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Bakovic M, Filipovic N, Ferhatovic Hamzic L, Kunac N, Zdrilic E, Vitlov Uljevic M, Kostic S, Puljak L, Vukojevic K. Changes in neurofilament 200 and tyrosine hydroxylase expression in the cardiac innervation of diabetic rats during aging. Cardiovasc Pathol 2017; 32:38-43. [PMID: 29175663 DOI: 10.1016/j.carpath.2017.11.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 11/10/2017] [Accepted: 11/10/2017] [Indexed: 11/19/2022] Open
Abstract
Changes in sensory and sympathetic innervation during diabetes mellitus (DM) can be a predictor of arrhythmias, silent myocardial ischemia, and chronic heart failure, but knowledge about these changes is still unsatisfactory. We analyzed whether prolonged DM induces changes in density of sensory and sympathetic nerve terminals of rat's heart and whether it contributes to cardiomyopathy during aging. DM was induced by i/p injecting 55 mg/kg streptozotocin to male Sprague-Dawley rats, while a control group received a citrate buffer. DM in the rats was validated by measuring blood glucose level. Animals were sacrificed after 2 weeks, 2 months, 6 months, and 12 months. Five areas of cardiac sections were analyzed. Antibodies raised against tyrosine hydroxylase (TH) and neurofilament 200 kDa (NF 200) were used to detect sympathetic and sensory fibers. TH immunoreactive fiber density increased in DM groups 2 weeks after induction, reaching a peek after 2 months, while in the later stages of DM (6 and 12 months), there was no significant difference compared to control. NF 200 immunoreactive fiber density increased 2 weeks after induction compared to control. There was no consistent pattern of change during the given period in both the DM or control groups. In the DM group, we found thickening of the left ventricle wall (P<.05) as the sign of cardiomyopathy. Our findings suggest that hyperglycemia as a hallmark of DM in early stages can lead to proliferation of sympathetic and sensory nerve terminals. This finding can contribute to a better understanding of the occurrence of arrhythmias and silent myocardial ischemia in DM.
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Affiliation(s)
- Marija Bakovic
- Laboratory for Neurocardiology, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Natalija Filipovic
- Laboratory for Neurocardiology, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Lejla Ferhatovic Hamzic
- Laboratory for Pain Reaserch, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Nenad Kunac
- Department of Pathology, Citology and Forensic medicine, University Hospital Split, Spinciceva 1, 21000 Split, Croatia
| | - Elena Zdrilic
- Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Marija Vitlov Uljevic
- Laboratory for Neurocardiology, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Sandra Kostic
- Laboratory for Microscopy, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Livia Puljak
- Laboratory for Pain Reaserch, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia
| | - Katarina Vukojevic
- Laboratory for Neurocardiology, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; Laboratory for Early Human Development, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia; Laboratory for Microscopy, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia.
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Johansen NJ, Frugier T, Hunne B, Brock JA. Increased peripherin in sympathetic axons innervating plantar metatarsal arteries in STZ-induced type I diabetic rats. Front Neurosci 2014; 8:99. [PMID: 24847201 PMCID: PMC4019865 DOI: 10.3389/fnins.2014.00099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/16/2014] [Indexed: 11/17/2022] Open
Abstract
A common characteristic of axonopathy is the abnormal accumulation of cytoskeletal proteins. We recently reported that streptozotocin (STZ)-induced type 1 diabetes produced a change in the morphology of sympathetic nerve fibers supplying rat plantar metatarsal arteries (PMAs). Here we investigated whether these morphological changes are associated with axonal accumulation of the type III intermediate filament peripherin and the microtubule protein β-tubulin III, as both are implicated in axonal remodeling. PMAs from hyperglycemic STZ-treated rats receiving a low dose of insulin (STZ-LI) were compared with those from normoglycemic STZ-treated rats receiving a high dose of insulin (STZ-HI) and vehicle-treated controls. Western blotting revealed an increase in protein expression level for peripherin in PMAs from STZ-LI rats but no change in that for β-tubulin III. In addition, there was an increase in the number of peripherin immunoreactive nerve fibers in the perivascular nerve plexus of PMAs from STZ-LI rats. Co-labeling for peripherin and neuropeptide Y (a marker for sympathetic axons) revealed that peripherin immunoreactivity increased in sympathetic axons. None of these changes were detected in PMAs from STZ-HI rats, indicating that increased peripherin in sympathetic axons of STZ-LI rats is likely due to hyperglycemia and provides a marker of diabetes-induced nerve damage.
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Affiliation(s)
- Niloufer J Johansen
- Department of Anatomy and Neuroscience, University of Melbourne Melbourne, VIC, Australia
| | - Tony Frugier
- Department of Anatomy and Neuroscience, University of Melbourne Melbourne, VIC, Australia
| | - Billie Hunne
- Department of Anatomy and Neuroscience, University of Melbourne Melbourne, VIC, Australia
| | - James A Brock
- Department of Anatomy and Neuroscience, University of Melbourne Melbourne, VIC, Australia
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Abstract
Autonomic neuropathy complicates diabetes by increasing patient morbidity and mortality. Surprisingly, considering its importance, development and exploitation of animal models has lagged behind the wealth of information collected for somatic symmetrical sensory neuropathy. Nonetheless, animal studies have resulted in a variety of insights into the pathogenesis, neuropathology, and pathophysiology of diabetic autonomic neuropathy (DAN) with significant and, in some cases, remarkable correspondence between rodent models and human disease. Particularly in the study of alimentary dysfunction, findings in intrinsic intramural ganglia, interstitial cells of Cajal and the extrinsic parasympathetic and sympathetic ganglia serving the bowel vie for recognition as the chief mechanism. A body of work focused on neuropathologic findings in experimental animals and human subjects has demonstrated that axonal and dendritic pathology in sympathetic ganglia with relative neuron preservation represents one of the neuropathologic hallmarks of DAN but it is unlikely to represent the entire story. There is a surprising selectivity of the diabetic process for subpopulations of neurons and nerve terminals within intramural, parasympathetic, and sympathetic ganglia and innervation of end organs, afflicting some while sparing others, and differing between vascular and other targets within individual end organs. Rather than resulting from a simple deficit in one limb of an effector pathway, autonomic dysfunction may proceed from the inability to integrate portions of several complex pathways. The selectivity of the diabetic process appears to confound a simple global explanation (e.g., ischemia) of DAN. Although the search for a single unifying pathogenetic hypothesis continues, it is possible that autonomic neuropathy will have multiple pathogenetic mechanisms whose interplay may require therapies consisting of a cocktail of drugs. The role of multiple neurotrophic substances, antioxidants (general or pathway specific), inhibitors of formation of advanced glycosylation end products and drugs affecting the polyol pathway may be complex and therapeutic elements may have both salutary and untoward effects. This review has attempted to present the background and current findings and hypotheses, focusing on autonomic elements including and beyond the typical parasympathetic and sympathetic nervous systems to include visceral sensory and enteric nervous systems.
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Affiliation(s)
- Robert E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
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Johansen NJ, Tripovic D, Brock JA. Streptozotocin-induced diabetes differentially affects sympathetic innervation and control of plantar metatarsal and mesenteric arteries in the rat. Am J Physiol Heart Circ Physiol 2012; 304:H215-28. [PMID: 23161877 DOI: 10.1152/ajpheart.00661.2012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In humans neural control of arterial vessels supplying skin in the extremities is particularly vulnerable to the effects of diabetes. Here the streptozotocin (STZ) rat model of type 1 diabetes was used to compare effects on neurovascular function in plantar metatarsal arteries (PMAs), which supply blood to skin of hind paw digits, with those in mesenteric arteries (MAs). Twelve weeks after STZ (60 mg/kg ip), wire myography was used to assess vascular function. In PMAs, lumen dimensions were unchanged but both nerve-evoked contractions and sensitivity to α(1) (phenylephrine, methoxamine)- and α(2) (clonidine)-adrenoceptor agonists were reduced. The density of perivascular nerve fibers was also reduced by ~25%. These changes were not observed in PMAs from STZ-treated rats receiving either a low dose of insulin that did not greatly reduce blood glucose levels or a high dose of insulin that markedly reduced blood glucose levels. In MAs from STZ-treated rats, nerve-evoked increases in force did not differ from control but, because lumen dimensions were ~20% larger, nerve-evoked increases in effective transmural pressure were smaller. Increases in effective transmural pressure produced by phenylephrine or α,β-methylene ATP in MAs from STZ-treated rats were not smaller than control, but the density of perivascular nerve fibers was reduced by ~10%. In MAs, the increase in vascular dimensions is primarily responsible for reducing effectiveness of nerve-evoked constrictions. By contrast, in PMAs decreases in both the density of perivascular nerve fibers and the reactivity of the vascular muscle appear to explain impairment of neurovascular transmission.
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Affiliation(s)
- Niloufer J Johansen
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
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Gibbons CH, Illigens BMW, Wang N, Freeman R. Quantification of sudomotor innervation: a comparison of three methods. Muscle Nerve 2010; 42:112-9. [PMID: 20544913 PMCID: PMC3048308 DOI: 10.1002/mus.21626] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Peripheral sudomotor dysfunction is present in many peripheral neuropathies, but structural assessments of sudomotor fibers rarely occur. We evaluated 36 diabetic and 72 healthy control subjects who underwent detailed neurologic examinations and punch skin biopsies. Physical exam findings were quantified by neuropathy impairment score in the lower limb. Skin biopsies quantified intraepidermal nerve fiber density (IENFD) and sweat gland nerve fiber density (SGNFD) by a manual, automated, and semiquantitative method. The automated and manual SGNFD correlated with the IENFD at the same site (r = 0.62, P < 0.05 automated method, r = 0.67, P < 0.05 manual method). As neuropathy worsened, the SGNFD at the distal leg declined (automated counting r = -0.81, P < 0.001; manual counting r = -0.88, P < 0.001). The semiquantitative method displayed poor inter- and intrareviewer reliability and correlated poorly with standard neuropathy evaluation scores. Our results suggest that sudomotor fibers can be rapidly and reproducibly quantified, and results correlate well with physical exam findings.
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Affiliation(s)
- Christopher H Gibbons
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, Boston, Massachusetts 02215, USA
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Gibbons CH, Illigens BMW, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology 2009; 72:1479-86. [PMID: 19398703 PMCID: PMC2677479 DOI: 10.1212/wnl.0b013e3181a2e8b8] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE To evaluate a novel method to quantify the density of nerve fibers innervating sweat glands in healthy control and diabetic subjects, to compare the results to an unbiased stereologic technique, and to identify the relationship to standardized physical examination and patient-reported symptom scores. METHODS Thirty diabetic and 64 healthy subjects had skin biopsies performed at the distal leg and distal and proximal thigh. Nerve fibers innervating sweat glands, stained with PGP 9.5, were imaged by light microscopy. Sweat gland nerve fiber density (SGNFD) was quantified by manual morphometry. As a gold standard, three additional subjects had biopsies analyzed by confocal microscopy using unbiased stereologic quantification. Severity of neuropathy was measured by standardized instruments including the Neuropathy Impairment Score in the Lower Limb (NIS-LL) while symptoms were measured by the Michigan Neuropathy Screening Instrument. RESULTS Manual morphometry increased with unbiased stereology (r = 0.93, p < 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p < 0.001), distal thigh (p < 0.01), and proximal thigh (p < 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r = -0.89, p < 0.001) and was concordant with symptoms of reduced sweat production (p < 0.01). CONCLUSIONS We describe a novel method to quantify the density of nerve fibers innervating sweat glands. The technique differentiates groups of patients with mild diabetic neuropathy from healthy control subjects and correlates with both physical examination scores and symptoms relevant to sudomotor dysfunction. This method provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies.
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Affiliation(s)
- Christopher H Gibbons
- Autonomic and Peripheral Nerve Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, MA 02215, USA
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Schmidt RE, Dorsey DA, Beaudet LN, Parvin CA, Yarasheski KE, Smith SR, Williamson JR, Peterson RG, Oates PJ. A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. Exp Neurol 2005; 192:407-19. [PMID: 15755558 DOI: 10.1016/j.expneurol.2004.12.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2004] [Revised: 12/09/2004] [Accepted: 12/15/2004] [Indexed: 10/25/2022]
Abstract
We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.
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Affiliation(s)
- Robert E Schmidt
- Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA.
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Schmidt RE. Neuronal preservation in the sympathetic ganglia of rats with chronic streptozotocin-induced diabetes. Brain Res 2001; 921:256-9. [PMID: 11720733 DOI: 10.1016/s0006-8993(01)03155-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Recent studies have reported that rat sympathetic neurons exposed to increased concentrations of glucose in vitro initiate an apoptotic program which culminates in neuronal cell death, a process proposed to contribute to the development of human diabetic autonomic neuropathy. We tested this hypothesis in an in vivo streptozotocin model of diabetic autonomic neuropathy using an unbiased counting method to quantitate neuron numbers in control and diabetic rats. Ten months of severe untreated diabetes failed to produce significant neuron loss in either the rat superior mesenteric or superior cervical sympathetic ganglia indicating that apoptotic neuronal cell death is unlikely to play a role in the pathogenesis of experimental diabetic autonomic neuropathy.
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Affiliation(s)
- R E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
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Schmidt RE, Dorsey DA, Beaudet LN, Plurad SB, Parvin CA, Yarasheski KE, Smith SR, Lang HJ, Williamson JR, Ido Y. Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes. J Neuropathol Exp Neurol 2001; 60:1153-69. [PMID: 11764088 DOI: 10.1093/jnen/60.12.1153] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
We have developed an animal model of diabetic autonomic neuropathy that is characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric nerves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chronic streptozotocin (STZ)-diabetic rats. Studies with the sorbitol dehydrogenase inhibitor SDI-158, which interrupts the conversion of sorbitol to fructose (and reactions dependent on the second step of the sorbitol pathway), have shown a dramatically increased frequency of NAD in ileal mesenteric nerves and SMG of SDI-treated versus untreated diabetics. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics, their distinctive ultrastructural appearance was identical to that previously reported in long-term untreated diabetics. An SDI effect was first demonstrated in the SMG of rats that were diabetic for as little as 5 wk and was maintained for at least 7.5 months. As in untreated diabetic rats, rats treated with SDI i) showed involvement of lengthy ileal, but not shorter, jejunal mesenteric nerves; ii) demonstrated NAD in paravascular mesenteric nerves distributed to myenteric ganglia while sparing adjacent perivascular axons ramifying within the vascular adventitia; and, iii) failed to develop NAD in the superior cervical ganglia (SCG). After only 2 months of SDI-treatment, tyrosine hydroxylase immunolocalization demonstrated marked dilatation of postganglionic noradrenergic axons in paravascular ileal mesenteric nerves and within the gut wall versus those innervating extramural mesenteric vasculature. The effect of SDI on diabetic NAD in SMG was completely prevented by concomitant administration of the aldose reductase inhibitor Sorbinil. Treatment of diabetic rats with Sorbinil also prevented NAD in diabetic rats not treated with SDI. These findings indicate that sorbitol pathway-linked metabolic imbalances play a critical role in the development of NAD in this model of diabetic sympathetic autonomic neuropathy.
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Affiliation(s)
- R E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
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Bitar MS, Pilcher CW, Khan I, Waldbillig RJ. Diabetes-induced suppression of IGF-1 and its receptor mRNA levels in rat superior cervical ganglia. Diabetes Res Clin Pract 1997; 38:73-80. [PMID: 9483370 DOI: 10.1016/s0168-8227(97)00077-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Insulin-like growth factor-I (IGF-I) is implicated in the development, survival and maintenance of function of sympathetic and sensory neurons. These neurons are affected at an early stage during the course of diabetes. Reverse transcriptase polymerase chain reaction (RT-PCR) based assay revealed that rat superior cervical ganglia (SCG) express mRNA transcripts for IGF-I and its receptor. Moreover, specific membrane protein binding sites for IGF-I within the SCG have also been demonstrated using competition-inhibition and affinity cross-linking techniques. An induction of diabetes with streptozotocin (STZ, 55 mg/kg, i.v.) produced a marked decrease in the SCG levels of mRNA transcripts for IGF-I and its receptor. Concentrations of circulating IGF-I and its receptor protein within the SCG were also reduced in this disease state. Insulin treatment partially prevented diabetes-related alterations in circulating IGF-I and the SCG-IGF-I system. Overall, the data described in this study may be of value in understanding the pathogenetic mechanism(s) responsible for the development of diabetic sympathetic neuropathy.
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Affiliation(s)
- M S Bitar
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait
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Ouyang A, Zimmerman K, Wong KL, Sharp D, Reynolds JC. Effect of celiac ganglionectomy on tachykinin innervation, receptor distribution and intestinal responses in the rat. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1996; 61:292-300. [PMID: 8988488 DOI: 10.1016/s0165-1838(96)00099-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Substance P (SP) is an important neurotransmitter in the control of intestinal motility and is found in both the enteric and sympathetic nervous systems. This study examined the effect of celiac ganglionectomy on (1) mechanical properties of the circular muscles of the duodenum, ileum and proximal colon, (2) circular muscle responses to SP and neurokinin A. (3) distribution of substance P-like immunoreactive nerves, and (4) the distribution of neurokinin 1 and neurokinin 2 receptors. Celiac ganglionectomy resulted in an effective sympathectomy as evidenced by a marked decrease in norepinephrine content and tyrosine hydroxylase staining in the duodenum, ileum and proximal colon. The in vitro length/tension characteristics of the circular muscle of the duodenum, ileum and colon were unchanged after ganglionectomy. In all regions of the gut studied, substance P and neurokinin A caused dose-dependent contractions that were unaltered by celiac ganglionectomy. Immunohistochemistry revealed moderate substance P-like immunoreactive fibers in the myenteric plexus, submucosal plexus and circular muscle of the ileum, while in the colon, substance P-like immunoreactivity was intense in the myenteric plexus, and moderate in the circular muscle. In vitro autoradiography showed minimal binding of SP (NK1 receptor) or neurokinin A (NK2 receptor) in the ileum and significantly greater binding in the circular muscle layer of the colon. Celiac ganglionectomy did not affect substance P-like immunoreactivity, or NK1 or NK2 receptor binding. A greater contractile response to neurokinins was seen in the colon than in the duodenum or ileum, which paralleled the receptor density. The studies demonstrate that surgical celiac ganglionectomy, unlike chemical sympathectomy, does not affect the substance P innervation, receptor density or physiological responses of the intestine. The greater contractile response of the colon than the ileum parallels the greater receptor density rather than the peptide content as determined by immunhistochemistry.
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Affiliation(s)
- A Ouyang
- Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia 19104, USA
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Abstract
The ultrastructure of peripheral sensory nerves was investigated in adult Wistar rats suffering from experimental diabetes mellitus 6 and 10 weeks after the injection of streptozotocin. Giant axons were seen in sections from the nerves of streptozotocin-treated rats; some contained masses of neurofilaments, others were predominantly filled with ill-defined vesicles. At the swollen axons, the myelin sheath was thinned or absent. In other regions, large intramyelinic vacuoles were observed. A number of nerve fibers broke down completely and underwent Wallerian degeneration. This was accompanied by Schwann cell proliferation and formation of Büngner bands. Concomitantly with axonal degeneration, nerve regeneration started from intact internodes. The pathomorphology of streptozotocin diabetic neuropathy closely resembles that of some toxic distal axonopathies. This points to a common metabolic basis of giant axonopathies of different etiology.
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Affiliation(s)
- I Jirmanová
- Institute of Physiology, Academy of Sciences, Czech Republic, Prague
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Tay SS, Wong WC. Gracile nucleus of streptozotocin-induced diabetic rats. JOURNAL OF NEUROCYTOLOGY 1991; 20:356-64. [PMID: 1869877 DOI: 10.1007/bf01355532] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
This study reports ultrastructural changes in the gracile nucleus of male Wistar rats after streptozotocin-induced diabetes. During the acute phase (3-7 days) degenerating electron-dense dendrites and axon terminals were dispersed in the neuropil. Degenerating dendrites were characterized by an electron-dense cytoplasm, swollen mitochondria, dilated endoplasmic reticulum and scattered ribosomes. Degenerating axon terminals were characterized by an electron-dense cytoplasm and clustering of small spherical agranular vesicles. Degenerating axon terminals may form part of a synaptic glomerulus with a central electron-dense dendrite, or they may form the central element of a synaptic glomerulus. These degenerating profiles were absent in the gracile nucleus of the 3 and 7 days insulin-treated post-streptozotocin rats. Macrophages were present in the neuropil and were in the process of engulfing neuronal elements. During the medium phase (1-6 months), most of the degenerating dendrites and axon terminals had been engulfed or removed by macrophages. During the late phase (9-12 months) a second wave of degeneration occurred in the gracile nucleus, similar to the acute phase. During the medium and late phases, dystrophic axonal profiles were also significantly increased in the rats after streptozotocin treatment. It is concluded that the ultrastructural changes observed in the gracile nucleus in the present study were the result of streptozotocin-induced diabetes rather than a toxic effect of streptozotocin, even in the acute phase.
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Affiliation(s)
- S S Tay
- Department of Anatomy, Faculty of Medicine, National University of Singapore
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Schmidt RE, Plurad DA, Roth KA. Effects of chronic experimental streptozotocin-induced diabetes on the noradrenergic and peptidergic innervation of the rat alimentary tract. Brain Res 1988; 458:353-60. [PMID: 2905198 DOI: 10.1016/0006-8993(88)90478-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Immunohistologic localization of tyrosine hydroxylase (TOH), dopamine-beta-hydroxylase (DBH) and selected neuropeptides (vasoactive intestinal polypeptide, gastrin-releasing peptide (GRP)/bombesin, substance P, Leu-enkephalin, Met-enkephalin, dynorphin B, neuropeptide Y (NPY), somatostatin) was used to investigate the innervation of the small bowel in a rat model of diabetic autonomic neuropathy. Paravascular mesenteric nerves (extrinsic) and intramural nerves of chronically (12-18 month) diabetic rats were characterized by the presence of numerous, markedly swollen dystrophic axons which stained intensely for TOH and DBH. The peptidergic complement of axons, however, showed no evidence of comparable dystrophic axonopathy.
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Affiliation(s)
- R E Schmidt
- Washington University School of Medicine, Department of Pathology, St. Louis, MO 63110
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Schmidt RE, Modert CW, Grabau GG. Orthograde and retrograde axonal transport of dopamine-beta-hydroxylase in ileal mesenteric nerves of rats with chronic streptozotocin diabetes. Brain Res 1987; 401:142-6. [PMID: 2434189 DOI: 10.1016/0006-8993(87)91173-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Rats with chronic streptozotocin-induced diabetes develop a neuropathy involving the ileal mesenteric nerves. Distal portions of these postganglionic sympathetic axons develop markedly dilated, dopamine-beta-hydroxylase (DBH)-containing dystrophic swellings. These findings led us to develop a quantitative method to examine orthograde and retrograde axonal transport of DBH in ileal mesenteric nerves. Surprisingly, no significant alteration in orthograde or retrograde axonal transport of DBH was identified.
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Schmidt RE, Grabau GG, Yip HK. Retrograde axonal transport of [125I]nerve growth factor in ileal mesenteric nerves in vitro: effect of streptozotocin diabetes. Brain Res 1986; 378:325-36. [PMID: 2425904 DOI: 10.1016/0006-8993(86)90936-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The retrograde axonal transport of intravenously administered [125I]nerve growth factor ([125I]NGF) was examined in ileal mesenteric nerves maintained for short periods in vitro. [125I]NGF was injected systemically, and at various times thereafter mesenteric pedicles were ligated and incubated in vitro in Krebs-Henseleit medium under a number of different conditions. Retrogradely transported [125I]NGF began to accumulate distal to the ligature after an initial lag period and increased in a linear fashion for 3-4 h. The amount of retrogradely transported [125I]NGF was proportional to the length of the ileum innervated by each pedicle, which allowed for comparison of ileal segments of different lengths. Retrograde axonal transport of [125I]NGF was inhibited by vinblastine, colchicine and incubation in the cold, and was decreased by agents that interfere with oxidative or glycolytic metabolism. The accumulation of retrogradely transported [125I]NGF in ileal mesenteric nerves of 1-9 day streptozotocin diabetic animals placed in an in vitro bath containing normal (5.5 mM) glucose was decreased 40% compared to control animals. The induction of diabetes in vivo resulted in a greater decrease in the early phases of [125I]NGF export from ileal mesenteric nerve terminals compared to later phases. Ileal mesenteric nerve segments derived from untreated controls were incubated in vitro in media containing increased concentrations of glucose (27.5 and 50 mM) without reproducing the NGF transport defect found in diabetic animals.
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