Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5–6 month old male Sprague Dawley rats received a focal injury (craniectomy + controlled cortical impact (CCI; n = 17)) or Sham injury (craniectomy alone; n = 12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n = 16) or saline (n = 13) every 48 h for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p = 0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p < 0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypoadrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCI-injured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p > 0.05) animals by post-injury day 29, but rapidly reversed by post-injury day 1 the hypoadrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0 s) compared to saline treated Sham animals (8.8 ± 1.7 s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCI-injured rats treated with saline (30.7 ± 5.5 s, p < 0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCI-induced hypogonadism, but does reverse craniectomy- and craniectomy + CCI-induced hypoadrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight.
Clarinol 1 G-80 (Lot 5385481001) was used in this study. There is an error in the description of Clarinol 1 G-80 in the fourth sentence of the first paragraph under the "CLA Administration" subheading in the Materials and Methods section. The description should be as follows: "Clarinol 1 G-80, is an oil mixture high in isomers of CLA (80%), comprised predominantly of c-9,t-11 (conjugated diene (CD)18:2) and t-10,c-12 (CD18:2) CLA (74.5%) with traces of oleic, palmitic and stearic acid (or safflower oil fatty acids)."A decimal error was made in the calculation of the dosage of Clarinol 1 intraperitoneally injected in the rats. A dose of 250mg/kg Clarinol 1 was delivered to the rats every other day (not 25 mg/kg every other day as stated in the article). This equates to~100 mg/kg of conjugated linoleic acid (CLA) per day and approximately two-fold the equivalent FDA recommended human dose (not half the FDA approved dose as stated in the article).There was an error in reporting the ages of the rats used in the study. Rats were assigned to the following groups: Sham + saline group (n = 5; 5-6 months of age), Sham + CLA group (n = 7; 5-6 months of age), controlled cortical impact (CCI) injury + saline group (n = 8; 15-16 months of age), CCI injury + CLA group (n = 9; 15-16 months of age). Since the incidence of traumatic brain injury increases in the elderly, aged rats were subjected to a CCI injury. The results indicate that Clarinol 1 at the dose injected intraperitoneally is detrimental to learning and memory in uninjured young adult rats, and limits cognitive recovery in aged rats following a CCI injury.The conclusions of the study focus on the effects of intraperitoneal CLA administration; conclusions cannot be drawn from the study data regarding the effects of oral administration of CLA, and discussion of the effects of dietary CLA in the article is speculative. The design of our experiment related to administration of CLA was motivated by the potential use of CLA in the treatment of TBI. Many individuals with TBI, particularly those with moderate to severe TBI cannot consume food, but can take treatments i.p., s.c. or i.v. Moreover, this experimental design allows us to know the exact amount delivered to each animal and avoid complications related to differences in consumption, or differences in intestinal uptake, of CLA by different animals. Potential differences in the effects of intermittent Clarinol 1 G-80 treatment (higher doses every other day), and between oral and intraperitoneal delivery, warrants further investigation.PLOS ONE | https://doi.org/10.1371/journal.pone.
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34Background: The identity and spatial distribution of prostatic cell types has been 35 determined in humans but not in dogs, even though aging-and prostate-related voiding 36 disorders are common in both species and mechanistic factors, such as prostatic collagen 37 accumulation, appear to be shared between species. In this publication we characterize 38 the regional distribution of prostatic cell types in the young intact dog to enable 39 comparisons with human and mice and we examine how the cellular source of 40 procollagen 1A1 changes with age in intact male dogs. 41Methods: A multichotomous decision tree involving sequential immunohistochemical 42 stains was validated for use in dog and used to identify specific prostatic cell types and 43 determine their distribution in the capsule, peripheral, periurethral and urethral regions of 44 the young intact canine prostate. Prostatic cells identified using this technique include 45 perivascular smooth muscle cells, pericytes, endothelial cells, luminal, intermediate, and 46 basal epithelial cells, neuroendocrine cells, myofibroblasts, fibroblasts, fibrocytes, and 47 other hematolymphoid cells. Corresponding images were made freely accessible through 48 the GUDMAP database at https://doi.org/10.25548/16-WMM4. 49 Results: The prostatic peripheral region harbors the largest proportion of epithelial cells. 50 Aging does not change the density of hematolymphoid cells, fibroblasts, and 51 myofibroblasts in the peripheral region or in the fibromuscular capsule, regions where we 52 previously observed aging-and androgen-mediated increases in prostatic collagen 53 abundance Instead, we observed aging-related changes the procollagen 1A1 positive 54 prostatic cell identity from a myofibroblast to a fibroblast. 55 Conclusions: Hematolymphoid cells and myofibroblasts are often identified as sources 56 of collagen in tissues prone to aging-related fibrosis. We show that these are not the likely 57 sources of pathological collagen synthesis in older intact male dogs. Instead, we identify 58 an aging-related shift in the prostatic cell type producing procollagen 1A1 that will help 59 direct development of cell type and prostate appropriate therapeutics for collagen 60 accumulation. 61 62 Keywords: fibrosis, BPH, Collagen, LUTS 63 64 1. Introduction 65 Men and dogs develop prostatic disorders spontaneously and in an aging-and 66 androgen-dependent fashion.[1-11] Human and dog prostates organize into distinct 67 anatomical zones with an externally bound fibromuscular capsule (anatomical features 68 not shared by the mouse prostate).[12] Careful histological and molecular analyses of 69 human prostate have revolutionized our understanding of the cell types of the prostate, 70revealing a gland that contains at least five epithelial cell types and three fibroblast-like 71 stromal cell types that are organized into three zones. [13, 14] Canine prostate cell types 72 and their spatial distribution across the gland have not been extensively examined using 73 modern molecular a...
Background The identity and spatial distribution of prostatic cell types has been determined in humans but not in dogs, even though aging- and prostate-related voiding disorders are common in both species and mechanistic factors, such as prostatic collagen accumulation, appear to be shared between species. In this publication we characterize the regional distribution of prostatic cell types in the young intact dog to enable comparisons with human and mice and we examine how the cellular source of procollagen 1A1 changes with age in intact male dogs. Methods A multichotomous decision tree involving sequential immunohistochemical stains was validated for use in dog and used to identify specific prostatic cell types and determine their distribution in the capsule, peripheral, periurethral and urethral regions of the young intact canine prostate. Prostatic cells identified using this technique include perivascular smooth muscle cells, pericytes, endothelial cells, luminal, intermediate, and basal epithelial cells, neuroendocrine cells, myofibroblasts, fibroblasts, fibrocytes, and other hematolymphoid cells. To enhance rigor and transparency, all high resolution images (representative images shown in the figures and biological replicates) are available through the GUDMAP database at https://doi.org/10.25548/16-WMM4 . Results The prostatic peripheral region harbors the largest proportion of epithelial cells. Aging does not change the density of hematolymphoid cells, fibroblasts, and myofibroblasts in the peripheral region or in the fibromuscular capsule, regions where we previously observed aging- and androgen-mediated increases in prostatic collagen abundance Instead, we observed aging-related changes the procollagen 1A1 positive prostatic cell identity from a myofibroblast to a fibroblast. Conclusions Hematolymphoid cells and myofibroblasts are often identified as sources of collagen in tissues prone to aging-related fibrosis. We show that these are not the likely sources of pathological collagen synthesis in older intact male dogs. Instead, we identify an aging-related shift in the prostatic cell type producing procollagen 1A1 that will help direct development of cell type and prostate appropriate therapeutics for collagen accumulation.
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