In Vivo Brain Levels of Acetylcholine and 5‐Hydroxytryptamine after Oleoylethanolamide or Palmitoylethanolamide Administrations are Mediated by PPARα Engagement

2021 ◽  
Author(s):  
Eric Murillo‐Rodríguez ◽  
Gloria Arankowsky‐Sandoval ◽  
Henning Budde ◽  
Claudio Imperatori ◽  
Sérgio Machado ◽  
...  
Keyword(s):  
Brain Levels

scholarly journals T165. ANTI-GLUTAMATERGIC PROPERTY OF N-ACETYLCYSTEINE DOCUMENTED IN VIVO WITH 1H MRS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S294-S294
Author(s):  
Dikoma Shungu ◽  
Xiangling Mao ◽  
Michelle Blate ◽  
Diana Vu ◽  
Guoxin Kang ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Occipital Cortex ◽  
Inhibition Mechanism ◽  
1H Mrs ◽  
Sample Mean ◽  
Brain Levels ◽  
Water Signal ◽  
Peak Areas ◽  
Rate Limiting

Abstract Background Deficits of brain glutathione (GSH), the primary antioxidant in living tissue, and associated redox imbalance are postulated to be implicated in schizophrenia. However, due to poor blood-brain barrier permeability of GSH, direct supplementation is ineffective in restoring its brain levels. Therefore, there has been great interest in investigating N-acetylcysteine (NAC), as a prodrug that can be deacetylated to supply cysteine (Cys), which crosses the BBB and is the rate-limiting substrate in brain GSH synthesis and restoration. Once inside the cell, Cys combines with glutamate (Glu) to initiate GSH synthesis in a reaction that is catalyzed by gamma-glutamyl cysteine ligase (GCL), the rate-limiting enzyme. Likely due to the in situ reaction of NAC-supplied Cys with Glu to spur GSH synthesis, NAC is believed to have anti-glutamatergic properties. However, direct in vivo evidence of NAC as an anti-glutamatergic agent is currently lacking. In this study, we used 1H MRS to monitor changes in brain levels of both GSH and Glu in response to 4 weeks of daily supplementation with NAC in healthy volunteer subjects. We postulated that 4 weeks of NAC treatment would elevate GSH and decrease Glu levels. Methods Subjects: Participants recruited for this study consisted of 12 mentally and physically healthy human volunteer (HV) subjects. NAC Supplementation: To investigate the effects of dietary NAC supplementation on cortical GSH and Glu levels, each HV subject underwent 1H MRS scans at baseline. Then a 4-week supplement of 900mg NAC tablets was provided, to be taken 2 per day for a daily NAC dose of 1800mg. Finally, each subject was brought back after 4 weeks for the post-NAC 1H MRS scans to assess the effect of the treatment on cortical GSH and Glu levels. Brain 1H MRS: In vivo cortical GSH spectra were recorded in 15 min on a 3.0 T GE MRI system from a 3cmx3cmx2cm occipital cortex voxel, using the standard J-editing technique, with TE/TR 68/1500ms and 290 interleaved excitations (580 total). Levels of Glu, uncontaminated with glutamine, were obtained from the same occipital cortex voxel in 6 min using the CT-PRESS method, with TE/TR 139ms/1500ms, and 129 chemical shift encoding steps in increments of 0.8ms in t1 dimension. Peak areas for both GSH and Glu were derived by frequency-domain fitting of the recorded spectra. The resulting peak areas were then expressed as ratios relative to the area of the unsuppressed tissue water signal in the voxel. Results GSH Levels: The effect of 4 weeks of NAC supplementation on GSH levels was a numerical increase that did not reach statistical significance relative to baseline (p=0.33). Glu Levels Following 4 weeks of NAC supplementation cortical Glu levels decreased significantly compared to baseline (p=0.04). Discussion This study has shown that following 4 weeks of taking NAC, brain Glu levels in HV decreased significantly, even though a numerical increase in GSH levels did not reach statistical significance. The observed Glu decrease at 4 weeks suggests a net increase in the consumption of intracellular Glu reserves in the GCL-catalyzed reaction that combines NAC-supplied Cys with Glu in GSH synthesis. The failure of GSH levels to increase significantly after NAC likely reflected the established “feedback inhibition” mechanism whereby GSH synthesis is shut off in a tissue with normal levels, with de novo synthesis due to NAC occurring only in a subset of subjects with “low” GSH levels (i.e., below the sample mean) at baseline. In summary, the results of this study support the role of NAC as an anti-glutamatergic agent, which seems to modulate Glu levels by increasing the availability of intracellular Cys that then combines with Glu to initiate GSH synthesis, leading to a lowering of total Glu levels as measured with MRS

scholarly journals Protection after Transient Focal Cerebral Ischemia by the N-Methyl-d-Aspartate Antagonist Dextrorphan is Dependent upon Plasma and Brain Levels

1991 ◽  
Vol 11 (6) ◽  
pp. 1015-1024 ◽  
Author(s):  
Gary K. Steinberg ◽  
David Kunis ◽  
Jamshid Saleh ◽  
Robert DeLaPaz
Keyword(s):  
Cerebral Ischemia ◽  
Side Effects ◽  
Plasma Levels ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Rabbit Model ◽  
High Signal ◽  
Brain Levels ◽  
Transient Focal Cerebral Ischemia

Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, the dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = −0.50, p < 0.02 for ischemic neuronal damage; r = −0.66, p < 0.001 for ischemic MRI high signal). All the rabbits with plasma levels > 2,000 ng/ml had < 12% cortical ischemic neuronal damage and < 34% MRI high signal. All rabbits with plasma levels > 3,000 ng/ml showed < 7% ischemic neuronal damage and < 11% MRI high signal. Plasma levels of ∼2,500 ng/ml correlated with brain dextrorphan levels of ∼6,000 ng/g. Unanesthetized rabbits with plasma levels of ∼2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent glutamate or NMDA-induced injury in neuronal culture.

scholarly journals Correlation of CGS 19755 Neuroprotection against in vitro Excitotoxicity and Focal Cerebral Ischemia

1995 ◽  
Vol 15 (5) ◽  
pp. 865-876 ◽  
Author(s):  
Miguel A. Pérez-Pinzón ◽  
Carolina M. Maier ◽  
Edward J. Yoon ◽  
Guo-Hua Sun ◽  
Rona G. Giffard ◽  
...  
Keyword(s):  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Primary Cultures ◽  
Arterial Occlusion ◽  
Neuroprotective Effects ◽  
Brain Levels ◽  
Cgs 19755

The in vivo neuroprotective effect and brain levels of cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from fetal mice were injured by exposure to 500 μM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 μmM, and against OGD the ED50 was 15.2 μM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 μM and 5 μM, respectively, at 1 h, 6 μM and 5 μM at 2 h, and 13 μM and 7 μM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

Fine Structural Changes in the Microvasculature of the Mouse Pinna: Aging and Radiation Injury

1974 ◽  
Vol 32 ◽  
pp. 54-55
Author(s):  
S. Phyllis Steamer ◽  
Rosemarie L. Devine
Keyword(s):  
Structural Changes ◽  
Radiation Treatment ◽  
Arterial Stenosis ◽  
Ultrastructural Changes ◽  
Vascular Effects ◽  
Microvascular Changes ◽  
Surrounding Connective Tissue ◽  
Fission Neutrons ◽  
Total Body

The importance of radiation damage to the skin and its vasculature was recognized by the early radiologists. In more recent studies, vascular effects were shown to involve the endothelium as well as the surrounding connective tissue. Microvascular changes in the mouse pinna were studied in vivo and recorded photographically over a period of 12-18 months. Radiation treatment at 110 days of age was total body exposure to either 240 rad fission neutrons or 855 rad 60Co gamma rays. After in vivo observations in control and irradiated mice, animals were sacrificed for examination of changes in vascular fine structure. Vessels were selected from regions of specific interest that had been identified on photomicrographs. Prominent ultrastructural changes can be attributed to aging as well as to radiation treatment. Of principal concern were determinations of ultrastructural changes associated with venous dilatations, segmental arterial stenosis and tortuosities of both veins and arteries, effects that had been identified on the basis of light microscopic observations. Tortuosities and irregularly dilated vein segments were related to both aging and radiation changes but arterial stenosis was observed only in irradiated animals.

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Structural analysis of the photosynthetic membrane from Ectothiorhodospira halochloris

1983 ◽  
Vol 41 ◽  
pp. 740-741
Author(s):  
H. Engelhardt ◽  
R. Guckenberger ◽  
W. Baumeister
Keyword(s):  
Lattice Structure ◽  
Bacterial Species ◽  
Hexagonal Lattice ◽  
Reaction Centre ◽  
Photosynthetic Membrane ◽  
Rhodopseudomonas Viridis ◽  
Photosynthetic Membranes ◽  
Ectothiorhodospira Halochloris ◽  
Main Components

Bacterial photosynthetic membranes contain, apart from lipids and electron transport components, reaction centre (RC) and light harvesting (LH) polypeptides as the main components. The RC-LH complexes in Rhodopseudomonas viridis membranes are known since quite seme time to form a hexagonal lattice structure in vivo; hence this membrane attracted the particular attention of electron microscopists. Contrary to previous claims in the literature we found, however, that 2-D periodically organized photosynthetic membranes are not a unique feature of Rhodopseudomonas viridis. At least five bacterial species, all bacteriophyll b - containing, possess membranes with the RC-LH complexes regularly arrayed. All these membranes appear to have a similar lattice structure and fine-morphology. The lattice spacings of the Ectothiorhodospira haloohloris, Ectothiorhodospira abdelmalekii and Rhodopseudomonas viridis membranes are close to 13 nm, those of Thiocapsa pfennigii and Rhodopseudomonas sulfoviridis are slightly smaller (∼12.5 nm).

The Infection of Cells by Bullet-Shaped Viruses

1969 ◽  
Vol 27 ◽  
pp. 372-373
Author(s):  
Frederick A. Murphy ◽  
Alyne K. Harrison ◽  
Sylvia G. Whitfield
Keyword(s):  
Electron Microscopy ◽  
Physical Properties ◽  
Host Cell ◽  
Thin Section ◽  
Cultured Cells ◽  
Cell Infection ◽  
Thin Section Electron Microscopy ◽  
Section Electron ◽  
Section Electron Microscopy

The bullet-shaped viruses are currently classified together on the basis of similarities in virion morphology and physical properties. Biologically and ecologically the member viruses are extremely diverse. In searching for further bases for making comparisons of these agents, the nature of host cell infection, both in vivo and in cultured cells, has been explored by thin-section electron microscopy.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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