scholarly journals Subcutaneous neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical strokes

2018 ◽  
Author(s):  
Denise Duricki ◽  
Sotiris Kakanos ◽  
Barbara Haenzi ◽  
Wayman Christina ◽  
Diana Cash ◽  
...  
Keyword(s):  
Muscle Spindles ◽  
Time Frame ◽  
Sensory Function ◽  
Subcutaneous Infusion ◽  
Delayed Treatment ◽  
Neurotrophin 3 ◽  
Cortical Stroke ◽  
High Doses ◽  
And Function ◽  
Sensorimotor Recovery

AbstractThere is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. We set out to determine whether subcutaneous supplementation of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically-feasible timeframe via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.

scholarly journals Corticospinal neuroplasticity and sensorimotor recovery in rats treated by infusion of neurotrophin-3 into disabled forelimb muscles started 24 h after stroke

2018 ◽  
Author(s):  
Denise A. Duricki ◽  
Svetlana Drndarski ◽  
Michel Bernanos ◽  
Tobias Wood ◽  
Karen Bosch ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
The Body ◽  
Bold Signal ◽  
Triceps Brachii ◽  
Sensory Afferents ◽  
Adult Rats ◽  
Adult Mice ◽  
Neurotrophin 3 ◽  
High Doses ◽  
Sensorimotor Recovery

AbstractStroke often leads to arm disability and reduced responsiveness to stimuli on the other side of the body. Neurotrophin-3 (NT3) is made by skeletal muscle during infancy but levels drop postnatally and into adulthood. It is essential for the survival and wiring-up of sensory afferents from muscle. We have previously shown that gene therapy delivery of human NT3 into the affected triceps brachii forelimb muscle improves sensorimotor recovery after ischemic stroke in adult and elderly rats. Here, to move this therapy one step nearer to the clinic, we set out to test the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after ischemic cortical stroke in adult rats. To simulate a clinically-feasible time-to-treat, twenty-four hours later rats were randomized to receive NT3 or vehicle by infusion into triceps brachii for four weeks using implanted minipumps. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory deficits on the affected forearm. There was no evidence of forepaw sensitivity to cold stimuli after stroke or NT3 treatment. MRI confirmed that treatment did not induce neuroprotection. Functional MRI during low threshold electrical stimulation of the affected forearm showed an increase in peri-infarct BOLD signal with time in both stroke groups and indicated that neurotrophin-3 did not further increase peri-infarct BOLD signal. Rather, NT3 induced spinal neuroplasticity including sprouting of the spared corticospinal and serotonergic pathways. Neurophysiology showed that NT3 treatment increased functional connectivity between the corticospinal tracts and spinal circuits controlling muscles on the treated side. After intravenous injection, radiolabelled NT3 crossed from bloodstream into the brain and spinal cord in adult mice with or without strokes. Our results show that delayed, peripheral infusion of neurotrophin-3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke.

scholarly journals Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

2019 ◽  
Vol 20 (14) ◽  
pp. 3541 ◽  
Author(s):  
Elisabetta Palazzo ◽  
Alessandra Marconi ◽  
Carlo Pincelli ◽  
Maria I. Morasso
Keyword(s):  
Tumor Development ◽  
Human Keratinocytes ◽  
Epidermal Differentiation ◽  
Trk Receptor ◽  
Neurotrophin 3 ◽  
Homeobox Transcription Factor ◽  
Epidermal Homeostasis ◽  
Transcription Regulators ◽  
And Function ◽  
Normal Epidermis

Well-regulated epidermal homeostasis depends on the function of different classes of factors, such as transcription regulators and receptors. Alterations in this homeostatic balance may lead to the development of cutaneous squamous tumorigenesis. The homeobox transcription factor DLX3 is determinant for a p53-dependent regulation of epidermal differentiation and modulates skin carcinogenesis. The maintenance of skin homeostasis also involves the action of neurotrophins (NTs) and their receptors, Trk and CD271. While Trk receptor overexpression is a hallmark of cancer, there are conflicting data on CD271 expression and function in cutaneous SCC (cSCC). Previous studies have reported NT receptors expression in head and neck SSC (HNSCC). We show that CD271 is expressed at low levels in primary cSCC cells and the number of CD271+ cells correlates with cell cohesion in SCC spheroids. In normal epidermis, CD271 is expressed in proliferative progenitor cells and DLX3 in terminally differentiated keratinocytes. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) increase DLX3 expression. In the absence of a functional BDNF receptor TrkB in keratinocytes, we hypothesize that the BDNF-dependent DLX3 response could be mediated via CD271. Altogether, our results support a putative CD271-DLX3 connection in keratinocytes, which might be crucial to preventing squamous skin cancer.

Chronic infusion of islet amyloid polypeptide causes anorexia in rats

1996 ◽  
Vol 271 (6) ◽  
pp. R1654-R1659 ◽  
Author(s):  
U. Arnelo ◽  
J. Permert ◽  
T. E. Adrian ◽  
J. Larsson ◽  
P. Westermark ◽  
...  
Keyword(s):  
Food Intake ◽  
Body Weight Gain ◽  
Islet Amyloid Polypeptide ◽  
Reduce Food Intake ◽  
Islet Amyloid ◽  
Minimal Effective Dose ◽  
Subcutaneous Infusion ◽  
Pathophysiological Role ◽  
Chronic Infusion ◽  
High Doses

Islet amyloid polypeptide (IAPP) is a hormonal peptide that at high doses has been shown to reduce food intake. In the present study, the dose-response effects of subcutaneous infusion of IAPP (0, 2, 7, and 25 pmol.kg-1.min-1) for 8 days on food intake and meal patterns in rats were investigated. At the end of the experiment, plasma was obtained and levels of IAPP were measured by radioimmunoassay. IAPP dose-dependently and transiently inhibited food intake. The minimal effective dose (2 pmol.kg-1.min-1) caused a small but significant (up to 14%, P < 0.01) inhibition of food intake that lasted 5 days. The highest dose administered (25 pmol.kg-1.min-1) had the greatest effect (up to 44%, P < 0.001), which lasted throughout the 8-day period. Reductions in feeding during light and dark phases occurred through a decrease in number of meals consumed rather than meal size or meal duration. IAPP also decreased body weight gain and water intake dose dependently. IAPP infusion of 2, 7, and 25 pmol.kg-1.min-1 increased plasma IAPP concentrations from a basal level of 10.3 +/- 0.7 pM to 35.1 +/- 5.4, 78.1 +/- 11.2, and 236.6 +/- 23.6 pM, respectively, values that are likely to be close to physiological and within the pathophysiological ranges. Thus IAPP may play an important physiological or pathophysiological role in control of food intake.

scholarly journals Remote Corticospinal Tract Degeneration After Cortical Stroke in Rats May Not Preclude Spontaneous Sensorimotor Recovery

2021 ◽  
pp. 154596832110413
Author(s):  
Michel R. T. Sinke ◽  
Geralda A. F. van Tilborg ◽  
Anu E. Meerwaldt ◽  
Caroline L. van Heijningen ◽  
Annette van der Toorn ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Corticospinal Tract ◽  
Sprague Dawley ◽  
Post Stroke ◽  
Neuronal Communication ◽  
Cortical Stroke ◽  
Magnetic Resonance Imaging Mri ◽  
And Behavior ◽  
Sensorimotor Recovery

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

scholarly journals High Doses of Caffeine during the Peripubertal Period in the Rat Impair the Growth and Function of the Testis

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Minji Park ◽  
Yuri Choi ◽  
Hyeonhae Choi ◽  
Ju-Yearn Yim ◽  
Jaesook Roh
Keyword(s):  
Leydig Cells ◽  
Ex Vivo ◽  
Body Weight Gain ◽  
Male Rats ◽  
Male Rat ◽  
Control Group ◽  
High Doses ◽  
And Function ◽  
The Impact ◽  
Caffeine Exposure

Prenatal caffeine exposure adversely affects the development of the reproductive organs of male rat offspring. Thus, it is conceivable that peripubertal caffeine exposure would also influence physiologic gonadal changes and function during this critical period for sexual maturation. This study investigated the impact of high doses of caffeine on the testes of prepubertal male rats. A total of 45 immature male rats were divided randomly into three groups: a control group and 2 groups fed 120 and 180 mg/kg/day of caffeine, respectively, via the stomach for 4 weeks. Caffeine caused a significant decrease in body weight gain, accompanied by proportional decreases in lean body mass and body fat. The caffeine-fed animals had smaller and lighter testes than those of the control that were accompanied by negative influences on the histologic parameters of the testes. In addition, stimulated-testosterone ex vivo production was reduced in Leydig cells retrieved from the caffeine-fed animals. Our results demonstrate that peripubertal caffeine consumption can interfere with the maturation and function of the testis, possibly by interrupting endogenous testosterone secretion and reducing the sensitivity of Leydig cells to gonadotrophic stimulation. In addition, we confirmed that pubertal administration of caffeine reduced testis growth and altered testis histomorphology.

Low-dose Interleukin-2 in the Treatment of Autoimmune Disease

2014 ◽  
Vol 10 (02) ◽  
pp. 157 ◽  
Author(s):  
John Koreth ◽  
Jerome Ritz ◽  
George C Tsokos ◽  
Alberto Pugliese ◽  
Thomas R Malek ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
Cell Function ◽  
Interleukin 2 ◽  
The Us ◽  
High Doses ◽  
And Function ◽  
Preclinical And Clinical Studies

CD4+ regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration (FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.

Modulation of rat testes lipid composition by hormones: effect of PRL and hCG

1988 ◽  
Vol 255 (4) ◽  
pp. E442-E448 ◽  
Author(s):  
E. Sebokova ◽  
A. Wierzbicki ◽  
M. T. Clandinin
Keyword(s):  
Chorionic Gonadotropin ◽  
Leydig Cells ◽  
Binding Capacity ◽  
Total Phospholipid ◽  
Testicular Tissue ◽  
Phospholipid Content ◽  
Refractory State ◽  
Phospholipid Ratio ◽  
High Doses ◽  
And Function

The effect of prolactin (PRL) and human chorionic gonadotropin (hCG) administration for 7 days on the composition and function of rat testicular plasma membrane was investigated. Refractory state in Leydig cells desensitized by hCG decreased the binding capacity for 125I-labeled hCG and also luteinizing hormone (LH)-induced adenosine 3',5'-cyclic monophosphate (cAMP) and testosterone production. In testicular membranes of hCG-treated animals, a depletion of cholesterol and an increase in total phospholipid content was observed after gonadotropin injection, thereby decreasing the cholesterol-to-phospholipid ratio. Injection of high doses of PRL had no effect on the binding capacity or affinity of the LH-hCG receptor but decreased the response of Leydig cells to LH in terms of cAMP and testosterone synthesis. PRL also increased total and esterified cholesterol and decreased free cholesterol and membrane phospholipid content. The fatty acid composition of testicular lipids was significantly and selectively influenced by both hormonal treatments. These observations suggest that metabolism of cholesterol and long-chain polyunsaturated fatty acids in testicular tissue is affected by chorionic gonadotropin and PRL and may provide the mechanism for regulating steroidogenic functions.

Effect of Fish Oil on Appetite and Other Symptoms in Patients With Advanced Cancer and Anorexia/Cachexia: A Double-Blind, Placebo-Controlled Study

2003 ◽  
Vol 21 (1) ◽  
pp. 129-134 ◽  
Author(s):  
Eduardo Bruera ◽  
Florian Strasser ◽  
J. Lynn Palmer ◽  
Jie Willey ◽  
Kathryn Calder ◽  
...  
Keyword(s):  
Nutritional Status ◽  
Fish Oil ◽  
Advanced Cancer ◽  
Caloric Intake ◽  
Well Being ◽  
Controlled Study ◽  
Double Blind ◽  
Baseline Weight ◽  
High Doses ◽  
And Function

Purpose: To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight and appetite. Patients and Methods: Sixty patients were randomly assigned to fish oil capsules or placebo. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and function were prospectively assessed at days 1 and 14. Results: The baseline weight loss was 16 ± 11 and 16 ± 8 kg in the fish oil (n = 30) and placebo (n = 30) group respectively, whereas the baseline appetite (0 mm = best and 10 mm = worst) was 58 ± 24 mm and 67 ± 19 mm, respectively (P = not significant). The mean daily dose was 10 ± 4 (fish oil group) and 9 ± 3 (placebo group) capsules, which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group. No significant differences in symptomatic or nutritional parameters were found (P < .05), and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses. Finally, the majority of the patients were not able to swallow more than 10 fish oil capsules per day, mainly because of burping and aftertaste. Conclusion: Fish oil did not significantly influence appetite, tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite.

scholarly journals Sympathetic neuroblasts undergo a developmental switch in trophic dependence

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 597-610 ◽  
Author(s):  
S.J. Birren ◽  
L. Lo ◽  
D.J. Anderson
Keyword(s):  
Neurotrophic Factors ◽  
Sympathetic Neurons ◽  
Neurotrophin Receptor ◽  
Neurotrophin 3 ◽  
Bona Fide ◽  
Neuronal Number ◽  
High Doses ◽  
Developmental Switch

Sympathetic neurons require NGF for survival, but it is not known when these cells first become dependent on neurotrophic factors. We have examined in vitro mitotically active sympathetic neuroblasts immuno-isolated from different embryonic stages, and have correlated this functional data with the expression of neurotrophin receptor mRNAs in vivo. Cells from E14.5 ganglia are supported by neurotrophin-3 (NT-3) in a serum-free medium, but not by NGF; NT-3 acts as a bona fide survival factor for these cells and not simply as a mitogen. By birth, sympathetic neurons are well-supported by NGF, whereas NT-3 supports survival only weakly and at very high doses. This change in neurotrophin-responsiveness is correlated with a reciprocal switch in the expression of trkC and trkA mRNAs by sympathetic neuroblasts in vivo. These data suggest that neurotrophic factors may control neuronal number at earlier stages of development than previously anticipated. They also suggest that the acquisition of NGF-dependence may occur, at least in part, through the loss of receptors for these interim survival factors.

scholarly journals Analisis In-Silico Struktur Tiga Dimensi Reseptor Trk A dan Trk B Protein Neurotrophin 3 Pada Gallus gallus (Chicken)

2020 ◽  
Vol 12 (2) ◽  
pp. 78-84
Author(s):  
Muhammad F. Rahman ◽  
Amiruddin Kasim ◽  
Muchlis L. Djirimu ◽  
I. Made Budiarsa
Keyword(s):  
Amino Acids ◽  
In Silico ◽  
Three Dimensional ◽  
Gallus Gallus ◽  
Dimensional Structure ◽  
Neurotrophin 3 ◽  
Trk A ◽  
And Function ◽  
Trk B ◽  
Ucsf Chimera

NT3 protein is expressed by Neurotrophin 3 (NTF-3) which plays a role in the process of differentiation, survival of peripheral and neuropathological of neurons. The information of structure and function of NT-3 proteins is still very limited, especially in Gallus gallus. This study aims to predict the three-dimensional structure of the Trk A and Trk B proteins in Gallus gallus. The target protein obtained from the UniProt server with access codes Q91009 (Trk A) and Q91987 (Trk B) using the 6kzc 1.A (PDB ID) template was analyzed in silico through a homology approach and describing the structural assessment using Chimera UCSF software. The analysis showed that the Trk A protein had a QMEAN value of -0.08, composed of 778 amino acids, mass 87334.30 Daltons, and Seq Identity 79.93%. Trk B had a QMEAN value of 0.16, consisting of 818 amino acids, mass 91732.05 Daltons, and Seq Identity 84.30%. Key words: NT3; homology; UCSF chimera; G. gallus

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