The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts ...(MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.
We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.
Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease.
Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism ...for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.
Vitamin B12 as a Treatment for Pain Buesing, Scott; Costa, Miranda; Schilling, Jan M ...
Pain physician,
01/2019, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Odprti dostop
First isolated as cyanocobalamin in 1948, vitamin B12 has been explored for pain treatment almost since its discovery. With the advent of the opioid epidemic, safer treatments for pain are needed.
...Our objective was to compile the latest information on potential mechanisms from animal studies and clinical trial data on vitamin B12 for the treatment of pain conditions.
We conducted a narrative review.
PubMed was searched using the terms "methylcobalamin pain", "hydroxycobalamin pain", "cyanocobalamin pain", and "vitamin B12 pain." Animal studies that identified mechanisms of action for the effects of pain were collected. Clinical trials utilizing larger, pharmaceutical doses of vitamin B12 (> 100 µg/dose) in pain treatment were identified and reviewed.
Animal studies support multiple beneficial effects of vitamin B12 including the regeneration of nerves and the inhibition of cyclooxygenase enzymes and other pain-signaling pathways. In addition, animal studies have demonstrated synergistic benefits of vitamin B12 combined with other pain medications, including nonsteroidal anti-inflammatory drugs and opiates. Clinical trials provide evidence for the effectiveness of vitamin B12 for the treatment of low back pain and neuralgia, although data is still fairly limited and optimal treatment regimens have not been identified.
More large, double-blind placebo-controlled trials are needed to fully establish efficacy and best dosing parameters.
Vitamin B12 may prove to be an adjunctive or integrative treatment for pain conditions. While more research is needed, considering the low incidence of side effects and overall safety, B12 may be an additional tool to consider for pain treatment.
Vitamin B12, cyanocobalamin, methylcobalamin, hydroxycobalamin, pain, chronic pain, neuropathy, low back pain.
Chronic pain is not a singular disorder and presents in various forms and phenotypes. Here we show data from a cohort of patients seeking treatment in a transdisciplinary pain clinic. Patients ...completed a multidimensional patient-reported battery as part of routine initial evaluation at baseline and at each of the four subsequent visits over 1-year follow-up (0, 1, 3, 6, 12 months). The goal of this work was to use unsupervised modeling approach to identify whether patients with chronic pain undergoing transdisciplinary intensive rehabilitation treatment: (1) can be derived based upon self-reported outcome measures at baseline (or before treatment initiation), (2) are clinically validated based on their clinical diagnosis and medication use, and (3) differ in treatment trajectories over 1 year of transdisciplinary treatment. We applied unsupervised clustering on baseline outcomes using nine patient-reported symptoms and examined treatment trajectories. The three-cluster solution was internally validated. Psychiatric diagnosis, chronic back pain-related disability and symptoms severity determined cluster assignment and treatment prognosis. Conversely, clinical pain severity had lesser effect. Furthermore, clusters showed stability over time despite symptoms improvement. The accurate and meaningful subgrouping of the underlying chronic pain phenotypes would greatly enhance treatment and provide personalized and effective pain management.
Abstract
People heterozygous for an activating mutation in protein kinase G1 (
PRKG1
, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice ...heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation.
Prkg1
R177Q/+
aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)—to increase wall stress in the ascending aorta—induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B
12
-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.
Mild traumatic brain injury is an all-too-common outcome from modern warfare and sport, and lacks a reproducible model for assessment of potential treatments and protection against it. Here we ...consider the use of surface acoustic wave (SAW) irradiation of C. elegans worms-without cavitation-as a potential, ethically reasonable animal-on-a-chip model for inducing traumatic brain injury in an animal, producing significant effects on memory and learning that could prove useful in a model that progress from youth to old age in but a few weeks. We show a significant effect by SAW on the ability of worms to learn post-exposure through associative learning chemotaxis. At higher SAW intensity, we find immediate, thorough, but temporary paralysis of the worms. We further explore the importance of homogeneous exposure of the worms to the SAW-driven ultrasound, an aspect poorly controlled in past efforts, if at all, and demonstrate the absence of cavitation through a change in fluids from a standard media for the worms to the exceedingly viscous polyvinyl alcohol. Likewise, we demonstrate that acoustic streaming, when present, is not directly responsible for paralysis nor learning disabilities induced in the worm, but is beneficial at low amplitudes to ensuring homogeneous ultrasound exposure.
Abstract Background Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for ...neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown. Methods Here, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1 ), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes. Results SynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function. Conclusions Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal-dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.
Traumatic brain injury (TBI) enhances pro-inflammatory responses, neuronal loss and long-term behavioral deficits. Caveolins (Cavs) are regulators of neuronal and glial survival signaling. Previously ...we showed that astrocyte and microglial activation is increased in Cav-1 knock-out (KO) mice and that Cav-1 and Cav-3 modulate microglial morphology. We hypothesized that Cavs may regulate cytokine production after TBI.
Controlled cortical impact (CCI) model of TBI (3 m/second; 1.0 mm depth; parietal cortex) was performed on wild-type (WT; C57Bl/6), Cav-1 KO, and Cav-3 KO mice. Histology and immunofluorescence microscopy (lesion volume, glia activation), behavioral tests (open field, balance beam, wire grip, T-maze), electrophysiology, electron paramagnetic resonance, membrane fractionation, and multiplex assays were performed. Data were analyzed by unpaired t tests or analysis of variance (ANOVA) with post-hoc Bonferroni's multiple comparison.
CCI increased cortical and hippocampal injury and decreased expression of MLR-localized synaptic proteins (24 hours), enhanced NADPH oxidase (Nox) activity (24 hours and 1 week), enhanced polysynaptic responses (1 week), and caused hippocampal-dependent learning deficits (3 months). CCI increased brain lesion volume in both Cav-3 and Cav-1 KO mice after 24 hours (P < 0.0001, n = 4; one-way ANOVA). Multiplex array revealed a significant increase in expression of IL-1β, IL-9, IL-10, KC (keratinocyte chemoattractant), and monocyte chemoattractant protein 1 (MCP-1) in ipsilateral hemisphere and IL-9, IL-10, IL-17, and macrophage inflammatory protein 1 alpha (MIP-1α) in contralateral hemisphere of WT mice after 4 hours. CCI increased IL-2, IL-6, KC and MCP-1 in ipsilateral and IL-6, IL-9, IL-17 and KC in contralateral hemispheres in Cav-1 KO and increased all 10 cytokines/chemokines in both hemispheres except for IL-17 (ipsilateral) and MIP-1α (contralateral) in Cav-3 KO (versus WT CCI). Cav-3 KO CCI showed increased IL-1β, IL-9, KC, MCP-1, MIP-1α, and granulocyte-macrophage colony-stimulating factor in ipsilateral and IL-1β, IL-2, IL-9, IL-10, and IL-17 in contralateral hemispheres (P = 0.0005, n = 6; two-way ANOVA) compared to Cav-1 KO CCI.
CCI caused astrocyte and microglial activation and hippocampal neuronal injury. Cav-1 and Cav-3 KO exhibited enhanced lesion volume and cytokine/chemokine production after CCI. These findings suggest that Cav isoforms may regulate neuroinflammatory responses and neuroprotection following TBI.
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