| 1. |
- Bagheri, Maryam, et al.
(författare)
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Amyloid Beta1-40-Induced Astrogliosis and the Effect of Genistein Treatment in Rat: A Three-Dimensional Confocal Morphometric and Proteomic Study
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP) in rats, to the presence of Aβ1–40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ1–40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ1–40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ1–40-induced astrogliosis was significantly ameliorated.
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| 2. |
- Bagheri, Maryam, et al.
(författare)
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Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimers disease
- 2011
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Ingår i: Neurobiology of Learning and Memory. - : Elsevier Science B.V., Amsterdam. - 1074-7427 .- 1095-9564. ; 95:3, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimers disease (AD) is a debilitating neurodegenerative disorder characterized by increased beta-amyloid (A beta) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10 mg/kg) on learning and memory impairments was assessed in intrahippocampal A beta((1-40))-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of A beta-lesioned rats. The A beta-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of A beta-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates A beta-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.
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| 3. |
- Bagheri, Maryam, et al.
(författare)
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Genistein inhibits aggregation of exogenous amyloid-beta(1-40) and alleviates astrogliosis in the hippocampus of rats
- 2012
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Ingår i: Brain Research. - : Elsevier. - 0006-8993 .- 1872-6240. ; 1429, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- We addressed the question of whether injection of Amyloid beta (Aβ)(1-40) in the rat brain is associated with pathology in the hippocampus, and if genistein has any protective effect against the neuronal damage caused by Aβ(1-40). Genistein is a plant-derived compound with a structure similar to that of the female sex hormone estrogen and it was recently shown that pretreatment with a single dose of genistein ameliorated learning and memory deficits in an (Aβ)(1-40) rat model of Alzheimer's disease. Here, we report that injection of the amyloid peptide into the hippocampus of rats led to formation of Aβ(1-40) positive aggregates close to the lateral blade of the dentate gyrus (DGlb). We also observed the following in the hippocampus: extensive cell death in the DGlb (P<0.0001), CA1 (P=0.03), and CA3 (P=0.002); an increased number of iNOS-expressing cells (P=0.01) and gliosis. Genistein given to rats by gavage 1h before injection of Aβ(1-40) inhibited the formation of Aβ(1-40) positive aggregates in the brain tissue and led to increased number of nNOS(+) (P=0.0001) cells in the hippocampus compared to sham-operated genistein-treated controls. Treatment with genistein also alleviated the extensive astrogliosis that occurred in Aβ(1-40)-injected hippocampus to a level similar to that observed in sham-operated rats. We conclude that the neurons in the DGlb are most sensitive to Aβ(1-40), and a single dose of genistein can ameliorate Aβ(1-40) induced pathology.
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| 4. |
- Bagheri, Maryam, et al.
(författare)
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Genistein inhibits Aβ1-40-induced astrogliosis : A three-dimensional confocal morphometric analysis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy, proliferation, and remodeling. Here, we performed 3D confocal microscopy to evaluate the morphology of reactive glial fibrillary acidic protein (GFAP-positive) astrocytes in an animal model of Alzheimer’s disease, and we also assessed the effect of the antiinflammatory agent genistein on amyloid-beta-induced astrogliosis. In 50 astrocytes/animal, we measured the area and volume of the nucleus, cell body, astrocyte (soma and branches) and territory (tissue covered by each astrocyte), and total length of the branches. Moreover, we quantified the intensity of GFAP immunoreactivity in the hippocampus. Injecting amyloid beta (Aβ)1–40 into the brain caused astrogliosis, observed as significantly higher GFAP intensity in the hippocampus, and also led to significant enlargement of astrocytes in this area, indicated by increased values for all the above-mentioned parameters. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the level seen in the shamoperated group, and Aβ1–40-induced enlargement of astrocytes was significantly inhibited. Interestingly, genistein also ameliorated the astrogliosis that was initiated by mechanical injury caused by insertion of the injection needle into the brain tissue. This was indicated by the observation that the mean cell body volume and area of astrocytes were significantly smaller in the genistein-treated rats, even in comparison with the sham-operated animals.
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| 5. |
- Bagheri, Maryam
(författare)
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Neuroprotective Effect of Genistein : Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.
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| 6. |
- Bagheri, Maryam, et al.
(författare)
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Protocol for Three-dimensional Confocal Morphometric Analysis of Astrocytes
- 2015
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Ingår i: Journal of Visualized Experiments. - : JOURNAL OF VISUALIZED EXPERIMENTS. - 1940-087X. ; :106, s. e53113-
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Tidskriftsartikel (refereegranskat)abstract
- As glial cells in the brain, astrocytes have diverse functional roles in the central nervous system. In the presence of harmful stimuli, astrocytes modify their functional and structural properties, a condition called reactive astrogliosis. Here, a protocol for assessment of the morphological properties of astrocytes is presented. This protocol includes quantification of 12 different parameters i.e. the surface area and volume of the tissue covered by an astrocyte (astrocyte territory), the entire astrocyte including branches, cell body, and nucleus, as well as total length and number of branches, the intensity of fluorescence immunoreactivity of antibodies used for astrocyte detection, and astrocyte density (number/1,000 mu m(2)). For this purpose three-dimensional (3D) confocal microscopic images were created, and 3D image analysis software such as Volocity 6.3 was used for measurements. Rat brain tissue exposed to amyloid beta(1-40) (A beta(1-40)) with or without a therapeutic intervention was used to present the method. This protocol can also be used for 3D morphometric analysis of other cells from either in vivo or in vitro conditions.
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| 7. |
- Dahlin, Lars B., et al.
(författare)
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Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject. Together with well-organized, parallel myelinated nerve fibres we show regenerative clusters with twisted nerve fibres, a sprouted axon from a node of Ranvier and other specific details. A novel 3D construction (with movie created) of a node of Ranvier with end segment of a degenerated axon and sprout of a regenerated one is captured. Many of these architectural elements are not described in the literature. Thus, X-ray phase contrast holographic nanotomography enables identifying specific morphological structures in 3D in peripheral nerve biopsies from a healthy subject and from patients with type 1 and 2 diabetes.
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| 8. |
- Ferreira, Nelson, et al.
(författare)
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Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain
- 2021
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Pain is a common non-motor symptom of Parkinsons disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (alpha-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of alpha-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the central nervous system (CNS). Pathological peripheral to CNS propagation of alpha-Syn aggregates along interconnected neuronal populations within sensory afferents, was concomitant with impaired nociceptive response, reflected by mechanical allodynia, reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers. Our findings show a link between the transneuronal propagation of alpha-Syn pathology with sensory neuron dysfunction and neuropathic impairment, suggesting promising avenues of investigation into the mechanisms underlying pain in PD.
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| 9. |
- Ghofrani, Saeed, et al.
(författare)
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Naringenin improves learning and memory in an Alzheimer's disease rat model : Insights into the underlying mechanisms
- 2015
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 764, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aβ) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aβ-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aβ-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aβ-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aβ-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.
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| 10. |
- Goncalves, Nadia P., et al.
(författare)
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Peripheral Nerve Regeneration Is Independent From Schwann Cell p75(NTR) Expression
- 2019
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Ingår i: Frontiers in Cellular Neuroscience. - : FRONTIERS MEDIA SA. - 1662-5102. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75(NTR) has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75(NTR) knockout mouse models and cannot dissect the specific role of p75(NTR) expressed by Schwann cells. In this present study, a conditional knockout model selectively deleting p75(NTR) expression in Schwann cells was generated, where p75(NTR) expression is replaced with that of an mCherry reporter. Silencing of Schwann cell p75(NTR) expression was confirmed in the sciatic nerve in vivo and in vitro, without altering axonal expression of p75(NTR). No difference in sciatic nerve myelination during development or following sciatic nerve crush injury was observed, as determined by quantification of both myelinated and unmyelinated nerve fiber densities, myelinated axonal diameter and myelin thickness. However, the absence of Schwann cell p75(NTR) reduced motor nerve conduction velocity after crush injury. Our data indicate that the absence of Schwann cell p75(NTR) expression in vivo is not critical for axonal regrowth or remyelination following sciatic nerve crush injury, but does play a key role in functional recovery. Overall, this represents the first step in redefining the role of p75(NTR) in the peripheral nervous system, suggesting that the Schwann cell-axon unit functions as a syncytium, with the previous published involvement of p75(NTR) in remyelination most likely depending on axonal/neuronal p75(NTR) and/or mutual glial-axonal interactions.
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| 11. |
- Goncalves, Nadia P., et al.
(författare)
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Schwann cell p75 neurotrophin receptor modulates small fiber degeneration in diabetic neuropathy
- 2020
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Ingår i: Glia. - : WILEY. - 0894-1491 .- 1098-1136. ; 68:12, s. 2725-2743
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic neuropathy has an incidence as high as 50% of diabetic patients and is characterized by damage to neurons, Schwann cells and blood vessels within the peripheral nervous system. The low-affinity neurotrophin receptor p75 (p75(NTR)), particularly expressed by the Schwann cells in the peripheral nerve, has previously been reported to play a role in developmental myelination and cell survival/death. Increased levels of p75(NTR), in the endoneurium and plasma from diabetic patients and rodent models of disease, have been observed, proposing that this receptor might be involved in the pathogenesis of diabetic neuropathy. Therefore, in this study, we addressed this hypothesis by utilizing a mouse model of selective nerve growth factor receptor (Ngfr) deletion in Schwann cells (SC-p75(NTR)-KO). Electron microscopy of sciatic nerves from mice with high fat diet induced obesity demonstrated how loss of Schwann cell-p75(NTR)aggravated axonal atrophy and loss of C-fibers. RNA sequencing disclosed several pre-clinical signaling alterations in the diabetic peripheral nerves, dependent on Schwann cell p75(NTR)signaling, specially related with lysosome, phagosome, and immune pathways. Morphological and biochemical analyses identified abundant lysosomes and autophagosomes in the C-fiber axoplasm of the diabetic SC-p75(NTR)-KO nerves, which together with increased Cathepsin B protein levels corroborates gene upregulation from the phagolysosomal pathways. Altogether, this study demonstrates that Schwann cell p75(NTR)deficiency amplifies diabetic neuropathy disease by triggering overactivation of immune-related pathways and increased lysosomal stress.
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| 12. |
- Hildebrand, Claes, et al.
(författare)
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The structure of myelinated axons in the CNS
- 2005. - 1
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Ingår i: Multiple Sclerosis As A Neuronal Disease. - New York : Elsevier Academic Press. - 0127387617 - 9780127387611 ; , s. 1-28
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This book examines the role of neurons in multiple sclerosis (MS) and the changes that occur in neurons as a result of MS. It places MS in a new and important perspective that not only explains the basis for symptom production, remission, and progress in MS, but also promises to open up new therapeutic possibilities. * Brings together the latest information from clinical, pathological, imaging, molecular, and pharmacological realms to explore the neurobiology of Multiple Sclerosis* Places MS in a new and important perspective that promises to open up new therapeutic avenues* Superbly illustrated and referenced
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| 13. |
- Jamali, Reza, 1967-, et al.
(författare)
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Continuous glucose monitoring system signals the occurrence of marked postprandial hyperglycemia in the elderly
- 2005
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Ingår i: Diabetes Technology & Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 7:3, s. 509-515
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to ascertain whether dysglycemic episodes occur in institutionalized elderly persons and, if that is the case, to determine whether such episodes are related to meal patterns. Another objective was to investigate the feasibility of subcutaneous (s.c.) glucose measurements in the elderly using a Medtronic MiniMed (Sylmar, CA) continuous glucose monitoring system (CGMS®). Methods: Nine nursing home residents (74-95 years old) without known diabetes or other metabolic disorders were included. The s.c. glucose level was measured for 3 days with the Medtronic MiniMed CGMS. Capillary blood glucose was measured four times daily with a Glucometer Elite® device (Bayer, Leverkusen, Germany). Body mass index and basal metabolic rate were calculated, and food intake was recorded. Results: The s.c. glucose level fluctuated noticeably over time, 22.5% of the values recorded during the 3-day period were ≥8 mmol/L, and values <3.5 mmol/L were rarely seen. A marked (>5 mmol/L) and short-term (2-4 h) increase in s.c. glucose was seen after a meal. The mean capillary blood glucose concentration was 7.5 ± 1.8 mmol/L. Capillary blood glucose ≥8 mmol/L was recorded on 32.5% of the measurement occasions, and no values were <3.5 mmol/L. The s.c. glucose values agreed with corresponding capillary blood glucose levels (mean r = 0.75, range 0.43-0.86). Five participants consumed less energy than recommended according to their age, weight, and physical activity level. Conclusions: Postprandial hyperglycemia frequently occurs in elderly people living in nursing homes. The CGMS is convenient to use to detect hyperglycemia in this age group.
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| 14. |
- Jamali, Reza, et al.
(författare)
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Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with Type I diabetes
- 2002
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Ingår i: Diabetes Technology and Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 4:3, s. 305-312
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Tidskriftsartikel (refereegranskat)abstract
- Laboratory animals are extensively used in diabetic research. However, it is not known whether the glucose dynamics in laboratory animals are similar to the dynamics in humans. The aim of the present study is to see whether the Medtronic MiniMed continuous subcutaneous glucose monitoring system can be used to record fluctuations of the glucose level in freely moving normal and insulin-treated diabetic rats. The monitoring system was applied during 3 days to normal and diabetic hyperglycemic and hypoglycemic rats treated with insulin implants. Corresponding data from type 1 diabetic patients with poor glycemic control were selected retrospectively in order to note the similarities and differences. In normal rats the subcutaneous glucose level varied slightly (median = 111 mg/dL). In hyperglycemic rats the subcutaneous glucose values fluctuated markedly around a median of 226 mg/dL. The fluctuations formed a short-wave pattern with a low amplitude, superimposed on a long-wave pattern with a high amplitude. The subcutaneous glucose profile seen in type 1 diabetic patients (median = 180 mg/dL) was similar to that observed in hyperglycemic rats. In hypoglycemic rats, the subcutaneous glucose level fluctuated moderately around a median of 55 mg/dL. In these rats the fluctuations formed a short-wave pattern with low amplitude, without any obvious long-wave pattern. The subcutaneous glucose values conformed to corresponding blood glucose measurements. We conclude that the Medtronic MiniMed continuous glucose monitoring system can be used to record the subcutaneous glucose level over time in freely moving rats.
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| 15. |
- Jamali, Reza, et al.
(författare)
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Differential neuropathies in hyperglycemic and hypoglycemic diabetic rats
- 2006
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Ingår i: Journal of Neuropathology & Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069. ; 65:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the effects of hyperglycemia and hypoglycemia on development of peripheral neuropathy in somatic motor and sensory nerves in type 1 diabetic BB/Wor rats. The animals were maintained in a hyper- or hypoglycemic state by treatment with insulin for 3 months. Nondiabetic siblings served as controls. Qualitative analysis of the gastrocnemius and sural nerves by light and electron microscopy revealed signs of Wallerian-type axonal degeneration and regeneration of large myelinated fibers in the hypoglycemic but not the hyperglycemic animals. Degeneration was more common in the gastrocnemius nerve than in the sural nerve. In hypoglycemic rats, myelinated fibers in both the gastrocnemius and sural nerves had significantly shorter internodes and smaller diameters. The decreased fiber diameter was related (r = -0.9) to the duration of severe hypoglycemia (≤2.5 mmol/L). Myelinated fiber occupancy was also decreased without any significant changes in fiber counts in both the gastrocnemius and sural nerves. In hyperglycemic rats, myelinated fibers in the sural nerve but not the gastrocnemius nerve had smaller diameters compared with controls. We conclude that hypoglycemia has a more severe impact on somatic motor nerves than on somatic sensory nerves, whereas hyperglycemia affects only somatic sensory nerves.
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| 16. |
- Jamali, Reza, et al.
(författare)
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Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic ΒB/Wor rats
- 2005
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 109:2, s. 198-206
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to find out whether dysglycaemia causes neuropathy in the vagus nerve of insulin-treated diabetic BB/Wor rats. Specimens were collected from the left vagus nerve proximal and distal to the level of recurrent laryngeal branch and from the recurrent branch itself in control rats and diabetic BB/Wor rats subjected to hyper- or hypoglycaemia. Myelinated and unmyelinated axons were counted and myelinated axon diameters were measured by electron microscopy. In controls, the vagus nerve proximal to the recurrent branch exhibited three regions in terms of fibre composition: part A was mainly composed of large myelinated axons, part B contained small myelinated and unmyelinated axons, and part C contained mainly unmyelinated axons. The distal level resembled part C at the proximal level and the recurrent branch resembled parts A and B. In hyperglycaemic rats, a normal picture was found at the proximal and distal levels of the vagus nerve and in the recurrent branch. In hypoglycaemic rats, signs of past and ongoing degeneration and regeneration of large myelinated axons were found at the proximal and distal levels and in the recurrent branch. We conclude that hypoglycaemia elicits degenerative alterations in large myelinated axons in the vagus and recurrent laryngeal nerves in diabetic BB/Wor rats. The absence of signs of neuropathy in unmyelinated and small myelinated axons suggests that the sensory and autonomic components of the nerve are less affected. In contrast, the hyperglycaemic rats examined here did not show obvious degenerative alterations.
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| 17. |
- Jamali, Reza, 1967-
(författare)
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Peripheral Hypoglycaemic Neuropathy in Type 1 Diabetic Rats : Morphologic and Metabolic Studies
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperglycaemia caused by insulin deficiency is believed to play a major role in the de-velopment of neuropathy in diabetic patients. The clinical and pathological features of diabetic neuropathy vary considerably, although sensory and autonomic dysfunctions are the most common characteristics. Normalisation of the blood glucose level by ef-fective insulin treatment decreases the incidence of diabetic neuropathy in patients. However, intensive insulin therapy may result in more frequent hypoglycaemic epi-sodes than are provoked by less ambitious diabetes control. Neuropathy might also be induced by severe hypoglycaemia in diabetes or insulinoma. Accordingly, it seems that the diversity in clinical symptoms of diabetic neuropathy may be due to the combined effects of hyperglycaemia and hypoglycaemia. Based on that assumption, the general aim of this project was to study the relationship between severe hypoglycaemia and pe-ripheral neuropathy in diabetic rats. To understand how the development of neuropathy is related to glycaemic control, we needed to be aware of the glucose dynamics in the animal model that we used. The aim was to ascertain whether the diabetic rats were similar to type 1 diabetic patients with regard to such dynamics. To achieve that goal, we used a MiniMed continuous glucose monitoring system (CGMS®) to measure sub-cutaneous glucose in freely moving rats over a period of 72 hours. The glucose monitor worked well, and it showed that the insulin-treated diabetic BB/Wor rats with a hyper-glycaemic insulin regimen have a glycaemic status similar to that of type 1 diabetic patients with poor glycaemic control. The diabetic rats with a hypoglycaemic regimen generally had low blood glucose levels.Prolonged hypoglycaemia led to axonal de- and regeneration of large myelinated fibres in vagus nerve destined to the laryngeal muscle. Axonal de- and regeneration was also observed in the gastrocnemius and sural nerves, although the frequency of degeneration was much lower in the sural nerve. Small myelinated and unmyelinated nerve fibres were normal in these nerves. These results suggest that hypoglycaemia preferentially damages muscle-related nerve fibres. In contrast, in the diabetic rats exposed to pro-longed hyperglycaemia, only the sural nerve exhibited decreased myelinated fibre diameter in the absence of obvious axonal degeneration.In situ glucose measurements by microdialysis showed that the glucose concentrations in blood and subcutaneous tissue were similar in healthy, diabetic hyperglycaemic, and diabetic hypoglycaemic rats. In the healthy and hyperglycaemic animals, the lowest glucose level was found in the peripheral nerve. Moreover, in controls, the glucose level was lower in muscle than in blood. In hypoglycaemic rats, there were no signifi-cant differences in glucose concentrations between different tissues.
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| 18. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 19. |
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| 20. |
- Mirrasekhian, Elahe, 1978-
(författare)
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Immune-to-Brain Signaling in Fever : The Brain Endothelium as Interface
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever is a brain-regulated elevation of body temperature that occurs in response to infectious and non-infectious stimuli. During inflammatory episodes, circulating cytokines that are released by activated immune cells, trigger the induction of cyclooxygenase (COX)-2 in the ventromedial preoptic area of the hypothalamus (the thermoregulation center). COX-2-dependent-prostaglandin (PG)E2 synthesis is essential for the generation of fever and upon an immune challenge, it is induced in several cells within the brain including the brain endothelial cells and perivascular macrophages. However, due to lack of experimental models with cell type-specific modulation of PGE2 synthesizing enzymes, the cellular source of pyrogenic PGE2 and its induction mechanism(s) remained obscure. Using such technology, we showed that the brain endothelium is the cellular source of pyrogenic PGE2 and that activation of brain endothelial IL-6 receptors by circulating IL-6 is critical for the PGE2 induction.Inhibition of PGE2 synthesis is assumed to be the mode of action of many antipyretic drugs, possibly including paracetamol. Given that paracetamol at a high dose has been shown to induce hypothermia by activation of the transient receptor potential ankyrin 1 (TRPA1) ion channel, we examined whether the antipyretic effect of paracetamol is also TRPA1 dependent. Our findings revealed that the antipyretic effect of paracetamol is independent of TRPA1 and associated with inhibition of the PGE2 synthesis in the brain.This thesis provides new insight into the molecular mechanism behind the febrile response in which the peripheral circulating IL-6 communicates with the brain by induction of pyrogenic PGE2 in the brain endothelium. It also demonstrates that the antipyretic effect of paracetamol is exerted by inhibition of the PGE2 synthesis in the brain.
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| 21. |
- Mohseni, Simin
(författare)
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Autophagy in insulin-induced hypoglycaemic neuropathy
- 2011
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Ingår i: PATHOLOGY. - : LIPPINCOTT WILLIAMS and WILKINS, 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA. - 0031-3025. ; 43:3, s. 254-260
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Autophagy in neurons has been linked to a growing number of pathological conditions in the CNS, but the role of this process in peripheral neuropathy has received little attention. This study aimed to determine whether autophagy is involved in development of peripheral neuropathy in hypoglycaemic diabetic rats. Methods: The lateral plantar nerves, ventral roots, and dorsal roots of insulin-treated diabetic hypoglycaemic rats were examined for structural signs of autophagy by electron microscopy. Results: Autophagy-associated vacuoles were found in myelinated axons exhibiting early pathological changes but not in the associated Schwann cells. When the damaged axons degenerated, their associated Schwann cells gradually died and were cleared from the endoneurium by macrophages. During axonal regeneration, extensive signs of autophagy-related structures such as autophagophores appeared in regenerating axons and in the cytoplasm of the associated Schwann cells in the Band of Bungner. Conclusion: Autophagy occurs in hypoglycaemic peripheral nerves in association with axonal de- and regeneration. The extensive signs of autophagy in regenerated axons suggest that autophagy may play a role in survival of the new axons.
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| 22. |
- Mohseni, Simin, 1959-
(författare)
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Hypoglycaemic neuropathy : Experimental studies in diabetic rats treated witn insulin implants
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insulin dependent diabetes mellitus is a metabolic disease that causes secondary complications such as peripheral neuropathy. it is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. In order to understand the pathophysiology of diabetic neuropathy many workers have examined nerves from diabetic rats. While most workers say that animals with high blood glucose levels develop neuropathy, some investigators report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. The general aim of the present study is to examine the long-term relation between glycaemia and peripheral neuropathy in diabetic BB/Wor rats. This necessitated establishment of a treatment regime allowing long-term survival of these sick animals.We found that maintenance of diabetic BB/Wor rats on an eu/hyperglycaemic or an eu-/hypoglycaemic regime with insulin implants worked well for our purpose.Unexpectedly, light and electron microscopic examination of plantar nerves in eu-/hyperglycaemic diabetic rats showed a normal picture. But, nerves from eu-/hypoglycemic rats showed severe qualitative changes, interpreted as axonal de- and regeneration. The total number of axons was subnormal and the myelinated fibres were shifted towards smaller diameters. Hence, eu-/hypoglycaemic diabetic BB/Wor rats but not eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.The immunohistochemical occurrence of epidermal protein gene product 9.5 immunoreactive axon profiles was normal in heel skin biopsies from eu/hypoglycaemic rats, but many profiles were short and thin. The content of the neuropeptide calcitonin gene-related peptide in skin biopsies was subnormal. The occurrence of end plate axon terminals labeled with antibodies against the vesicular acetylcholine transporter protein was subnormal in sections from a plantar muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals were abnormally small. Hence, the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.Electron microscopic examination of L5 dorsal roots from eu/hypoglycaemic rats showed a normal morphology and normal numbers of axons. In L5 ventral roots the picture varied: in 2 rats it was normal and 3 rats showed signs of axonal degeneration. The L5 dorsal root ganglion and the L5 ventral horn showed a normal picture. Hence, eu-/hypoglycaemia affects ventral root axons but not dorsal root axons. Moreover, the degree of ventral root pathology is variable and sensory and motor neuron perikarya are not affected.
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| 23. |
- Mohseni, Simin, 1959-, et al.
(författare)
-
Hypoglycaemic neuropathy : Occurrence of axon terminals in plantar skin and plantar muscle of diabetic BB/Wor rats treated with insulin implants
- 2000
-
Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 99:3, s. 257-262
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Tidskriftsartikel (refereegranskat)abstract
- It is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. However, experience from insulinoma patients and experimental studies show that hypoglycaemia may also cause neuropathy. Accordingly, the plantar nerves of diabetic eu-/hypoglycaemic BB/Wor rats treated with insulin implants exhibit a distinct neuropathy. To what extent hypoglycaemic neuropathy affects axon terminals in skin and muscle is unknown. In the present study we examine the occurrence of epidermal axon profiles and the neuropeptide calcitonin gene-related peptide (CGRP) in plantar skin, and of end plate axon terminals in a plantar muscle of diabetic BB/Wor rats subjected to long periods of hypoglycaemia. The number of protein gene product-immunoreactive axon profiles was found to be normal in heel skin biopsy specimens from eu-/hypoglycaemic rats, but many profiles were short and thin. The content of CGRP in the skin biopsy samples was significantly below normal. After staining with antibodies against the vesicular acetylcholine transporter protein, the occurrence of end plate axon terminals was significantly reduced in sections from the flexor hallucis brevis muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals tended to be abnormally small in these rats. We conclude that the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.
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| 24. |
- Mohseni, Simin, et al.
(författare)
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Hypoglycaemic neuropathy in BB/Wor rats treated with insulin implants : Electron microscopic observations
- 1998
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 96:2, s. 151-156
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-dependent diabetes mellitus is a chronic metabolic disease that causes long-term secondary complications such as neuropathy. The occurrence of diabetic neuropathy has generally been thought of as being associated with hyperglycaemia. However, in a previous light microscopic examination of plantar nerves in diabetic BB/Wor rats treated with insulin implants we found that eu-/hyperglycaemic rats present a normal picture, whereas eu-/hypoglycaemic rats show severe changes. The aim of the present work is to supplement our previous light microscopic report with electron microsocpic data from the lateral plantar nerve of normal, eu-/hyperglycaemic and eu-/hypoglycaemic BB/Wor rats. Under the electron microscope lateral plantar nerves collected from eu-/hyperglycaemic rats presented a qualitatively normal picture. In addition, the fibre numbers and the size distribution of the myelinated fibres were normal. In contrast, specimens from eu-/hypoglycaemic BB/Wor rats showed severe qualitative changes, interpreted as signs of axonal de- and regeneration. The total number of axons was somewhat subnormal and the sizes of the myelinated fibres were strongly shifted towards smaller diameters. These data confirm our previous light microscopic observations. We conclude that eu-/hypoglycaemic BB/Wor rats treated with insulin implants, but not similarly treated eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.
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| 25. |
- Mohseni, Simin, 1959-
(författare)
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Hypoglycaemic neuropathy in diabetic BB/Wor rats treated with insulin implants affects ventral root axons but not dorsal root axons
- 2000
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 100:4, s. 415-420
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Tidskriftsartikel (refereegranskat)abstract
- It is believed that hyperglycaemia underlies diabetic neuropathy. However, low blood glucose values may also cause pathological changes in peripheral nerves and in neuronal perikarya. This study examined spinal roots, dorsal root ganglia and the ventral horn at the segmental level L5 in long-term insulin-treated eu-/hypoglycaemic diabetic rats with an obvious plantar nerve pathology. The purpose was to determine whether hypoglycaemic neuropathy affects sensory and/or motor neurons at root and/or perikaryal levels. Electron microscopic examination of dorsal roots from eu-/hypoglycaemic rats showed a normal qualitative morphology and normal numbers of unmyelinated and myelinated axons. In ventral roots the picture varied. Whereas two rats exhibited an essentially normal morphology, three rats presented moderate or marked signs of pathology such as clusters of small and medium-sized myelinated axons, medium-sized myelinated axons with abnormally thin sheaths, large unmyelinated axons and signs of past or ongoing axonal degeneration. Light microscopic examination of the L5 dorsal root ganglion and ventral horn showed a qualitatively normal picture in eu-/hypoglycaemic rats and the mean number of large ventral horn neurons per section was normal. These results suggest that the type of eu-/hypoglycaemia examined here affects ventral root axons but not dorsal root axons, that the degree of ventral root pathology is variable and that sensory and motor neuron perikarya do not appear to be affected.
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| 26. |
- Mohseni, Simin
(författare)
-
Hypoglycemic neuropathy
- 2001
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Ingår i: Acta Neuropathologica. - 0001-6322 .- 1432-0533. ; 102:5, s. 413-421
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Forskningsöversikt (refereegranskat)abstract
- Hypoglycemia is a relatively common condition primarily affecting diabetic patients treated with insulin or other hypoglycemic drugs and insulinoma patients. Clinical experience and experimental studies show that hypoglycemia may cause alterations both in the central (CNS) and the peripheral (PNS) nervous system. Hypoglycemic effects on the CNS include various symptoms such as irritability and lack of concentration, disruption of cognitive functions, convulsions and unconsciousness. As for pathology, a loss of neurons has been noted, being more obvious in the cerebral cortex and the hippocampus than in the brain stem, cerebellum and spinal cord. Myelin damage and glial changes have also been observed in the CNS. The development of pathological changes in the brain has mainly been studied on autopsy material from patients who died in insulin coma and in animals exposed to a severe hypoglycemia and showing an isoelectric electroencephalogram. It has been suggested that hypoglycemic loss of neurons in the brain is related to excititoxic actions of aspartate on N-methyl-D-aspartate receptors. With respect to the PNS, scattered clinical observations in humans and experimental studies in animals show that hypoglycemia causes a distal axonopathy including both degenerative and regenerative events. In this respect, motor axons seem to be more vulnerable than sensory axons. Animal experiments show that a peripheral neuropathy may develop even in cases with a mild hypoglycemia compatible with a generally normal behavior. The cellular mechanisms behind the development of hypoglycemic. PNS alterations are unknown. To elucidate the pathophysiology of hypoglycemic neuropathy more basic research is needed.
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| 27. |
- Mohseni, Simin, et al.
(författare)
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Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve : Implications for diabetic neuropathy
- 2017
-
Ingår i: Brain and Behavior. - : Wiley Online Library. - 2162-3279 .- 2162-3279. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy-related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy. Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM. Subjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g-ratio versus subjects who remained NGT. At follow-up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline. We conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy.
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| 28. |
- Mohseni, Simin
(författare)
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Neurologic damage in hypoglycemia.
- 2014
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Ingår i: Handbook of Clinical Neurology. - : Elsevier. - 9780444534804 ; , s. 513-32
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Bokkapitel (refereegranskat)abstract
- Hypoglycemia occurs in diabetic patients as a consequence of treatment with hypoglycemic agents, in insulinoma patients as a result of excessive insulin production, and in infants as a result of abnormal regulation of metabolism. Profound hypoglycemia can cause structural and functional disturbances in both the central (CNS) and the peripheral nervous system (PNS). The brain is damaged by a short and severe episode of hypoglycemia, whereas PNS pathology appears after a mild and prolonged episode. In the CNS, damaged mitochondria, elevated intracellular Ca2(+) level, released cytochrome c to the cytosol, extensive production of superoxide, increased caspase-3 activity, release of aspartate and glutamate from presynaptic terminals, and altered biosynthetic machinery can lead to neuronal cell death in the brain. Considering the PNS, chronic hypoglycemia is associated with delayed motor and sensory conduction velocities in peripheral nerves. With respect to pathology, hypoglycemic neuropathy in the PNS is characterized by Wallerian-like axonal degeneration that starts at the nerve terminal and progresses to a more proximal part of the axon, and motor axons to the muscles may be more severely damaged than sensory axons. Since excitatory neurotransmitters primarily involve the neuron in the CNS, this "dying back" pattern of axonal damage in the PNS may involve mechanisms other than excitotoxicity.
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| 29. |
- Mohseni, Simin, et al.
(författare)
-
Neuropathy in diabetic BB/Wor rats treated with insulin implants
- 1998
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 96:2, s. 144-150
-
Tidskriftsartikel (refereegranskat)abstract
- To elucidate the pathophysiology of diabetic neuropathy many workers have examined nerve specimens from diabetic rats. While most workers found that animals with high blood glucose levels develop neuropathy, some researchers report that the peripheral nerves are normal in hyperglycaemic rats. Hypoglycaemia may also cause neuropathy. Some workers suggest that neuropathy is linked to fluctuations of the blood glucose level. In the present study we examine plantar nerves of diabetic BB/ Wor rats maintained on an eu-/hyperglycaemic or an eu-/ hypoglycaemic regime with insulin implants. Treatment with implants worked well. Light microscopic examination of nerve fibres in non-diabetic control rats and in eu-/ hyperglycaemic diabetic rats showed a normal picture. Preparations from eu-/hypoglycemic rats showed irregular myelin sheaths and signs of Wallerian degeneration. The lengths and diameters of the largest internodes were significantly subnormal. We conclude, that periodic moderate hypoglycaemia, but not periodic moderate hyperglycaemia, elicits neuropathy in diabetic BB/Wor rats treated with insulin implants.
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| 30. |
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| 31. |
- Moula, Alireza, et al.
(författare)
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Kognition, emotion och "life management"
- 2009
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Ingår i: Empowermentorienterat socialt arbete. - Lund : Studentlitteratur. - 9789144045634 ; , s. 85-96
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 32. |
- Osman, Ayman A. M., et al.
(författare)
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Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:3, s. 625-632
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Tidskriftsartikel (refereegranskat)abstract
- We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p < 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA(1c) level may underlie this differential regulation.
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| 33. |
- Osman, Ayman
(författare)
-
Autophagy in Peripheral Neuropathy
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor.Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy.In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury.Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.
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| 34. |
- Samuelsson, Kristin, et al.
(författare)
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Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy.
- 2016
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Ingår i: PLOS ONE. - : : San Francisco, CA : Public Library of Science. - 1932-6203. ; 11:9
-
Tidskriftsartikel (refereegranskat)abstract
- Twenty-five percent of polyneuropathies are idiopathic. Microangiopathy has been suggested to be a possible pathogenic cause of chronic idiopathic axonal polyneuropathy (CIAP). Dysfunction of the autophagy pathway has been implicated as a marker of neurodegeneration in the central nervous system, but the autophagy process is not explored in the peripheral nervous system. In the current study, we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of 10 patients with CIAP, 11 controls with inflammatory neuropathy and 10 controls without sensory polyneuropathy. We did not find any significant difference in endoneurial microangiopathic markers in patients with CIAP compared to normal controls, though we did find a correlation between basal lamina area thickness and age. Unexpectedly, we found a significantly larger basal lamina area thickness in patients with vasculitic neuropathy. Furthermore, we found a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls. It is unclear if the alteration in the autophagy pathway is a consequence or a cause of the neuropathy. Our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial blood vessels in peripheral nerves. The significantly higher density of autophagy structures in sural nerves obtained from patients with CIAP and inflammatory neuropathy vs. controls indicates the involvement of this pathway in neuropathy, particularly in CIAP, since the increase in density of autophagy-related structures was more pronounced in patients with CIAP than those with inflammatory neuropathy. To our knowledge this is the first report investigating signs of autophagy process in peripheral nerves in patients with CIAP and inflammatory neuropathy.
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| 35. |
- Sepehr, Arian, et al.
(författare)
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Lactate damages primary hippocampal neurons in vitro.
- 2010
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Ingår i: Cell biology international. - 1095-8355. ; 34:1, s. 61-65
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, rat primary cultures were used to study the effect of lactate on the survival of hippocampal neurons in the presence or absence of glucose. Our results showed no extensive cell damage under glucose-free conditions compared with glucose-rich conditions. Addition of 10 and 50 mM lactate to glucose-free and glucose-rich media increased the cell damage significantly, as observed by morphology and lactate dehydrogenase activity. The results of the present study suggest that primary neurons in vitro are not sensitive to glucose deficiency and the presence of lactate damages the neurons in a concentration-dependent manner.
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| 36. |
- Sepehr, Arian, et al.
(författare)
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Neuron survival in vitro is more influenced by the developmental age of the cells than by glucose condition
- 2009
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Ingår i: Cytotechnology (Dordrecht). - : Springer Science and Business Media LLC. - 0920-9069 .- 1573-0778. ; 61:1-2, s. 73-79
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to determine whether the sensitivity to varying glucose conditions differs for the peripheral and central nervous system neurons at different developmental stages. Ventral horn neurons (VHN) and dorsal root ganglion neurons (DRG) from rats of different postnatal ages were exposed to glucose-free or glucose-rich culture conditions. Following 24 h at those conditions, the number of protein gene product 9.5 positive (PGP(+)) DRG neurons and choline acetyltransferase positive (ChAT(+)) VHN were counted and their neurite lengths and soma diameters were measured. For both DRG and VHN, the highest number of cells with and without neurite outgrowth was seen when cells from postnatal day 4 donors were cultured, while the lowest cell numbers were when neurons were from donors early after birth and grown under glucose-free conditions. The length of the neurites and the soma diameter for VHN were not affected by either glucose level or age. DRG neurons, however, exhibited the shortest neurites and smallest soma diameter when neurons were obtained and cultured early after birth. Our results indicate that survival of neurons in vitro is more influenced by the developmental stage than by glucose concentrations.
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| 37. |
- Ulrichsen, Maj, et al.
(författare)
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Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury
- 2022
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral nerve regeneration relies on the ability of Schwann cells to support the regrowth of damaged axons. Schwann cells re-differentiate when reestablishing contact with the sprouting axons, with large fibers becoming remyelinated and small nociceptive fibers ensheathed and collected into Remak bundles. We have previously described how the receptor sortilin facilitates neurotrophin signaling in peripheral neurons via regulated trafficking of Trk receptors. This study aims to characterize the effects of sortilin deletion on nerve regeneration following sciatic crush injury. We found that Sort1(-)(/)(-) mice displayed functional motor recovery like that of WT mice, with no detectable differences in relation to nerve conduction velocities and morphological aspects of myelinated fibers. In contrast, we found abnormal ensheathment of regenerated C-fibers in injured Sort1(-)(/)(-) mice, demonstrating a role of sortilin for Remak bundle formation following injury. Further studies on Schwann cell signaling pathways showed a significant reduction of MAPK/ERK, RSK, and CREB phosphorylation in Sort1(-)(/)(-) Schwann cells after stimulation with neurotrophin-3 (NT-3), while Schwann cell migration and myelination remained unaffected. In conclusion, our results demonstrate that loss of sortilin blunts NT-3 signaling in Schwann cells which might contribute to the impaired Remak bundle regeneration after sciatic nerve injury.
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