis and suppressing oxidative stress. World J Diabetes 2025; 16:93130. [PMID: 39959279 PMCID: PMC11718478 DOI: 10.4239/wjd.v16.i2.93130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 09/15/2024] [Accepted: 10/31/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities. The effects mediated by the silent information regulator type 2 homolog-1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy (T2DPN), potentially breaking this harmful cycle. AIM To validate the effectiveness of electroacupuncture (EA) in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1α axis. METHODS The effects of EA were evaluated through assessments of metabolic changes, morphological observations, and functional examinations of the sciatic nerve, along with measurements of inflammation and oxidative stress. Proteins related to the SIRT1/PGC-1α axis, involved in the regulation of mitochondrial biogenesis and antioxidative stress, were detected in the sciatic nerve using Western blotting to explain the underlying mechanism. A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis. RESULTS In addition to diabetes-related metabolic changes, T2DPN rats showed significant reductions in pain threshold after 9 weeks, suggesting abnormal peripheral nerve function. EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats. The SIRT1/PGC-1α axis, which was downregulated in the model group, was upregulated by EA intervention. The endogenous antioxidant system related to the SIRT1/PGC-1α axis, previously inhibited in diabetic rats, was reactivated. A similar trend was observed in inflammatory markers. When SIRT1 was inhibited in diabetic rats, these beneficial effects were abolished. CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats, and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1α axis.
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Affiliation(s)
- Chong-Xi Yuan
- Department of Traditional Chinese Medicine, Suzhou Xiangcheng People's Hospital, Suzhou 215100, Jiangsu Province, China
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Xuan Wang
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
- College of Traditional Chinese Medicine, Jiangsu Vocational College of Medicine, Yancheng 224000, Jiangsu Province, China
| | - Yun Liu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Tian-Cheng Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zhi Yu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Bin Xu
- Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Wang Y, Ortiz R, Chang A, Nasseef T, Rubalcaba N, Munson C, Ghaw A, Balaji S, Kwon Y, Athreya D, Kedharnath S, Kulkarni PP, Ferris CF. Following changes in brain structure and function with multimodal MRI in a year-long prospective study on the development of Type 2 diabetes. FRONTIERS IN RADIOLOGY 2025; 5:1510850. [PMID: 40018732 PMCID: PMC11865244 DOI: 10.3389/fradi.2025.1510850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 01/27/2025] [Indexed: 03/01/2025]
Abstract
Aims To follow disease progression in a rat model of Type 2 diabetes using multimodal MRI to assess changes in brain structure and function. Material and methods Female rats (n = 20) were fed a high fat/high fructose diet or lab chow starting at 90 days of age. Diet fed rats were given streptozotocin to compromise pancreatic beta cells, while chow fed controls received vehicle. At intervals of 3, 6, 9, and 12 months, rats were tested for changes in behavior and sensitivity to pain. Brain structure and function were assessed using voxel based morphometry, diffusion weighted imaging and functional connectivity. Results Diet fed rats presented with elevated plasma glucose levels as early as 3 months and a significant gain in weight by 6 months as compared to controls. There were no significant changes in cognitive or motor behavior over the yearlong study but there was a significant increase in sensitivity to peripheral pain in diet fed rats. There were region specific decreases in brain volume e.g., basal ganglia, thalamus and brainstem in diet fed rats. These same regions showed elevated measures of water diffusivity evidence of putative vasogenic edema. By 6 months, widespread hyperconnectivity was observed across multiple brain regions. By 12 months, only the cerebellum and hippocampus showed increased connectivity, while the hypothalamus showed decreased connectivity in diet fed rats. Conclusions Noninvasive multimodal MRI identified site specific changes in brain structure and function in a yearlong longitudinal study of Type 2 diabetes in rats. The identified diabetic-induced neuropathological sites may serve as biomarkers for evaluating the efficacy of novel therapeutics.
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Affiliation(s)
- Yingjie Wang
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Richard Ortiz
- Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, United States
| | - Arnold Chang
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Taufiq Nasseef
- Department of Mathematics, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, Riyadh, Saudi
| | - Natalia Rubalcaba
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Chandler Munson
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Ashley Ghaw
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Shreyas Balaji
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Yeani Kwon
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Deepti Athreya
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Shruti Kedharnath
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Praveen P. Kulkarni
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
| | - Craig F. Ferris
- Center for Translational NeuroImaging, Northeastern University, Boston, MA, United States
- Department of Psychology and Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
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Ivanov EV, Akhmetshina MR, Gizatulina AR, Gavrilova SA. Evaluation of Peripheral Neuropathy in Rat Models of Metabolic Syndrome and Diabetes Mellitus. Bull Exp Biol Med 2024:10.1007/s10517-024-06198-6. [PMID: 39259466 DOI: 10.1007/s10517-024-06198-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Indexed: 09/13/2024]
Abstract
The dynamics of nephropathy development in rats with type 2 diabetes mellitus, caused by a high-fat diet and the streptozotocin administration (25 mg/kg), and metabolic syndrome, caused by addition of 20% fructose solution to the diet, was evaluated during the experiment. Models with moderate severity of metabolic changes without significant changes in body weight were obtained after 24 weeks. To study neuropathy severity, the method of electroneuromyography was used; the velocities of motor and sensory excitation propagation along the caudal nerve fibers were measured. In modeled diabetes mellitus against the background of hyperglycemia, a marked decrease in motor and sensory propagation rates was observed, and an increase in the response durations was noted from week 12 to week 24, indicating pronounced neuropathy. In the fructose model, the motor response duration increased from week 12, which possibly indicates the development of peripheral neuropathy.
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Affiliation(s)
- E V Ivanov
- Lomonosov Moscow State University, Moscow, Russia.
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Eid SA, Elzinga SE, Guo K, Hinder LM, Hayes JM, Pacut CM, Koubek EJ, Hur J, Feldman EL. Transcriptomic profiling of sciatic nerves and dorsal root ganglia reveals site-specific effects of prediabetic neuropathy. Transl Res 2024; 270:24-41. [PMID: 38556110 PMCID: PMC11166517 DOI: 10.1016/j.trsl.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/01/2024] [Accepted: 03/24/2024] [Indexed: 04/02/2024]
Abstract
Peripheral neuropathy (PN) is a severe and frequent complication of obesity, prediabetes, and type 2 diabetes characterized by progressive distal-to-proximal peripheral nerve degeneration. However, a comprehensive understanding of the mechanisms underlying PN, and whether these mechanisms change during PN progression, is currently lacking. Here, gene expression data were obtained from distal (sciatic nerve; SCN) and proximal (dorsal root ganglia; DRG) injury sites of a high-fat diet (HFD)-induced mouse model of obesity/prediabetes at early and late disease stages. Self-organizing map and differentially expressed gene analyses followed by pathway enrichment analysis identified genes and pathways altered across disease stage and injury site. Pathways related to immune response, inflammation, and glucose and lipid metabolism were consistently dysregulated with HFD-induced PN, irrespective of injury site. However, regulation of oxidative stress was unique to the SCN while dysregulated Hippo and Notch signaling were only observed in the DRG. The role of the immune system and inflammation in disease progression was supported by an increase in the percentage of immune cells in the SCN with PN progression. Finally, when comparing these data to transcriptomic signatures from human patients with PN, we observed conserved pathways related to metabolic dysregulation across species, highlighting the translational relevance of our mouse data. Our findings demonstrate that PN is associated with distinct site-specific molecular re-programming in the peripheral nervous system, identifying novel, clinically relevant therapeutic targets.
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Affiliation(s)
- Stéphanie A. Eid
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sarah E. Elzinga
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kai Guo
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lucy M. Hinder
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - John M. Hayes
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Crystal M. Pacut
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Emily J. Koubek
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Junguk Hur
- Department of Biomedical Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58202, USA
| | - Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
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Hume C, Baglot SL, Javorcikova L, Lightfoot SHM, Scheufen J, Hill MN. Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats. Int J Obes (Lond) 2024; 48:981-992. [PMID: 38528095 DOI: 10.1038/s41366-024-01512-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 03/05/2024] [Accepted: 03/07/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND 4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for developing of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. METHODS Pregnant Sprague Dawley rats were exposed to vaporized THC (100 mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE (n = 24) or control (n = 24) litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. RESULTS PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when on HFD/LFD, regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. CONCLUSIONS PCE may not promote obesity development but may increase risk for diabetes and abnormal eating habits under certain biological and environmental conditions. Overall, this data enhances current understanding of the potential impacts of PCE.
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Affiliation(s)
- Catherine Hume
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
- Department of Cell Biology & Anatomy | Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
| | - Samantha L Baglot
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
- Graduate Program in Neuroscience, University of Calgary, Calgary, AB, Canada
| | - Lucia Javorcikova
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
- Graduate Program in Neuroscience, University of Calgary, Calgary, AB, Canada
| | - Savannah H M Lightfoot
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
- Graduate Program in Neuroscience, University of Calgary, Calgary, AB, Canada
| | - Jessica Scheufen
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
- Graduate Program in Neuroscience, University of Calgary, Calgary, AB, Canada
| | - Matthew N Hill
- Hotchkiss Brain Institute | Mathison Centre for Mental Health Research & Education | Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
- Department of Cell Biology & Anatomy | Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
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Wang CL, Skeie JM, Allamargot C, Goldstein AS, Nishimura DY, Huffman JM, Aldrich BT, Schmidt GA, Teixeira LBC, Kuehn MH, Yorek M, Greiner MA. Rat Model of Type 2 Diabetes Mellitus Recapitulates Human Disease in the Anterior Segment of the Eye. THE AMERICAN JOURNAL OF PATHOLOGY 2024:S0002-9440(24)00073-7. [PMID: 38403162 DOI: 10.1016/j.ajpath.2024.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 02/01/2024] [Accepted: 02/09/2024] [Indexed: 02/27/2024]
Abstract
Changes in the anterior segment of the eye due to type 2 diabetes mellitus (T2DM) are not well-characterized, in part due to the lack of a reliable animal model. This study evaluates changes in the anterior segment, including crystalline lens health, corneal endothelial cell density, aqueous humor metabolites, and ciliary body vasculature, in a rat model of T2DM compared with human eyes. Male Sprague-Dawley rats were fed a high-fat diet (45% fat) or normal diet, and rats fed the high-fat diet were injected with streptozotocin i.p. to generate a model of T2DM. Cataract formation and corneal endothelial cell density were assessed using microscopic analysis. Diabetes-related rat aqueous humor alterations were assessed using metabolomics screening. Transmission electron microscopy was used to assess qualitative ultrastructural changes ciliary process microvessels at the site of aqueous formation in the eyes of diabetic rats and humans. Eyes from the diabetic rats demonstrated cataracts, lower corneal endothelial cell densities, altered aqueous metabolites, and ciliary body ultrastructural changes, including vascular endothelial cell activation, pericyte degeneration, perivascular edema, and basement membrane reduplication. These findings recapitulated diabetic changes in human eyes. These results support the use of this model for studying ocular manifestations of T2DM and support a hypothesis postulating blood-aqueous barrier breakdown and vascular leakage at the ciliary body as a mechanism for diabetic anterior segment pathology.
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Affiliation(s)
- Cheryl L Wang
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Jessica M Skeie
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa
| | - Chantal Allamargot
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Office of the Vice President for Research, Central Microscopy Research Facility, University of Iowa, Iowa City, Iowa
| | - Andrew S Goldstein
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa
| | - Darryl Y Nishimura
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa
| | - James M Huffman
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Benjamin T Aldrich
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa
| | - Gregory A Schmidt
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa
| | - Leandro B C Teixeira
- Department of Pathobiological Sciences, University of Wisconsin-Madison School of Veterinary Medicine, Madison, Wisconsin
| | - Markus H Kuehn
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Center for the Prevention and Treatment of Visual Loss, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa
| | - Mark Yorek
- Center for the Prevention and Treatment of Visual Loss, Iowa City Veterans Affairs Health Care System, Iowa City, Iowa
| | - Mark A Greiner
- Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa; Iowa Lions Eye Bank, Coralville, Iowa.
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Machet J, Park M, Richardson A, Carnell M, Mouat MA, Smith NJ, Turner N, Cochran BJ, Rye KA, Di Girolamo N. Type 2 diabetes influences intraepithelial corneal nerve parameters and corneal stromal-epithelial nerve penetration sites. J Diabetes Investig 2023; 14:591-601. [PMID: 36727569 PMCID: PMC10034950 DOI: 10.1111/jdi.13974] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/16/2022] [Accepted: 01/01/2023] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION The quantification of intraepithelial corneal basal nerve parameters by in vivo confocal microscopy represents a promising modality to identify the earliest manifestations of diabetic peripheral neuropathy. However, its diagnostic accuracy is hampered by its dependence on neuron length, with minimal consideration for other parameters, including the origin of these nerves, the corneal stromal-epithelial nerve penetration sites. This study sought to utilize high-resolution images of murine corneal nerves to analyze comprehensively the morphological changes associated with type 2 diabetes progression. MATERIALS AND METHODS βIII-Tubulin immunostained corneas from prediabetic and type 2 diabetic mice and their respective controls were imaged by scanning confocal microscopy and analyzed automatically for nerve parameters. Additionally, the number and distribution of penetration sites was manually ascertained and the average length of the axons exiting them was computed. RESULTS The earliest detectable changes included a significant increase in nerve density (6.06 ± 0.41% vs 8.98 ± 1.99%, P = 0.03) and branching (2867.8 ± 271.3/mm2 vs 4912.1 ± 1475.3/mm2 , P = 0.03), and in the number of penetration sites (258.80 ± 20.87 vs 422.60 ± 63.76, P = 0.0002) at 8 weeks of age. At 16 weeks, corneal innervation decreased, most notably in the periphery. The number of penetration sites remained significantly elevated relative to controls throughout the monitoring period. Similarly, prediabetic mice exhibited an increased number of penetration sites (242.2 ± 13.55 vs 305.6 ± 30.96, P = 0.003) without significant changes to the nerves. CONCLUSIONS Our data suggest that diabetic peripheral neuropathy may be preceded by a phase of neuron growth rather than regression, and that the peripheral cornea is more sensitive than the center for detecting changes in innervation.
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Affiliation(s)
- Joshua Machet
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Mijeong Park
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Alexander Richardson
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Michael Carnell
- Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, Australia
| | - Margaret A Mouat
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nicola J Smith
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nigel Turner
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
- Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
| | - Blake J Cochran
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Kerry-Anne Rye
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
| | - Nick Di Girolamo
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
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11
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Qureshi S, Ali G, Muhammad T, Idrees M, Ullah S, Ali Khan S, Ullah R, Khan R, Ul-Haq Z, Haseeb Mohsin A, Kong IK. Thiadiazine-thione derivatives ameliorate STZ-induced diabetic neuropathy by regulating insulin and neuroinflammatory signaling. Int Immunopharmacol 2022; 113:109421. [PMID: 36403520 DOI: 10.1016/j.intimp.2022.109421] [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: 06/25/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 11/18/2022]
Abstract
Diabetes Mellitus is accompanied by chronic hyperglycemia, inflammation, and related molecular processes, which leads to diabetic neuropathy. In this work, we tested Thiadiazine-thione (TDT) synthetic derivatives TDT1 and TDT2 against streptozotocin (STZ)-induced diabetic neuropathy. Sprague Dawley's rats, SH-SY5Y neuronal and BV2 microglial cells were employed in this work, followed by behavioral, biochemical, and morphological studies utilizing RT-qPCR, ELISA, Immunoblotting, immunohistochemistry, Immunofluorescence, and in silico analyses. TDT1 and TDT2 abolished STZ-induced allodynia and hyperalgesia. Next, we examined IRS1/PI3K/AKT signaling to assess TDT1 and TDT2's impact on diabetic neuropathy. STZ downregulated IRS1, PI3K, AKT mRNA and protein expression in rat spinal cord and SH-SY5Y neuronal cells. TDT1 and TDT2 improved IRS1, PI3k, and AKT mRNA and protein expression. STZ elevated GSK3β mRNA and protein expression in vivo and in vitro, whereas TDT1 and TDT2 mitigated it. STZ increased the expression of inflammatory mediators such as p-NF-κB, TNF-α, and COX-2 in rat spinal cord lysates. TDT1 and TDT2 co-treatment with STZ decreased inflammatory cytokine expression by ameliorating astrocytosis (revealed by increased GFAP) and microgliosis (indicated by increased Iba1). TDT1 and TDT2 reduced STZ-induced JNK, Iba1, and COX-2 upregulation in BV2 microglial cells validating our in vivo findings. In silico molecular docking and MD simulations analyses suggested that TDT1 and TDT2 have IRS binding affinity, however, both compounds had an identical binding affinity, but distinct interaction pattern with IRS protein residues. Overall, these findings demonstrate that TDT derivatives mitigated STZ-induced neuropathy through modulating the insulin and inflammatory signaling pathways.
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Affiliation(s)
- Sonia Qureshi
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan; Krembil Research Institute, University Health Network, M5G 1L7, Toronto, Ontario, Canada
| | - Gowhar Ali
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
| | - Tahir Muhammad
- Molecular Neuropsychiatry and Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Muhammad Idrees
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea; Institute of Agriculture and Life Science, Gyeongsang National University, Gyeongnam Province, Republic of Korea
| | - Sultan Ullah
- Department of Molecular Medicine, UF Scripps Biomedical Research, Jupiter, FL, 33458, USA
| | - Salman Ali Khan
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Rahim Ullah
- Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan
| | - Rasool Khan
- Institute of chemical sciences, University of Peshawar, Peshawar, Pakistan
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Institute of chemical sciences, University of Peshawar, Peshawar, Pakistan
| | | | - Il-Keun Kong
- Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea; Institute of Agriculture and Life Science, Gyeongsang National University, Gyeongnam Province, Republic of Korea; The Kingkong Co. Ltd., Gyeongsang National University, Jinju 52828, Gyeongnam Province, Republic of Korea
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12
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Wiggins AM, Sorge RE. An improved model of type 2 diabetes with effects on glucose tolerance, neuropathy and retinopathy with and without obesity. Physiol Behav 2022; 248:113740. [PMID: 35167879 PMCID: PMC10714886 DOI: 10.1016/j.physbeh.2022.113740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/02/2022] [Accepted: 02/10/2022] [Indexed: 12/01/2022]
Abstract
RATIONALE Type 2 diabetes (T2D) costs billions of dollars annually, is also associated with pain (diabetic neuropathy), as well as retinopathy, lower urinary tract/urinary bladder dysfunction, depression, and systemic inflammation, affecting quality of life for patients. To that end, animal models are utilized to explore potential treatments, but may not reflect the complexity of the condition. OBJECTIVE We aimed to test an improved model of T2D that more closely mimics the clinical mechanisms and symptoms in an outbred strain of mouse. FINDINGS Male and female CD-1 mice (n = 72) were fed one of four diets: regular chow (REG), our Standard American Diet (SAD), a revised SAD (SAD2), or the commonly-used high-fat diet (HFD). Overall, HFD- and SAD-fed mice had significant weight gain and increased fat mass. Following injury, the SAD- and SAD2-fed mice showed protracted recovery, but the HFD-fed mice did not. Similarly, SAD- and SAD2-fed mice showed impaired retinal function compared to REG-fed mice, but the HFD-fed mice did not. CONCLUSIONS The SAD and SAD2 more closely model the problematic dietary intake and subsequent clinical symptoms associated with T2D. POTENTIAL IMPACT OF STUDY The adjusted SAD2 may be a better representation of a human-translatable diet than the SAD and HFD, and may allow for increased advances in the investigation of T2D-related symptoms.
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Affiliation(s)
- Asia M Wiggins
- Department of Psychology, University of Alabama at Birmingham, United States
| | - Robert E Sorge
- Department of Psychology, University of Alabama at Birmingham, United States.
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13
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Hossain MJ, Kendig MD, Letton ME, Morris MJ, Arnold R. Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions. Diabetes Metab J 2022; 46:198-221. [PMID: 35385634 PMCID: PMC8987683 DOI: 10.4093/dmj.2021.0347] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/25/2022] [Indexed: 11/08/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the 'Neurodiab' criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.
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Affiliation(s)
- Md Jakir Hossain
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Michael D. Kendig
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Meg E. Letton
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Margaret J. Morris
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
| | - Ria Arnold
- Department of Pharmacology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise Physiology, School of Medical Sciences, University of New South Wales (UNSW) Sydney, Sydney, Australia
- Department of Exercise and Rehabilitation, School of Medical, Indigenous and Health Science, University of Wollongong, Wollongong, Australia
- Corresponding author: Ria Arnold https://orcid.org/0000-0002-7469-6587 Department of Exercise Physiology, School of Health Sciences, UNSW Sydney, Sydney, NSW 2052, Australia E-mail:
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14
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Southam K, Sousa C, Daniel A, Taylor BV, Foa L, Premilovac D. Development and characterisation of a rat model that exhibits both metabolic dysfunction and neurodegeneration seen in type 2 diabetes. J Physiol 2022; 600:1611-1630. [PMID: 35128667 PMCID: PMC9541365 DOI: 10.1113/jp282454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/02/2022] [Indexed: 11/27/2022] Open
Abstract
Abstract Accurate modelling type 2 diabetes and diabetic complications in rodents has proven a challenge, largely as a result of the long‐time course of disease development in humans. In the present study, we aimed to develop and comprehensively characterise a new rodent model of type 2 diabetes. To do this, we fed Sprague–Dawley rats a high fat/high sugar diet (HFD) to induce obesity and dyslipidaemia. After 3 weeks, we s.c. implanted osmotic mini pumps to enable a 14 day, slow infusion of streptozotocin (STZ; lower dose = 100 mg kg−1; higher dose = 120 mg kg−1) to dose‐dependently reduce pancreatic beta cell mass. After removing the mini pumps, we monitored animals for 4 months using a battery of tests to assess both metabolic and neurodegenerative changes across time. Our data demonstrate the combination of the HFD and lower dose STZ leads to induction of early‐stage type 2 diabetes defined by moderate hyperglycaemia, hyperinsulinaemia and impaired glucose tolerance, at the same time as the retention of an obese phenotype. By contrast, combining the HFD and higher dose STZ leads to induction of later‐stage type 2 diabetes defined by frank hyperglycaemia, hypoinsulinaemia (but not insulin depletion) and severely impaired glucose tolerance, at the same time as retaining an obese phenotype. Regardless of dose of STZ (and level of hyperglycaemia), all diabetic rats exhibited signs of peripheral neurodegeneration in the skin and muscle. Thus, this model recapitulates many of the complex metabolic disturbances seen in type 2 diabetes and provides an excellent platform for investigating the pathophysiological mechanisms that lead to diabetic complications such as peripheral neuropathy. Key points
Type 2 diabetes is a major health concern and markedly increases risk cardiovascular and neurodegenerative diseases. Accurate modelling of type 2 diabetes is a major challenge and has impeded our ability to understand the mechanisms that contribute to complications of type 2 diabetes. We have developed a method of inducing different stages of type 2 diabetes using a high fat/high sugar diet and 14 day infusion of streptozotocin to dose‐dependently destroy pancreatic beta cell mass. Over 4 months, we comprehensively characterised these animals and confirmed that they develop sustained metabolic dysfunction and progressive peripheral neurodegeneration as seen in type 2 diabetes. This new model will improve our ability to investigate the pathophysiological mechanisms that link type 2 diabetes with complications such as neurodegeneration.
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Affiliation(s)
- Katherine Southam
- Tasmanian School of Medicine College of Health and Medicine University of Tasmania Hobart Tasmania Australia
- Menzies Institute for Medical Research College of Health and Medicine University of Tasmania Hobart Tasmania Australia
| | - Chantal Sousa
- Tasmanian School of Medicine College of Health and Medicine University of Tasmania Hobart Tasmania Australia
| | - Abraham Daniel
- Tasmanian School of Medicine College of Health and Medicine University of Tasmania Hobart Tasmania Australia
- School of Pharmacy and Pharmacology College of Health and Medicine University of Tasmania Hobart Tasmania Australia
| | - Bruce V Taylor
- Menzies Institute for Medical Research College of Health and Medicine University of Tasmania Hobart Tasmania Australia
| | - Lisa Foa
- Tasmanian School of Medicine College of Health and Medicine University of Tasmania Hobart Tasmania Australia
- School of Psychological Sciences College of Health and Medicine University of Tasmania Hobart Tasmania Australia
| | - Dino Premilovac
- Tasmanian School of Medicine College of Health and Medicine University of Tasmania Hobart Tasmania Australia
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15
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Jolivalt CG, Aghanoori MR, Navarro-Diaz MC, Han MM, Sanchez G, Guernsey L, Quach D, Johe K, Fernyhough P, Calcutt NA. Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes. J Diabetes Res 2022; 2022:8566970. [PMID: 35967127 PMCID: PMC9372526 DOI: 10.1155/2022/8566970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/17/2022] [Indexed: 12/03/2022] Open
Abstract
AIMS Mitochondrial dysfunction contributes to many forms of peripheral and central nervous system degeneration. Therapies that protect mitochondrial number and function have the potential to impact the progression of conditions such as diabetic neuropathy. We therefore assessed indices of mitochondrial function in dorsal root ganglia (DRG) and brain cortex of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and tested the therapeutic impact of a neurogenic compound, NSI-189, on both mitochondrial function and indices of peripheral and central neurological dysfunction. MATERIALS AND METHODS ZDF rats were maintained for 16 weeks of untreated diabetes before the start of oral treatment with NSI-189 for an additional 16 weeks. Nerve conduction velocity, sensitivity to tactile and thermal stimuli, and behavioral assays of cognitive function were assessed monthly. AMP-activated protein kinase (AMPK) phosphorylation, mitochondrial protein levels, and respiratory complex activities were assessed in the DRG and brain cortex after 16 weeks of treatment with NSI-189. RESULTS Treatment with NSI-189 selectively elevated the expression of protein subunits of complexes III and V and activities of respiratory complexes I and IV in the brain cortex, and this was accompanied by amelioration of impaired memory function and plasticity. In the sensory ganglia of ZDF rats, loss of AMPK activity was ameliorated by NSI-189, and this was accompanied by reversal of multiple indices of peripheral neuropathy. CONCLUSIONS Efficacy of NSI-189 against dysfunction of the CNS and PNS function in type 2 diabetic rats was accompanied by improvement of mitochondrial function. NSI-189 exhibited actions at different levels of mitochondrial regulation in central and peripheral tissues.
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Affiliation(s)
- C. G. Jolivalt
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - M. R. Aghanoori
- Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - M. C. Navarro-Diaz
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - M. M. Han
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - G. Sanchez
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - L. Guernsey
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
| | - D. Quach
- Neuralstem Inc., Germantown, MD, USA
| | - K. Johe
- Neuralstem Inc., Germantown, MD, USA
| | - P. Fernyhough
- Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - N. A. Calcutt
- University of California San Diego, Department of Pathology, La Jolla, CA, USA
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16
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Liu G, Feng S, Yan J, Luan D, Sun P, Shao P. Antidiabetic potential of polysaccharides from Brasenia schreberi regulating insulin signaling pathway and gut microbiota in type 2 diabetic mice. Curr Res Food Sci 2022; 5:1465-1474. [PMID: 36119371 PMCID: PMC9478496 DOI: 10.1016/j.crfs.2022.09.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/17/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
This study aimed to investigate the hypoglycemic activities and gut microbial regulation effects of polysaccharides from Brasenia schreberi (BS) in diabetic mice induced by high-fat diet and streptozotocin. Our data indicated that BS polysaccharides not only improved the symptoms of hyperglycemia and relieved metabolic endotoxemia-related inflammation but also optimized the gut microbiota composition of diabetic mice with significantly decreased Firmicutes/Bacteroidetes ratios. More importantly, altered gut microbiota components may affect liver glycogen and muscle glycogen by increasing the mRNA expression of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (Akt) in the liver of mice through modulated the abundance of beneficial bacteria (Lactobacillus). Altogether, our findings, for the first time, demonstrate that BS polysaccharides may be used as a beneficial probiotic agent that reverses gut microbiota dysbiosis and the hypoglycemic mechanisms of BS polysaccharides may be related to enhancing the abundance of Lactobacillus to activate PI3K/Akt-mediated signaling pathways in T2DM mice.
Brasenia schreberi polysaccharides ameliorated hyperglycemia and dyslipidemia in mice. The polysaccharides regulated glucose metabolism through activating PI3K-Akt pathway. The polysaccharides modulated gut microbiota profile of diabetic mice.
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Affiliation(s)
- Gaodan Liu
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Simin Feng
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
- Key Laboratory of Food Macromolecular Resources Processing Technology Research (Zhejiang University of Technology), China National Light Industry, People's Republic of China
- Corresponding author. Department of Food Science and technology, Zhejiang University of Technology, Hangzhou, 310014, People's Republic of China.
| | - Jiadan Yan
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Di Luan
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Peilong Sun
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
| | - Ping Shao
- Department of Food Science and Engineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, People's Republic of China
- Key Laboratory of Food Macromolecular Resources Processing Technology Research (Zhejiang University of Technology), China National Light Industry, People's Republic of China
- Corresponding author. College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, 310014, People's Republic of China.
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17
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Animal models of diabetic microvascular complications: Relevance to clinical features. Biomed Pharmacother 2021; 145:112305. [PMID: 34872802 DOI: 10.1016/j.biopha.2021.112305] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes has become more common in recent years worldwide, and this growth is projected to continue in the future. The primary concern with diabetes is developing various complications, which significantly contribute to the disease's mortality and morbidity. Over time, the condition progresses from the pre-diabetic to the diabetic stage and then to the development of complications. Years and enormous resources are required to evaluate pharmacological interventions to prevent or delay the progression of disease or complications in humans. Appropriate screening models are required to gain a better understanding of both pathogenesis and potential therapeutic agents. Different species of animals are used to evaluate the pharmacological potentials and study the pathogenesis of the disease. Animal models are essential for research because they represent most of the structural, functional, and biochemical characteristics of human diseases. An ideal screening model should mimic the pathogenesis of the disease with identifiable characteristics. A thorough understanding of animal models is required for the experimental design to select an appropriate model. Each animal model has certain advantages and limitations. The present manuscript describes the animal models and their diagnostic characteristics to evaluate microvascular diabetic complications.
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18
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Eid SA, Feldman EL. Advances in diet-induced rodent models of metabolically acquired peripheral neuropathy. Dis Model Mech 2021; 14:273425. [PMID: 34762126 PMCID: PMC8592018 DOI: 10.1242/dmm.049337] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Peripheral neuropathy (PN) is a severe complication that affects over 30% of prediabetic and 60% of type 2 diabetic (T2D) patients. The metabolic syndrome is increasingly recognized as a major driver of PN. However, basic and translational research is needed to understand the mechanisms that contribute to nerve damage. Rodent models of diet-induced obesity, prediabetes, T2D and PN closely resemble the human disease and have proven to be instrumental for the study of PN mechanisms. In this Perspective article, we focus on the development, neurological characterization and dietary fat considerations of diet-induced rodent models of PN. We highlight the importance of investigating sex differences and discuss some of the challenges in translation from bench to bedside, including recapitulating the progressive nature of human PN and modeling neuropathic pain. We emphasize that future research should overcome these challenges in the quest to better mimic human PN in animal models.
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Affiliation(s)
- Stéphanie A Eid
- Department of Neurology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Eva L Feldman
- Department of Neurology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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19
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Bouali-Benazzouz R, Landry M, Benazzouz A, Fossat P. Neuropathic pain modeling: Focus on synaptic and ion channel mechanisms. Prog Neurobiol 2021; 201:102030. [PMID: 33711402 DOI: 10.1016/j.pneurobio.2021.102030] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 02/22/2021] [Indexed: 12/28/2022]
Abstract
Animal models of pain consist of modeling a pain-like state and measuring the consequent behavior. The first animal models of neuropathic pain (NP) were developed in rodents with a total lesion of the sciatic nerve. Later, other models targeting central or peripheral branches of nerves were developed to identify novel mechanisms that contribute to persistent pain conditions in NP. Objective assessment of pain in these different animal models represents a significant challenge for pre-clinical research. Multiple behavioral approaches are used to investigate and to validate pain phenotypes including withdrawal reflex to evoked stimuli, vocalizations, spontaneous pain, but also emotional and affective behaviors. Furthermore, animal models were very useful in investigating the mechanisms of NP. This review will focus on a detailed description of rodent models of NP and provide an overview of the assessment of the sensory and emotional components of pain. A detailed inventory will be made to examine spinal mechanisms involved in NP-induced hyperexcitability and underlying the current pharmacological approaches used in clinics with the possibility to present new avenues for future treatment. The success of pre-clinical studies in this area of research depends on the choice of the relevant model and the appropriate test based on the objectives of the study.
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Affiliation(s)
- Rabia Bouali-Benazzouz
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
| | - Marc Landry
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Abdelhamid Benazzouz
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Pascal Fossat
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
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20
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Clarkson-Townsend DA, Douglass AJ, Singh A, Allen RS, Uwaifo IN, Pardue MT. Impacts of high fat diet on ocular outcomes in rodent models of visual disease. Exp Eye Res 2021; 204:108440. [PMID: 33444582 PMCID: PMC7946735 DOI: 10.1016/j.exer.2021.108440] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/23/2020] [Accepted: 01/05/2021] [Indexed: 02/08/2023]
Abstract
High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.
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Affiliation(s)
- Danielle A Clarkson-Townsend
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA
| | - Amber J Douglass
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA
| | - Anayesha Singh
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Emory Center for Ethics, Emory University, Atlanta, GA, USA
| | - Rachael S Allen
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Ivie N Uwaifo
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Neuroscience, Emory University, Atlanta, GA, USA
| | - Machelle T Pardue
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
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21
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Jiao H, Lim AS, Fazio Coles TE, McQuade RM, Furness JB, Chinnery HR. The effect of high-fat diet-induced metabolic disturbance on corneal neuroimmune features. Exp Eye Res 2020; 201:108298. [PMID: 33069696 DOI: 10.1016/j.exer.2020.108298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 01/10/2023]
Abstract
PURPOSE The highly innervated cornea is susceptible to nerve loss secondary to systemic diseases such as diabetes and metabolic disturbances caused by high-fat diet. In this study, we characterize the effect of high-fat diet on the mouse corneal neuroimmune phenotype, including changes to corneal nerve density and resident immune cells, alongside the clinical assessment of corneal thickness and endothelial cell density. METHODS Male C57Bl6/J mice, aged 10 weeks, were fed a high-fat diet (60 kcal% fat, 5.2 kcal/g) or control diet (10 kcal%, 3.8 kcal/g) for 16 weeks. At the study endpoint, metabolic parameters (HbA1c, weight, fasting glucose, body fat) were measured to confirm metabolic disturbance. Clinical imaging of the anterior segment was performed using optical coherence tomography to measure the corneal epithelial and stromal thickness. Corneal sensory nerves were visualized using flatmount immunostaining and confocal microscopy. The topographical distribution and density of sensory nerves (BIII-tubulin+), intraepithelial CD45+ and MHC- II+ cells, stromal macrophages (IBA1+CD206+) and endothelial cells (ZO-1+) were analysed using FIJI. RESULTS High-fat diet mice had significantly higher blood HbA1c, higher body weight, a higher percentage of body fat and elevated fasting glucose compared to the control diet mice. Corneal epithelial and stromal thickness was similar in both groups. The sum length of the basal nerve plexus was lower in the central and peripheral cornea of mice fed a high-fat diet. In contrast, the sum length of superficial nerve terminals was similar between groups. Epithelial immune cell density was two-fold higher in the central corneas of high-fat diet mice compared to control diet mice. IBA1+CD206+ macrophage density was similar in the anterior stroma of both groups but was significantly higher in the posterior stroma of the peripheral cornea in the high-fat diet mice compared to controls. The percentage of nerve-associated MHC-II+ cells in the epithelium and stroma was higher in HFD mice compared to controls. Endothelial cell density was similar in the corneas of high-fat diet mice compared to controls. CONCLUSION Together with corneal neuropathy, corneal immune cells in mice fed a high-fat diet were differentially affected depending on their topographical distribution and location within cornea, and appeared in closer proximity to epithelial and stromal nerves, suggesting a local neuroimmune disruption induced by systemic metabolic disturbance.
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Affiliation(s)
- Haihan Jiao
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Alicia Sl Lim
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Therese E Fazio Coles
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Rachel M McQuade
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia; Department of Medicine, Western Health, Melbourne University, Sunshine, Victoria, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Holly R Chinnery
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia.
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22
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Hossain MJ, Kendig MD, Wild BM, Issar T, Krishnan AV, Morris MJ, Arnold R. Evidence of Altered Peripheral Nerve Function in a Rodent Model of Diet-Induced Prediabetes. Biomedicines 2020; 8:biomedicines8090313. [PMID: 32872256 PMCID: PMC7555926 DOI: 10.3390/biomedicines8090313] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/26/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Peripheral neuropathy (PN) is a debilitating complication of diabetes that affects >50% of patients. Recent evidence suggests that obesity and metabolic disease, which often precede diabetes diagnosis, may influence PN onset and severity. We examined this in a translationally relevant model of prediabetes induced by a cafeteria (CAF) diet in Sprague–Dawley rats (n = 15 CAF versus n = 15 control). Neuropathy phenotyping included nerve conduction, tactile sensitivity, intraepidermal nerve fiber density (IENFD) and nerve excitability testing, an in vivo measure of ion channel function and membrane potential. Metabolic phenotyping included body composition, blood glucose and lipids, plasma hormones and inflammatory cytokines. After 13 weeks diet, CAF-fed rats demonstrated prediabetes with significantly elevated fasting blood glucose, insulin and impaired glucose tolerance as well as obesity and dyslipidemia. Nerve conduction, tactile sensitivity and IENFD did not differ; however, superexcitability was significantly increased in CAF-fed rats. Mathematical modeling demonstrated this was consistent with a reduction in sodium–potassium pump current. Moreover, superexcitability correlated positively with insulin resistance and adiposity, and negatively with fasting high-density lipoprotein cholesterol. In conclusion, prediabetic rats over-consuming processed, palatable foods demonstrated altered nerve function that preceded overt PN. This work provides a relevant model for pathophysiological investigation of diabetic complications.
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Affiliation(s)
- Md Jakir Hossain
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (M.J.H.); (M.D.K.); (B.M.W.); (M.J.M.)
| | - Michael D. Kendig
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (M.J.H.); (M.D.K.); (B.M.W.); (M.J.M.)
| | - Brandon M. Wild
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (M.J.H.); (M.D.K.); (B.M.W.); (M.J.M.)
| | - Tushar Issar
- Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (T.I.); (A.V.K.)
| | - Arun V. Krishnan
- Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; (T.I.); (A.V.K.)
| | - Margaret J. Morris
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (M.J.H.); (M.D.K.); (B.M.W.); (M.J.M.)
| | - Ria Arnold
- School of Medical Sciences, UNSW Sydney, Sydney, NSW 2052, Australia; (M.J.H.); (M.D.K.); (B.M.W.); (M.J.M.)
- Correspondence: ; Tel.: +61-293858709
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23
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Schwarz D, Hidmark AS, Sturm V, Fischer M, Milford D, Hausser I, Sahm F, Breckwoldt MO, Agarwal N, Kuner R, Bendszus M, Nawroth PP, Heiland S, Fleming T. Characterization of experimental diabetic neuropathy using multicontrast magnetic resonance neurography at ultra high field strength. Sci Rep 2020; 10:7593. [PMID: 32371885 PMCID: PMC7200726 DOI: 10.1038/s41598-020-64585-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/20/2020] [Indexed: 11/25/2022] Open
Abstract
In light of the limited treatment options of diabetic polyneuropathy (DPN) available, suitable animal models are essential to investigate pathophysiological mechanisms and to identify potential therapeutic targets. In vivo evaluation with current techniques, however, often provides only restricted information about disease evolution. In the study of patients with DPN, magnetic resonance neurography (MRN) has been introduced as an innovative diagnostic tool detecting characteristic lesions within peripheral nerves. We developed a novel multicontrast ultra high field MRN strategy to examine major peripheral nerve segments in diabetic mice non-invasively. It was first validated in a cross-platform approach on human nerve tissue and then applied to the popular streptozotocin(STZ)-induced mouse model of DPN. In the absence of gross morphologic alterations, a distinct MR-signature within the sciatic nerve was observed mirroring subtle changes of the nerves' fibre composition and ultrastructure, potentially indicating early re-arrangements of DPN. Interestingly, these signal alterations differed from previously reported typical nerve lesions of patients with DPN. The capacity of our approach to non-invasively assess sciatic nerve tissue structure and function within a given mouse model provides a powerful tool for direct translational comparison to human disease hallmarks not only in diabetes but also in other peripheral neuropathic conditions.
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Affiliation(s)
- Daniel Schwarz
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany.
| | - Asa S Hidmark
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, INF 410, Heidelberg, Germany
| | - Volker Sturm
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - Manuel Fischer
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - David Milford
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - Ingrid Hausser
- Institute of Pathology IPH, Heidelberg University Hospital, INF 224, Heidelberg, Germany
| | - Felix Sahm
- Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, INF 224, Heidelberg, Germany
- CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael O Breckwoldt
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - Nitin Agarwal
- Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, INF 366, Heidelberg, Germany
| | - Rohini Kuner
- Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, INF 366, Heidelberg, Germany
| | - Martin Bendszus
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - Peter P Nawroth
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, INF 410, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany
- Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg Center for Molecular Biology (ZMBH) and Heidelberg University Hospital University, Heidelberg, Germany
- Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany
| | - Sabine Heiland
- Department of Neuroradiology, Heidelberg University Hospital, INF 400, Heidelberg, Germany
| | - Thomas Fleming
- Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, INF 410, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Helmholtz Center Munich, Neuherberg, Germany
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24
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Preguiça I, Alves A, Nunes S, Gomes P, Fernandes R, Viana SD, Reis F. Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy. Nutrients 2020; 12:nu12010250. [PMID: 31963709 PMCID: PMC7019796 DOI: 10.3390/nu12010250] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 12/12/2022] Open
Abstract
Unhealthy dietary habits are major modifiable risk factors for the development of type 2 diabetes mellitus, a metabolic disease with increasing prevalence and serious consequences. Microvascular complications of diabetes, namely diabetic peripheral neuropathy (DPN), retinopathy (DR), and nephropathy (DN), are associated with high morbidity rates and a heavy social and economic burden. Currently, available therapeutic options to counter the evolution of diabetic microvascular complications are clearly insufficient, which strongly recommends further research. Animal models are essential tools to dissect the molecular mechanisms underlying disease progression, to unravel new therapeutic targets, as well as to evaluate the efficacy of new drugs and/or novel therapeutic approaches. However, choosing the best animal model is challenging due to the large number of factors that need to be considered. This is particularly relevant for models induced by dietary modifications, which vary markedly in terms of macronutrient composition. In this article, we revisit the rodent models of diet-induced DPN, DR, and DN, critically comparing the main features of these microvascular complications in humans and the criteria for their diagnosis with the parameters that have been used in preclinical research using rodent models, considering the possible need for factors which can accelerate or aggravate these conditions.
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Affiliation(s)
- Inês Preguiça
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
| | - André Alves
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Sara Nunes
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Pedro Gomes
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Center for Health Technology and Services Research (CINTESIS), University of Porto, 4200-450 Porto, Portugal
| | - Rosa Fernandes
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
| | - Sofia D. Viana
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, Pharmacy, 3046-854 Coimbra, Portugal
| | - Flávio Reis
- Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; (I.P.); (A.A.); (S.N.); (P.G.); (R.F.); (S.D.V.)
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
- Correspondence: ; Tel.: +351-239-480-053
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25
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Himeno T, Kamiya H, Nakamura J. Diabetic polyneuropathy: Progress in diagnostic strategy and novel target discovery, but stagnation in drug development. J Diabetes Investig 2019; 11:25-27. [PMID: 31755662 PMCID: PMC6944845 DOI: 10.1111/jdi.13188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/20/2019] [Accepted: 11/20/2019] [Indexed: 12/14/2022] Open
Affiliation(s)
- Tatsuhito Himeno
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hideki Kamiya
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Jiro Nakamura
- Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
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26
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Lu M, Yi T, Xiong Y, Wang Q, Yin N. Cortex Mori Radicis extract promotes neurite outgrowth in diabetic rats by activating PI3K/AKT signaling and inhibiting Ca2+ influx associated with the upregulation of transient receptor potential canonical channel 1. Mol Med Rep 2019; 21:320-328. [PMID: 31939614 PMCID: PMC6896399 DOI: 10.3892/mmr.2019.10839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 10/16/2019] [Indexed: 01/16/2023] Open
Abstract
Cortex Mori Radicis extract (CMR) has various pharmacological properties, such as anti‑inflammatory, anti‑allergic and anti‑hyperglycemic effects. However, the effects and mechanisms of CMR in the neuroregeneration of diabetic peripheral neuropathy (DPN) are unclear. In the present study, the effects of CMR on neurite outgrowth of dorsal root ganglia (DRG) neurons in diabetic rats were investigated and its underlying mechanisms were explored. SD rats were subjected to a high‑fat diet with low‑dose streptozotocin to induce a Type II diabetes model with peripheral neuropathy. CMR was then applied for four weeks continuously with or without injection of small interfere (si)RNA targeting the transient receptor potential canonical channel 1 (TRPC1) via the tail vein. Blood glucose levels, the number of Nissl bodies, neurite outgrowth and growth cone turning in DRG neurons were evaluated. The expression of TRPC1 protein, Ca2+ influx and activation of the PI3K/AKT signaling pathway were also investigated. The results of the present study showed that CMR significantly lowered blood glucose levels, reversed the loss of Nissl bodies, induced neurite outgrowth and restored the response of the growth cone of DRG neurons in diabetic rats. CMR exerted neurite outgrowth‑promoting effects by increasing TRPC1 expression, reducing Ca2+ influx and enhancing AKT phosphorylation. siRNA targeting TRPC1 in the CMR group abrogated its anti‑diabetic and neuroregenerative effects, suggesting the involvement of TRPC1 in the biological effects of CMR on DPN.
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Affiliation(s)
- Min Lu
- Department of Histology and Embryology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Tao Yi
- College of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Yong Xiong
- College of Acupuncture and Moxibustion, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Qian Wang
- Department of Pathogen Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Nina Yin
- Department of Anatomy, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
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27
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Jolivalt CG, Marquez A, Quach D, Navarro Diaz MC, Anaya C, Kifle B, Muttalib N, Sanchez G, Guernsey L, Hefferan M, Smith DR, Fernyhough P, Johe K, Calcutt NA. Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes 2019; 68:2143-2154. [PMID: 31492662 PMCID: PMC6804627 DOI: 10.2337/db19-0271] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 08/26/2019] [Indexed: 02/06/2023]
Abstract
While peripheral neuropathy is the most common complication of long-term diabetes, cognitive deficits associated with encephalopathy and myelopathy also occur. Diabetes is a risk factor for Alzheimer disease (AD) and increases the risk of progression from mild cognitive impairment to AD. The only current recommendation for preventing or slowing the progression of peripheral neuropathy is to maintain close glycemic control, while there is no recommendation for central nervous system disorders. NSI-189 is a new chemical entity that when orally administered promotes neurogenesis in the adult hippocampus, increases hippocampal volume, enhances synaptic plasticity, and reduces cognitive dysfunction. To establish the potential for impact on peripheral neuropathy, we first showed that NSI-189 enhances neurite outgrowth and mitochondrial functions in cultured adult rat primary sensory neurons. Oral delivery of NSI-189 to murine models of type 1 (female) and type 2 (male) diabetes prevented multiple functional and structural indices of small and large fiber peripheral neuropathy, increased hippocampal neurogenesis, synaptic markers and volume, and protected long-term memory. NSI-189 also halted progression of established peripheral and central neuropathy. NSI-189, which is currently in clinical trials for treatment of major depressive disorder, offers the opportunity for the development of a single therapeutic agent against multiple indices of central and peripheral neuropathy.
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Affiliation(s)
- Corinne G Jolivalt
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | - Alexandra Marquez
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | | | | | - Carlos Anaya
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | - Betelhem Kifle
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | - Nabeel Muttalib
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | - Gabriela Sanchez
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | - Lucy Guernsey
- Department of Pathology, University of California, San Diego, La Jolla, CA
| | | | - Darrel R Smith
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
| | - Paul Fernyhough
- St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Nigel A Calcutt
- Department of Pathology, University of California, San Diego, La Jolla, CA
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28
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Mangus LM, Rao DB, Ebenezer GJ. Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review. Toxicol Pathol 2019; 48:59-70. [PMID: 31221022 DOI: 10.1177/0192623319855969] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Analysis of intraepidermal nerve fibers (IENFs) in skin biopsy samples has become a standard clinical tool for diagnosing peripheral neuropathies in human patients. Compared to sural nerve biopsy, skin biopsy is safer, less invasive, and can be performed repeatedly to facilitate longitudinal assessment. Intraepidermal nerve fiber analysis is also more sensitive than conventional nerve histology or electrophysiological tests for detecting damage to small-diameter sensory nerve fibers. The techniques used for IENF analysis in humans have been adapted for large and small animal models and successfully used in studies of diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV-associated sensory neuropathy, among others. Although IENF analysis has yet to become a routine end point in nonclinical safety testing, it has the potential to serve as a highly relevant indicator of sensory nerve fiber status in neurotoxicity studies, as well as development of neuroprotective and neuroregenerative therapies. Recently, there is also interest in the evaluation of IENF via skin biopsy as a biomarker of small fiber neuropathy in the regulatory setting. This article provides an overview of the anatomic and pathophysiologic principles behind IENF analysis, its use as a diagnostic tool in humans, and applications in animal models with focus on comparative methodology and considerations for study design.
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Affiliation(s)
- Lisa M Mangus
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, USA.,Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
| | - Deepa B Rao
- US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD, USA
| | - Gigi J Ebenezer
- Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
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29
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Effects of diabetes mellitus on myenteric neuronal density and sodium channel expression in the rat ileum. Brain Res 2018; 1708:1-9. [PMID: 30500400 DOI: 10.1016/j.brainres.2018.11.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 11/09/2018] [Accepted: 11/26/2018] [Indexed: 12/25/2022]
Abstract
Diabetes mellitus (DM) may lead to gastrointestinal motility disorders. Rodent models of DM indicate the presence of morpho-functional abnormalities of the enteric nervous system. Here, we evaluated whether experimental DM can cause changes in the excitatory cholinergic fibers, neuronal density, and voltage-gated sodium channel (Nav) expression in the myenteric plexus of the ileum. After streptozotocin-induced hyperglycemia in female rats progressed for eight weeks, triple immunofluorescence labeling experiments revealed that the neuronal density in DM rats was significantly lower than that in control. On average, the density of total neurons reduced by 52.2% (p = 0.0001), cholinergic neurons by 50.0% (p = 0.0068), and nitrergic neurons by 54.8% (p = 0.0042). The number of neurons per ganglionic area was also significantly reduced (to 28.2% of total neurons, p = 0.0002; 27.7% of cholinergic neurons, p = 0.0002, and 32.1% of nitrergic neurons, p = 0.0016). Furthermore, the density of the cholinergic fibers at the surface of the longitudinal muscle was significantly reduced (DM: 24 ± 3%; p = 0.003, control: 41 ± 2%); however, western-blot analysis did not indicate a reduction in the expression of choline acetyltransferase (ChAT) in the DM group. The Nav1.6 isoform was detected in different myenteric neurons of the ileum. RT-qPCR data did not suggest an alteration of transcripts for ChAT, neuronal nitric oxide synthase, Nav1.3, Nav1.6, or Nav1.7. Our data support the view that chronic DM leads to a reduction of excitatory cholinergic fibers and neuronal density. However, changes in sodium channel expression pattern, which could cause neuronal dysfunction, were not detected.
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Ward R, Valenzuela JP, Li W, Dong G, Fagan SC, Ergul A. Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex. Am J Physiol Heart Circ Physiol 2018; 315:H1402-H1413. [PMID: 30118341 PMCID: PMC6297815 DOI: 10.1152/ajpheart.00390.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/31/2018] [Accepted: 08/15/2018] [Indexed: 02/07/2023]
Abstract
Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a domain critical to memory and learning. Therefore, we had two aims for this study: 1) to determine the impact of diabetes on hippocampal neurovascular remodeling and the resulting cognitive impairment after stroke using two models with varying disease severity, and 2) to compare the effects of ischemia on hippocampal neurovascular injury in diabetic male and female animals. Stroke was induced by middle cerebral artery occlusion (MCAO) by either the suture or embolic method in control and diabetic age-matched male and female Wistar rats. Hippocampal neuronal density, vascular architecture, and microglial activation as well as cognitive outcomes were measured. Embolic MCAO induced greater neuronal degeneration, pathological vascularization, microglial activation, and cognitive impairment in diabetes as compared with control animals or 60-min MCAO. Although diabetic males had lower neuronal density at baseline, diabetic females had more neurodegeneration after stroke. Control animals recovered cognitive function by day 14 after stroke; diabetic animals showed deficits regardless of sex. These results suggest that mechanisms underlying cognitive decline in diabetes may differ in males and females and provide further insight to the impact of diabetes on stroke severity and poststroke cognitive impairment. NEW & NOTEWORTHY The present study is the first to provide comparative information on the effects of diabetes and ischemia on cognitive outcomes in both sexes while also evaluating the neurovascular structure in the hippocampus, a critical region for cognitive and memory-related tasks.
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Affiliation(s)
- Rebecca Ward
- Departments of Neuroscience and Regenerative Medicine, Augusta University , Augusta, Georgia
| | | | - Weiguo Li
- Department of Physiology, Augusta University , Augusta, Georgia
- Charlie Norwood Veterans Administration Medical Center , Augusta, Georgia
| | - Guangkuo Dong
- Department of Physiology, Augusta University , Augusta, Georgia
- Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy , Augusta, Georgia
| | - Susan C Fagan
- Charlie Norwood Veterans Administration Medical Center , Augusta, Georgia
- Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy , Augusta, Georgia
| | - Adviye Ergul
- Department of Physiology, Augusta University , Augusta, Georgia
- Charlie Norwood Veterans Administration Medical Center , Augusta, Georgia
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Abstract
PURPOSE OF REVIEW This review will summarize recent findings of the effect of supplemental fatty acids, with an emphasis on omega-3 polyunsaturated fatty acids, as a treatment for diabetic peripheral neuropathy. RECENT FINDINGS Pre-clinical studies have provided evidence that treating diabetic rodents with δ linolenic acid (omega-6 18:3) and to a greater extent with eicosapentaenoic and docosahexaenoic acids (omega-3 20:5 and 22:6, respectively) improve and even reverse vascular and neural deficits. Additional studies have shown resolvins, metabolites of eicosapentaenoic and docosahexaenoic acids, can induce neurite outgrowth in neuron cultures and that treating type 1 or type 2 diabetic mice with resolvin D1 or E1 provides benefit for peripheral neuropathy similar to fish oil. Omega-3 polyunsaturated fatty acids derived from fish oil and their derivatives have anti-inflammatory properties and could provide benefit for diabetic peripheral neuropathy. However, clinical trials are needed to determine whether this statement is true.
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Affiliation(s)
- Mark A Yorek
- Department of Veterans Affairs Iowa City Health Care System, Room 127, Building 41, Iowa City, IA, 52246, USA.
- Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52242, USA.
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