Growth factors and myelin regeneration in multiple sclerosis

1997 ◽  
Vol 3 (2) ◽  
pp. 113-120 ◽  
Author(s):  
Henry de F Webster
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factors ◽  
Growth Factor ◽  
Structural Characteristics ◽  
Autoimmune Encephalomyelitis ◽  
Myelin Sheaths ◽  
Igf I ◽  
Lesion Severity ◽  
Experimental Autoimmune

Insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and ciliary neurotrophic factor (CNTF) are multifunctional growth factors which are found in the CNS. Oligodendroglia are the cells that form and maintain myelin sheaths and many in vitro experiments have shown that these growth factors promote the proliferation, differentiation and survival of cells in the oligodendroglial lineage. Since myelin breakdown is often severe in multiple sclerosis (MS), the possibility of growth factor use in the treatment of MS has been considered and recently, IGF-I treatment has been shown to reduce lesion severity and promote myelin regeneration in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This review briefly summarizes the structural characteristics of these growth factors and the actions which might help reduce oligodendrocyte-myelin sheath injury in MS and promote myelin regeneration.

scholarly journals Featured Article: Modulation of the OGF–OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis

2018 ◽  
Vol 243 (4) ◽  
pp. 361-369 ◽  
Author(s):  
Michael D Ludwig ◽  
Ian S Zagon ◽  
Patricia J McLaughlin
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokine ◽  
Low Dose ◽  
Serum Levels ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Low Dose Naltrexone ◽  
Experimental Autoimmune

The endogenous neuropeptide opioid growth factor, chemically termed [Met5]-enkephalin, has growth inhibitory and immunomodulatory properties. Opioid growth factor is distributed widely throughout most tissues, is autocrine and paracrine produced, and interacts at the nuclear-associated receptor, OGFr. Serum levels of opioid growth factor are decreased in patients with multiple sclerosis and in animals with experimental autoimmune encephalomyelitis suggesting that the OGF-OGFr pathway becomes dysregulated in this disease. This study begins to assess other cytokines that are altered following opioid growth factor or low-dose naltrexone modulation of the OGF-OGFr axis in mice with experimental autoimmune encephalomyelitis using serum samples collected in mice treated for 10 or 20 days and assayed by a multiplex cytokine assay for inflammatory markers. Cytokines of interest were validated in mice at six days following immunization for experimental autoimmune encephalomyelitis. In addition, selected cytokines were validated with serum from MS patients treated with low-dose naltrexone alone or low-dose naltrexone in combination with glatiramer acetate (Copaxone®). Experimental autoimmune encephalomyelitis mice had elevated levels of 7 of 10 cytokines. Treatment with opioid growth factor or low-dose naltrexone resulted in elevated expression levels of the IL-6 cytokine, and significantly reduced IL-10 values, relative to saline-treated experimental autoimmune encephalomyelitis mice. TNF-γ values were increased in experimental autoimmune encephalomyelitis mice relative to normal, but were not altered by opioid growth factor or low-dose naltrexone. IFN-γ levels were reduced in opioid growth factor- or low-dose naltrexone-treated experimental autoimmune encephalomyelitis mice relative to saline-treated mice at 10 days, and elevated relative to normal values at 20 days. Validation studies revealed that within six days of immunization, opioid growth factor or low-dose naltrexone modulated IL-6 and IL-10 cytokine expression. Validation in human serum revealed markedly reduced IL-6 cytokine levels in MS patients taking low-dose naltrexone relative to standard care. In summary, modulation of the OGF-OGFr pathway regulates some inflammatory cytokines, and together with opioid growth factor serum levels, may begin to form a panel of valid biomarkers to monitor progression of multiple sclerosis and response to therapy. Impact statement Modulation of the opioid growth factor (OGF)–OGF receptor (OGFr) alters inflammatory cytokine expression in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Multiplex cytokine assays demonstrated that mice with chronic EAE and treated with either OGF or low-dose naltrexone (LDN) had decreased expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and the anti-inflammatory cytokine IL-10 within 10 days or treatment, as well as increased serum expression of the pro-inflammatory cytokine IL-6, relative to immunized mice receiving saline. Multiplex data were validated using ELISA kits and serum from MS patients treated with LDN and revealed decreased in IL-6 levels in patients taking LDN relative to standard care alone. These data, along with serum levels of OGF, begin to formulate a selective biomarker profile for MS that is easily measured and effective at monitoring disease progression and response to therapy.

Modulation of growth factor incorporation into ECM of human osteoblast-like cells in vitro by 17 beta-estradiol

1994 ◽  
Vol 267 (6) ◽  
pp. E990-E1001 ◽  
Author(s):  
M. Slater ◽  
J. Patava ◽  
K. Kingham ◽  
R. S. Mason
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Bone Growth ◽  
Transforming Growth Factor ◽  
Bone Matrix ◽  
Tgf Beta ◽  
Subsequent Formation ◽  
Igf I

Human fetal osteoblast-like cells formed a regular multilayered structure in vitro with an extensive collagen-based extracellular matrix. With colloidal gold immunocytochemistry, labels for alkaline phosphatase and osteocalcin were distributed in a relatively diffuse pattern, in contrast to the bone growth factors, insulin-like growth factors I and II (IGF-I and IGF-II), transforming growth factor-beta 1 (TGF-beta 1), and basic fibroblast growth factor, which were colocalized in the collagenous matrix of the multilayer. The inclusion of 17 beta-estradiol (10(-11) to 10(-9) M) in the culture medium increased multilayer depths, increased labeling for IGF-I, IGF-II, and TGF-beta 1, and resulted in earlier detection of TGF-beta 1 label. In contrast, the increase in multilayer depth resulting from treatment with human platelets, an exogenous source of growth factors, was not accompanied by an increase in matrix IGF-I, IGF-II, or TGF-beta 1 label, suggesting a particular effect of estradiol to facilitate this process. Because growth factors in bone matrix may act as coupling agents when released during resorption, reduced growth factor incorporation in the presence of reduced sex steroid concentrations may lead to uncoupling of resorption and subsequent formation.

scholarly journals Possible mechanism for acceleration of meiotic progression of bovine follicular oocytes by growth factors in vitro

Reproduction ◽  
2002 ◽  
pp. 135-142 ◽  
Author(s):  
M Sakaguchi ◽  
T Dominko ◽  
N Yamauchi ◽  
ML Leibfried-Rutledge ◽  
T Nagai ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Kinase Activity ◽  
Polar Body ◽  
Control Group ◽  
Meiotic Cell ◽  
Treatment Groups ◽  
Igf I ◽  
Polar Body Extrusion

The mechanism for the accelerating effects of epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the meiotic cell cycle of bovine oocytes cultured in vitro was investigated. Cumulus-oocyte complexes (COCs) were obtained from small (< or = 3 mm in diameter), medium (4-6 mm in diameter) or large (7-10 mm in diameter) ovarian follicles and cultured with or without a combination of EGF and IGF-I (growth factors). Growth factors significantly increased the frequency of first polar body extrusion of oocytes derived from small follicles at 16 h of culture (PB16 oocytes; with growth factors: 75%; without growth factors: 55%), but did not increase the frequency in oocytes from medium or large follicles. COCs from small follicles were cultured with individual growth factors and sampled for kinase activity. The frequencies of polar body extrusion in EGF only (67%) and EGF + IGF-I (75%) treatment groups were significantly higher than those in the control (no growth factor) group (49%), but not significantly higher than in the IGF-I only group (63%). The H1 kinase activity at 6-8 h of culture in each group increased significantly from the baseline value at 0 h of culture, and the H1 kinase activities in the EGF only, IGF-I only and EGF + IGF-I treatment groups were significantly higher than those in the control group at 8 h of culture. MAP kinase activity was significantly higher than the baseline value and significantly higher than that in the control group at 6 h of culture in the EGF treatment group only. In conclusion, EGF and IGF-I act on COCs from small follicles to accelerate the meiotic cell cycle of the oocytes. This accelerating effect may be related to increased H1 and MAP kinase activities during the early stages of maturation.

scholarly journals Inhibition of Ethanol Neurotoxicity by Treatment with Growth Factors and Estrogen

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jason Zell ◽  
Jeremy Montague ◽  
Tomas Lopez ◽  
Mudd Laura
Keyword(s):  
Growth Factors ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Ethanol Ingestion ◽  
Fetal Alcohol ◽  
Simultaneous Treatment ◽  
Nerve Growth ◽  
Neuronal Viability ◽  
Igf I

Ethanol ingestion by pregnant women is the primary cause of fetal alcohol syndrome, which is characterized by brain abnormalities and decreased mental capacity. In the present study,cultured neurons from embryonic rat cortices were used to study the effects of ethanol on cell survival and the potential for neuroprotection by certain growth factors and estrogen. Neurons were grown in the presence of a glial plane and in the absence of serum. Survival was assessed following chronic treatment with ethanol (45 mM) in the presence and absence of either nerve growth factor (NGF, 100ng/ml), basic fibroblast growth factor (bFGF, 5ng/ml), insulin-like growth factor I or II (IGF-I, IGF-II, both 10ng/ml), or estrogen (Es, 10nM) added on days one and four in vitro. On day in vitro 4 (DIV4) ethanol effects on neuronal viability were significantly prevented by NGF, bFGF, IGF-I, and Es. DIV6 survival of ethanol-treated neurons was increased significantly by treatment with NGF, bFGF, IGF-I, IGF-II, and Es. Nerve growth factor, bFGF, and IGF-I effects were shown to be dose-dependent. Administration of 1-100 ng/ml NGF, 0.05-5 ng/ml bFGF and 0.1-10ng/ml IGF-I led to statistically significant effects at 10, 5, and 1 ng/ml, respectively. Thus, ethanol’s effect on neuronal survival may be inhibited by simultaneous treatment with physiological doses of these factors.

Effects of local growth factors on the secretory function of bovine corpus luteum during the oestrous cycle and pregnancy in vitro

1996 ◽  
Vol 8 (6) ◽  
pp. 1003 ◽  
Author(s):  
J Liebermann ◽  
D Schams ◽  
A Miyamoto
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Corpus Luteum ◽  
Luteal Phase ◽  
Late Pregnancy ◽  
Oestrous Cycle ◽  
Tnf Alpha ◽  
Igf I ◽  
Factor Alpha

The impact of insulin-like growth factor-I (IGF-I) basic fibroblast growth factor (bFGF), endothelin-1 (ET-1), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-alpha (TGF-alpha) and platelet-derived growth factor (PDGF) on the release of progesterone (P4) and oxytocin (OT) from individual bovine corpora lutea at different stages of the oestrous cycle and pregnancy was evaluated with a microdialysis system (MDS) in vitro. IGF-I (1 microgram mL-1) induced significantly the acute effects on P4 release at the late luteal stage (Days 15-18) and early pregnancy (Days 60-120), whereas bFGF (100 ng mL-1) was extremely effective in stimulating P4 release particularly during the mid-luteal stage (Days 8-12). Both peptides stimulated (P < 0.05) the release of OT throughout the three luteal stages and during early and late pregnancy (Days 30-60 and Days 150-210). ET-1 (100 ng mL-1) clearly inhibited P4 release during the early (Days 5-7) and mid-luteal phase and stimulated OT release only during the mid-luteal stage (P < 0.001). TNF-alpha (100 ng mL-1) stimulated the release of P4 exclusively at the early luteal phase (P < 0.05), whereas OT secretion was increased by TNF-alpha during all stages of the oestrous cycle (P < 0.001). TGF-alpha and PDGF (100 ng mL-1) were effective in stimulating P4 release particularly during late pregnancy (P < 0.05). In contrast, stimulation of OT secretion by TGF-alpha was maximal during the late-luteal stage (P < 0.001), whereas PDGF significantly increased OT secretion during the oestrous cycle (except the early luteal stage) and pregnancy (P < 0.001). The data demonstrate distinct and stage-specific effects of growth factors on P4 and OT secretion in vitro. IGF-I, bFGF and TGF-alpha may play an important role in corpus luteum (CL) function during the oestrous cycle and pregnancy since they are locally expressed and synthesized, there are receptors for these growth factors, and they have been demonstrated to exert biological effects on the CL.

scholarly journals Σχεδιασμός, σύνθεση και αξιολόγηση νανοσωματιδίων με εγκλωβισμό πεπτιδίων των πρωτεινών της μυελίνης

2021 ◽  
Author(s):  
Ηρώ Τριανταφυλλάκου
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Glycolic Acid ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Το αντικείμενο της παρούσας ΔΔ ήταν η ανάπτυξη πολυμερικών νανοσωματιδίων με εγκλωβισμένα πεπτιδικά ανάλογα που εμπλέκονται στην εμφάνιση και εξέλιξη της σκλήρυνσης κατά πλάκας (ΣΚΠ, Multiple Sclerosis, MS), καθώς και η βιολογική αξιολόγηση αυτών. Συγκεκριμένα, αναπτύχθηκαν σωματίδια πολυ(γλυκολικού-γαλακτικού) οξέος [poly(lactic-co-glycolic) acid, PLGA] με εγκλωβισμένα πεπτίδια με βάση τον επίτοπο 35-55 της μυελικής γλυκοπρωτεΐνης των ολιγοδενδριτών (Myelin Oligodendrocyte Glycoprotein, ΜΟG) με βάση την αλληλουχία που συναντάται στους μύες (rMOG), συζευγμένα ή μη με μόρια σακχαριτών. Η σύζευξη των πεπτιδικών αναλόγων με μόρια σακχαριτών όπως η μαννόζη και η γλυκοζαμίνη στόχευσε στην πιθανή αλληλεπίδραση με τους υποδοχείς μαννόζης που βρίσκονται στα δενδριτικά κύτταρα, κύρια αντιγονοπαρουσιαστικά κύτταρα που εμπλέκονται στην ΣΚΠ, με τους οποίους υποδοχείς παρουσιάζουν ισχυρή προσδετική ικανότητα και με σκοπό την ανάπτυξη ανοσοανοχής απέναντι στην νόσο.Η διατριβή περιλαμβάνει τον σχεδιασμό και την ανάπτυξη PLGA νανοσωματιδίων που θα φέρουν εγκλωβισμένα τα πεπτιδικά ανάλογα, παρέχοντας αυξημένη σταθερότητα στα πεπτιδικά ανάλογα και παρέχοντας την δυνατότητα βραδείας αποδέσμευσης από την πολυμερική μήτρα. Τα νανοσωματίδια που αναπτύχθηκαν μελετήθηκαν ως προς τα φυσικοχημικά τους χαρακτηριστικά ώστε να βελτιστοποιηθεί η μεθοδολογία σύνθεσης. Επιπλέον, πραγματοποιήθηκε μελέτη της βραδείας αποδέσμευσης και ποσοτικός προσδιορισμός τόσο της αρχικά εγκλωβισμένης ουσίας όσο και της ημερήσιας αποδέσμευσης σε φυσιολογικό ορό in vitro. Τέλος, τα συντεθειμένα νανοσωματίδια αξιολογήθηκαν βιολογικά in vivo στο πειραματικό μοντέλο της ΣΚΠ, την πειραματική αυτοάνοση εγκεφαλομυελίτιδα (Experimental Autoimmune Encephalomyelitis, EAE) με χρήση δύο μοντέλων ανοσοποίησης, προφυλακτικού και θεραπευτικού σε θηλυκούς μύες του γένους C57BL/6. Οι ιστοί που ελήφθησαν από τους μύες μελετήθηκαν για διηθήσεις και καταστροφές της λευκής ουσίας που οφείλονται στην ασθένεια ενώ μελετήθηκαν και τα επίπεδα κυτταροκινών στον ορό αίματος στα διάφορα στάδια εξέλιξης της νόσου.

scholarly journals IFP35 family proteins promote neuroinflammation and multiple sclerosis

2021 ◽  
Vol 118 (32) ◽  
pp. e2102642118
Author(s):  
Xizhong Jing ◽  
Yongjie Yao ◽  
Danning Wu ◽  
Hao Hong ◽  
Xu Feng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Immune Cells ◽  
Neutralizing Antibodies ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Multiple Cells ◽  
Excessive Activation ◽  
Experimental Autoimmune

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

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