scholarly journals Vitamin D Deficiency Induces Chronic Pain and Microglial Phenotypic Changes in Mice

2021 ◽  
Vol 22 (7) ◽  
pp. 3604
Author(s):  
Nicola Alessio ◽  
Carmela Belardo ◽  
Maria Consiglia Trotta ◽  
Salvatore Paino ◽  
Serena Boccella ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Vitamin D ◽  
Chronic Pain ◽  
Vitamin D Deficiency ◽  
Morphological Analysis ◽  
Pain Perception ◽  
Ex Vivo ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects

The bioactive form of vitamin .D, 1,25-dihydroxyvitamin D (1,25D3), exerts immunomodulatory actions resulting in neuroprotective effects potentially useful against neurodegenerative and autoimmune diseases. In fact, vitamin D deficiency status has been correlated with painful manifestations associated with different pathological conditions. In this study, we have investigated the effects of vitamin D deficiency on microglia cells, as they represent the main immune cells responsible for early defense at central nervous system (CNS), including chronic pain states. For this purpose, we have employed a model of low vitamin D intake during gestation to evaluate possible changes in primary microglia cells obtained from postnatal day(P)2-3 pups. Afterwards, pain measurement and microglia morphological analysis in the spinal cord level and in brain regions involved in the integration of pain perception were performed in the parents subjected to vitamin D restriction. In cultured microglia, we detected a reactive—activated and proliferative—phenotype associated with intracellular reactive oxygen species (ROS) generation. Oxidative stress was closely correlated with the extent of DNA damage and increased β-galactosidase (B-gal) activity. Interestingly, the incubation with 25D3 or 1,25D3 or palmitoylethanolamide, an endogenous ligand of peroxisome proliferator-activated-receptor-alpha (PPAR-α), reduced most of these effects. Morphological analysis of ex-vivo microglia obtained from vitamin-D-deficient adult mice revealed an increased number of activated microglia in the spinal cord, while in the brain microglia appeared in a dystrophic phenotype. Remarkably, activated (spinal) or dystrophic (brain) microglia were detected in a prominent manner in females. Our data indicate that vitamin D deficiency produces profound modifications in microglia, suggesting a possible role of these cells in the sensorial dysfunctions associated with hypovitaminosis D.

Vitamin D Levels Correlate with Metabolic Syndrome Criteria in Algerian Patients: The Ex-vivo Immunomodulatory Effect of α, 25 Dihydroxyvitamin D3

2020 ◽  
Vol 20 (8) ◽  
pp. 1282-1294
Author(s):  
Meroua Bouchemal ◽  
Djennat Hakem ◽  
Malha Azzouz ◽  
Chafia Touil-Boukoffa ◽  
Dalila Mezioug
Keyword(s):  
Metabolic Syndrome ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Active Metabolite ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
No Production ◽  
Immunomodulatory Effects ◽  
Immune Balance ◽  
Vitamin D Levels

Background: Metabolic syndrome (MetS) is a combination of metabolic disorders with increased risks for several diseases, such as cardiovascular diseases and diabetes. It is associated with the presence of various inflammatory molecules. Vitamin D plays an important role in the regulation of metabolism homeostasis. Objective: The main goal of this work is to investigate vitamin D levels among Algerian MetS patients and its possible outcomes on key molecules of the immune response, as well, the immunomodulatory effects of its active metabolite. Methods: We evaluated vitamin D status by the electrochemiluminescence method, Nitric Oxide (NO) levels by the Griess method and Matrix Metalloproteinases (MMPs) activities such as MMP-2 and MMP-9 by zymography in plasma of patients and healthy controls (HC). The immunomodulatory effects of the active metabolite of vitamin D (α-25 (OH)2D3) on the production of NO, IL-6, IL-10, TGF- β and s-CTLA-4 were assessed by Griess method and ELISA, in peripheral blood mononuclear cells (PBMCs) of Algerian MetS patients and HC. MMPs activities were also determined ex-vivo, while iNOS expression was assessed by immunofluorescence staining. Results: Severe vitamin D deficiency was registered in Algerian MetS patients. The deficiency was found to be associated with an elevated in vivo NO production and high MMPs activity. Interestingly, α-25 (OH)2D3 declined the NO/iNOS system and IL-6 production, as well as MMPs activities. However, the ex-vivo production of IL-10, TGF-β increased in response to the treatment. We observed in the same way, the implication of s-CTLA-4 in MetS, which was markedly up-regulated with α-25 (OH)2D3. Conclusion: Our report indicated the relationship between MetS factors and Vitamin D deficiency. The ex-vivo findings emphasize its impact on maintaining regulated immune balance.

scholarly journals Association between vitamin D deficiency and exercise capacity in patients with CKD, a cross-sectional analysis

2020 ◽  
Author(s):  
Emma L Watson ◽  
Thomas J Wilkinson ◽  
Tom F O’Sullivan ◽  
Luke A Baker ◽  
Douglas W Gould ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Exercise Capacity ◽  
Muscle Mass ◽  
Ex Vivo ◽  
Muscle Size ◽  
Cross Sectional ◽  
Cross Sectional Analysis ◽  
Sectional Analysis

AbstractEvidence is growing for a role of vitamin D in regulating skeletal muscle mass, strength and functional capacity. Given the role the kidneys play in activating total vitamin D, and the high prevalence of vitamin D deficiency in Chronic Kidney Disease (CKD), it is possible that deficiency contributes to the low levels of physical function and muscle mass in these patients. This is a secondary cross-sectional analysis of previously published interventional study, with ex vivo follow up work. 34 CKD patients at stages G3b-5 (eGFR 25.5 ± 8.3ml/min/1.73m2; age 61 ± 12 years) were recruited, with a sub-group (n=20) also donating a muscle biopsy. Vitamin D and associated metabolites were analysed in plasma by liquid chromatography tandem-mass spectroscopy and correlated to a range of physiological tests of muscle size, function, exercise capacity and body composition. The effects of 1α,25(OH)2D3 supplementation on myogenesis and myotube size was investigated in primary skeletal muscle cells from vitamin D deficient donors. In vivo, there was no association between total or active vitamin D and muscle size or strength, but a significant correlation with was seen with the total form. Ex vivo, 1α,25(OH)2D3 supplementation reduced IL-6 mRNA expression, but had no effect upon proliferation, differentiation or myotube diameter. This early preliminary work suggests that vitamin D deficiency is not a prominent factor driving the loss of muscle mass in CKD, but may play a role in reduced exercise capacity.

scholarly journals Modulation of activity and conduction in single dorsal column axons by kilohertz-frequency spinal cord stimulation

2017 ◽  
Vol 117 (1) ◽  
pp. 136-147 ◽  
Author(s):  
Nathan D. Crosby ◽  
John J. Janik ◽  
Warren M. Grill
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Spinal Cord Stimulation ◽  
Pain Perception ◽  
Conduction Block ◽  
Dorsal Column ◽  
Platinum Electrodes ◽  
Sprague Dawley ◽  
Transient Nature ◽  
Central Nervous System Activity

Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a potential paresthesia-free treatment for chronic pain. However, the effects of KHF-SCS on spinal dorsal column (DC) axons and its mechanisms of action remain unknown. The objectives of this study were to quantify activation and conduction block of DC axons by KHF-SCS across a range of frequencies (1, 5, 10, or 20 kHz) and waveforms (biphasic pulses or sinusoids). Custom platinum electrodes delivered SCS to the T10/T11 dorsal columns of anesthetized male Sprague-Dawley rats. Single DC axons and compound action potentials were recorded during KHF-SCS to evaluate SCS-evoked activity. Responses to KHF-SCS in DC axons included brief onset firing, slowly accommodating asynchronous firing, and conduction block. The effects of KHF-SCS mostly occurred well above motor thresholds, but isolated units were activated at amplitudes shown to reduce behavioral sensitivity in rats. Activity evoked by SCS was similar across a range of frequencies (5–20 kHz) and waveforms (biphasic and sinusoidal). Stimulation at 1-kHz SCS evoked more axonal firing that was also more phase-synchronized to the SCS waveform, but only at amplitudes above motor threshold. These data quantitatively characterize the central nervous system activity that may modulate pain perception and paresthesia, and thereby provide a foundation for continued investigation of the mechanisms of KHF-SCS and its optimization as a therapy for chronic pain. Given the asynchronous and transient nature of DC activity, it is unlikely that the same mechanisms underlying conventional SCS (i.e., persistent, periodic DC activation) apply to KHF-SCS. NEW & NOTEWORTHY Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a new mode of SCS that may offer better pain relief than conventional SCS. However, the mechanism of action is poorly characterized, especially the effects of stimulation on dorsal column (DC) axons, which are the primary target of stimulation. This study provides the first recordings of single DC axons during KHF-SCS to quantify DC activity that has the potential to mediate the analgesic effects of KHF-SCS.

scholarly journals 1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

2020 ◽  
Vol 10 (10) ◽  
pp. 731
Author(s):  
Muhammad Faheem ◽  
Syed Hussain Ali ◽  
Abdul Waheed Khan ◽  
Mahboob Alam ◽  
Umair Ilyas ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Pain Perception ◽  
Chronic Constriction Injury ◽  
Neuroprotective Effect ◽  
Underlying Mechanism ◽  
Contributing Factors ◽  
Neuroprotective Effects ◽  
In Silico Studies

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia (p < 0.001) and allodynia (p < 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS (p < 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.

scholarly journals Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model

2020 ◽  
Vol 134 (18) ◽  
pp. 2521-2534 ◽  
Author(s):  
Vianne Nsengiyumva ◽  
Smriti M. Krishna ◽  
Corey S. Moran ◽  
Joseph V. Moxon ◽  
Susan K. Morton ◽  
...  
Keyword(s):  
Vitamin D ◽  
Extracellular Matrix ◽  
Mouse Model ◽  
Vitamin D Deficiency ◽  
Ex Vivo ◽  
Aortic Aneurysms ◽  
Matrix Metalloproteinase 2 ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Abdominal Aortic

Abstract Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P&lt;0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P&lt;0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.

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