Browsing by Subject "NERVE GROWTH-FACTOR"

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  • Diniz, Cassiano R.A.F.; Casarotto, Plinio C.; Resstel, Leonardo; Samia, R.L. Joca (2018)
    Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress.
  • Pham, Dan Duc; Bruelle, Celine; Do, Hai Thi; Pajanoja, Ceren; Jin, Congyu; Olkkonen, Vesa M.; Eriksson-Rosenberg, Ove; Jauhiainen, Matti; Lalowski, Maciej; Lindholm, Dan (2019)
    Lipid-induced toxicity is part of several human diseases, but the mechanisms involved are not fully understood. Fatty liver is characterized by the expression of different growth and tissue factors. The neurotrophin, nerve growth factor (NGF) and its pro-form, pro-NGF, are present in fatty liver together with p75 neurotrophin receptor (p75NTR). Stimulation of human Huh7 hepatocyte cells with NGF and pro-NGF induced Sterol-regulator-element-binding protein-2 (SREBP2) activation and increased Low-Density Lipoprotein Receptor (LDLR) expression. We observed that phosphorylation of caspase-2 by p38 MAPK was essential for this regulation involving a caspase-3-mediated cleavage of SREBP2. RNA sequencing showed that several genes involved in lipid metabolism were altered in p75NTR-deficient mouse liver. The same lipogenic genes were downregulated in p75NTR gene-engineered human Huh7 cells and reciprocally upregulated by stimulation of p75NTRs. In the knock-out mice the serum cholesterol and triglyceride levels were reduced, suggesting a physiological role of p75NTRs in whole-body lipid metabolism. Taken together, this study shows that p75NTR signaling influences a network of genes involved in lipid metabolism in liver and hepatocyte cells. Modulation of p75NTR signaling may be a target to consider in various metabolic disorders accompanied by increased lipid accumulation.
  • Veronese, N.; Sergi, G.; Stubbs, B.; Bourdel-Marchasson, I.; Tessier, D.; Sieber, C.; Strandberg, T.; Gillain, S.; Barbagallo, M.; Crepaldi, G.; Maggi, S.; Manzato, E.; EUGMS Special Interest Grp Diabet (2017)
    Background/aim: Deficiency of acetyl-L-carnitine (ALC) and L-carnitine (LC) appears to play a role in peripheral diabetic neuropathy, although the evidence in humans is still limited. We conducted a systematic review and meta-analysis investigating the effect of ALC on pain and electromyographic parameters in people with diabetic neuropathy. Methods: A literature search in major databases, without language restriction, was undertaken. Eligible studies were randomized controlled trials (RCTs) or pre-and post-test studies. The effect of ALC supplementation on pain perception and electromyographic parameters in patients with diabetic neuropathy was compared vs. a control group (RCTs). The effect of ALC/LC on electromyographic parameters were also calculated vs. baseline values. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were used for summarizing outcomes. Results: Six articles, with a total of 711 diabetic participants, were included. Three RCTs (340 treated with ALC vs. 203 placebo and 115 with methylcobalamine) showed that ALC reduces pain perception (SMD = -0.45; 95% CI: -0.86 to -0.04; P = 0.03; I-2 = 85%). Compared to controls, ALC supplementation improved nerve conduction velocity and amplitude response for ulnar nerve (both sensory and motor component). Compared to baseline values, ALC/LC supplementation improved nerve conduction velocity for all the sensory and motor nerves (except ulnar and peroneal) investigated and the amplitude of all nerves. The onset of adverse events was generally limited to minor side effects. Conclusion: ALC appears to be effective in reducing pain due to diabetic neuropathy compared to active or placebo controls and improving electromyographic parameters in these patients. (C) 2017 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
  • Moquin, Alexandre; Ji, Jeff; Neibert, Kevin; Winnik, Francoise M.; Maysinger, Dusica (2018)
    Polymersomes are attractive nanocarriers for hydrophilic and lipophilic drugs; they are more stable than liposomes, tunable, and relatively easy to prepare. The copolymer composition and molar mass are critical features that determine the physicochemical properties of the polymersomes including the rate of drug release. We used the triblockcopolymer, poly(2-methyl-2-oxazoline)-block-poly-(dimethysiloxane)-block-poly(2-methyl-2-oxazoline) (PIVIOXA-PDIVIS-PMOXA), to form amphipathic polymersomes capable of loading proteins and small hydrophobic agents. The selected agents were unstable neurotrophins (nerve growth factor and brain -derived neurotrophic factor), a large protein CD109, and the fluorescent drug curcumin. We prepared, characterized, and tested polymersomes loaded with selected agents in 2D and 3D biological models. Curcumin-loaded and rhodamine-bound PMOXA-PDMS-PMOXA polymersomes were used to visualize them inside cells. NMethyl-D-aspartate receptor (NNIDAR) agonists and antagonists were also covalently attached to the surface of polymersomes for targeting neurons. Labeled and unlabeled polymersomes with or without loaded agents were characterized using dynamic light scattering (DLS), UV-vis fluorescence spectroscopy, and asymmetrical flow field-flow fractionation (AF(4)). Polymersomes were imaged and tested for biological activity in human and murine fibroblasts, murine macrophages, primary murine dorsal root ganglia, and murine hippocampal cultures. Polymersomes were rapidly internalized and there was a clear intracellular co-localization of the fluorescent drug (curcumin) with the fluorescent rhodamine-labeled polymersomes. Polymersomes containing CD109, a glycosylphosphatidylinositol-anchored protein, promoted cell migration in the model of wound healing. Nerve growth factor-loaded polymersomes effectively enhanced neurite outgrowth in dissociated and explanted dorsal root ganglia. Brain -derived neurotrophic factor increased dendritic spine density in serum-deprived hippocampal slice cultures. NMDAR agonist-and antagomst-functionalized polymersomes targeted selectively neurons over filial cells in mixed cultures. Collectively, the study reveals the successful incorporation into polymersomes of biologically active trophic factors and small hydrophilic agents that retain their biological activity in vitro, as demonstrated in selected central and peripheral tissue models.
  • Korpi, Esa R.; Lindholm, Dan; Panula, Pertti; Tienari, Pentti J.; Haltia, Matti (2020)
  • Mitra, Sumonto; Turconi, Giorgio; Darreh-Shori, Taher; Mätlik, Kärt; Aquilino, Matilde; Eriksdotter, Maria; Andressoo, Jaan-Olle (2021)
    Gradual decline in cholinergic transmission and cognitive function occurs during normal aging, whereas pathological loss of cholinergic function is a hallmark of different types of dementia, including Alzheimer's disease (AD), Lewy body dementia (LBD), and Parkinson's disease dementia (PDD). Glial cell line-derived neurotrophic factor (GDNF) is known to modulate and enhance the dopamine system. However, how endogenous GDNF influences brain cholinergic transmission has remained elusive. In this study, we explored the effect of a twofold increase in endogenous GDNF (Gdnf hypermorphic mice, Gdnf(wt/hyper)) on cholinergic markers and cognitive function upon aging. We found that Gdnf(wt/hyper) mice resisted an overall age-associated decline in the cholinergic index observed in the brain of Gdnf(wt/wt) animals. Biochemical analysis revealed that the level of nerve growth factor (NGF), which is important for survival and function of central cholinergic neurons, was significantly increased in several brain areas of old Gdnf(wt/hyper) mice. Analysis of expression of genes involved in cholinergic transmission in the cortex and striatum confirmed modulation of cholinergic pathways by GDNF upon aging. In line with these findings, Gdnf(wt/hyper) mice did not undergo an age-related decline in cognitive function in the Y-maze test, as observed in the wild type littermates. Our results identify endogenous GDNF as a potential modulator of cholinergic transmission and call for future studies on endogenous GDNF function in neurodegenerative disorders characterized by cognitive impairments, including AD, LBD, and PDD.
  • Umemori, Juzoh; Winkel, Frederike; Didio, Giuliano; Pou, Maria Llach; Castren, Eero (2018)
    The network hypothesis of depression proposes that mood disorders reflect problems in information processing within particular neural networks. Antidepressants (AD), including selective serotonin reuptake inhibitors (SSRI), function by gradually improving information processing within these networks. AD have been shown to induce a state of juvenile-like plasticity comparable to that observed during developmental critical periods: Such critical-period-like plasticity allows brain networks to better adapt to extrinsic and intrinsic signals. We have coined this drug-induced state of juvenile-like plasticity iPlasticity.' A combination of iPlasticity induced by chronic SSRI treatment together with training, rehabilitation, or psychotherapy improves symptoms of neuropsychiatric disorders and issues underlying the developmentally or genetically malfunctioning networks. We have proposed that iPlasticity might be a critical component of AD action. We have demonstrated that iPlasticity occurs in the visual cortex, fear erasure network, extinction of aggression caused by social isolation, and spatial reversal memory in rodent models. Chronic SSRI treatment is known to promote neurogenesis and to cause dematuration of granule cells in the dentate gyrus and of interneurons, especially parvalbumin interneurons enwrapped by perineuronal nets in the prefrontal cortex, visual cortex, and amygdala. Brain-derived neurotrophic factor (BDNF), via its receptor tropomyosin kinase receptor B, is involved in the processes of synaptic plasticity, including neurogenesis, neuronal differentiation, weight of synapses, and gene regulation of synaptic formation. BDNF can be activated by both chronic SSRI treatment and neuronal activity. Accordingly, the BDNF/tropomyosin kinase receptor B pathway is critical for iPlasticity, but further analyses will be needed to provide mechanical insight into the processes of iPlasticity.
  • Huhtaniska, Sanna; Jaaskelainen, Erika; Heikka, Tuomas; Moilanen, Jani S.; Lehtiniemi, Heli; Tohka, Jussi; Manjon, Jose V.; Coupe, Pierrick; Bjornholm, Lassi; Koponen, Hannu; Veijola, Juha; Isohanni, Matti; Kiviniemi, Vesa; Murray, Graham K.; Miettunen, Jouko (2017)
    High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.
  • Suleimanova, Alina; Talanov, Max; Gafurov, Oleg; Gafarov, Fail; Koroleva, Ksenia; Virenque, Anais; Noe, Francesco M.; Mikhailov, Nikita; Nistri, Andrea; Giniatullin, Rashid (2020)
    Extracellular ATP and serotonin (5-HT) are powerful triggers of nociceptive firing in the meninges, a process supporting headache and whose cellular mechanisms are incompletely understood. The current study aimed to develop, with the neurosimulator NEURON, a novel approach to explore in silico the molecular determinants of the long-lasting, pulsatile nature of migraine attacks. The present model included ATP and 5-HT release, ATP diffusion and hydrolysis, 5-HT uptake, differential activation of ATP P2X or 5-HT3 receptors, and receptor subtype-specific desensitization. The model also tested the role of branched meningeal fibers with multiple release sites. Spike generation and propagation were simulated using variable contribution by potassium and sodium channels in a multi-compartment fiber environment. Multiple factors appeared important to ensure prolonged nociceptive firing potentially relevant to long-lasting pain. Crucial roles were observed in: (i) co-expression of ATP P2X2 and P2X3 receptor subunits; (ii) intrinsic activation/inactivation properties of sodium Nav1.8 channels; and (iii) temporal and spatial distribution of ATP/5-HT release sites along the branches of trigeminal nerve fibers. Based on these factors we could obtain either persistent activation of nociceptive firing or its periodic bursting mimicking the pulsating nature of pain. In summary, our model proposes a novel tool for the exploration of peripheral nociception to test the contribution of clinically relevant factors to headache including migraine pain.
  • Castren, E.; Antila, H. (2017)
    Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs activate neurotrophin signaling and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate; the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of currently existing drugs into new indications.
  • Bondarenko, Olesja; Saarma, Mart (2021)
    Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood-brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision "ideal" NTF for Parkinson's disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed.
  • Mueller-Schwefe, Gerhard; Ahlbeck, Karsten; Aldington, Dominic; Alon, Eli; Coaccioli, Stefano; Coluzzi, Flaminia; Huygen, Frank; Jaksch, Wolfgang; Kalso, Eija; Kocot-Kepska, Magdalena; Kress, Hans-Georg; Mangas, Ana Cristina; Ferri, Cesar Margarit; Morlion, Bart; Nicolaou, Andrew; Perez Hernandez, Concepcion; Pergolizzi, Joseph; Schaefer, Michael; Sichere, Patrick (2014)
  • Fred, Senem Merve; Laukkanen, Liina; Brunello, Cecilia A.; Vesa, Liisa; Göös, Helka; Cardon, Iseline; Moliner, Rafael; Maritzen, Tanja; Varjosalo, Markku; Casarotto, Plinio C.; Castren, Eero (2019)
    Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB activation. Here, using MS, we found that a single intraperitoneal injection of fluoxetine disrupts the interaction of several proteins with TRKB in the hippocampus of mice. These proteins included members of adaptor protein complex-2 (AP-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking ? subunit of the AP-2 complex (AP2M) was confirmed to be disrupted by both acute and repeated fluoxetine treatments. Of note, fluoxetine disrupted the coupling between full-length TRKB and AP2M, but not the interaction between AP2M and the TRKB C-terminal region, indicating that the fluoxetine-binding site in TRKB lies outside the TRKB:AP2M interface. ELISA experiments revealed that in addition to fluoxetine, other chemically diverse antidepressants, such as imipramine, rolipram, phenelzine, ketamine, and its metabolite 2R,6R-hydroxynorketamine, also decreased the interaction between TRKB and AP2M in vitro. Silencing the expression of AP2M in a TRKB-expressing mouse fibroblast cell line (MG87.TRKB) increased cell-surface expression of TRKB and facilitated its activation by brain-derived neurotrophic factor (BDNF), observed as levels of phosphorylated TRKB. Moreover, animals haploinsufficient for the Ap2m1 gene displayed increased levels of active TRKB, along with enhanced cell-surface expression of the receptor in cultured hippocampal neurons. Taken together, our results suggest that disruption of the TRKB:AP2M interaction is a common mechanism underlying TRKB activation by several chemically diverse antidepressants.
  • Rantamäki, Tomi; Kemppainen, Susanna; Autio, Henri; Staven, Saara; Koivisto, Hennariikka; Kojima, Masami; Antila, Hanna; Miettinen, Pasi O.; Kärkkäinen, Elisa; Karpova, Nina; Vesa, Liisa; Lindemann, Lothar; Hoener, Marius C.; Tanila, Heikki; Castren, Eero (2013)