1,354,926 research outputs found
Painless Nerve Growth Factor: A TrkA biased agonist mediating a broad neuroprotection via its actions on microglia cells
No full textNerve Growth Factor (NGF) is a therapeutic candidate for Alzheimer's disease, based on its well known actions on basal forebrain cholinergic neurons. However, because of its pro-nociceptive activity, in current clinical trials NGF has to be administered intraparenchymally into the brain by neurosurgery via cell or gene therapy approaches. To prevent the NGF pain-inducing collateral effects, thus avoiding the necessity for local brain injection, we developed painless NGF (hNGFp), based on the human genetic disease Hereditary Sensory and Autonomic Neuropathy type V (HSAN V). hNGFp has similar neurotrophic activity as wild type human NGF, but its pain sensitizing activity is tenfold lower. Pharmacologically, hNGFp is a biased receptor agonist of NGF TrkA receptor. The results of recent studies shed new light on the neuroprotective mechanism by hNGFp and are highly relevant for the planning of NGF-based clinical trials. The intraparenchymal delivery of hNGFp, as used in clinical trials, was simulated in the 5xFAD mouse model and found to be inefficacious in reducing Aβ plaque load. On the contrary, the same dose of hNGFp administered intranasally, which was rather widely biodistributed in the brain and did not induce pain sensitization, blocked APP processing into amyloid and restored synaptic plasticity and memory in this aggressive neurodegeneration model. This potent and broad neuroprotection by hNGFp was found to be mediated by hNGFp actions on glial cells. hNGFp increases inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. Independent work has shown that NGF has a potent anti-inflammatory action on microglia and steers them towards a neuroprotective phenotype. These studies demonstrate that microglia cells are a new target cell of NGF in the brain and have therapeutic significance: i) they establish that the neuroprotective actions of hNGFp relies on a widespread exposure of the brain, ii) they identify a new anti-neurodegenerative pathway, linking hNGFp to inflammatory chemokines and cytokines via microglia, a common target for new therapeutic opportunities for neurodegenerative diseases, iii) they extend the neuroprotective potential of hNGFp beyond its classical cholinergic target, thereby widening the range of neurological diseases for which this neurotrophic factor might be used therapeutically, iv) they help interpreting the results of current NGF clinical trials in AD and the design of future trials with this new potent therapeutic candidate
Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells
No full textIntroduction: The melanocortin peptides have marked anti-inflammatory potential, primarily through inhibition of proinflammatory cytokine production and action on phagocytic cell functions. Gout is an acute form of arthritis caused by the deposition of urate crystals, in which phagocytic cells and cytokines play a major pathogenic role. We examined whether alpha-melanocyte-stimulating hormone (α-MSH) and its synthetic derivative (CKPV)2 influence urate crystal-induced monocyte (Mo) activation and neutrophil responses in vitro.Methods: Purified Mos were stimulated with monosodium urate (MSU) crystals in the presence or absence of melanocortin peptides. The supernatants were tested for their ability to induce neutrophil activation in terms of chemotaxis, production of reactive oxygen intermediates (ROIs), and membrane expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The proinflammatory cytokines interleukin (IL)-1β, IL-8, and tumor necrosis factor-alpha (TNF-α) and caspase-1 were determined in the cell-free supernatants. In parallel experiments, purified neutrophils were preincubated overnight with or without melanocortin peptides before the functional assays.Results: The supernatants from MSU crystal-stimulated Mos exerted chemoattractant and priming activity on neutrophils, estimated as ROI production and CD11b membrane expression. The supernatants of Mos stimulated with MSU in the presence of melanocortin peptides had less chemoattractant activity for neutrophils and less ability to prime neutrophils for CD11b membrane expression and oxidative burst. MSU crystal-stimulated Mos produced significant levels of IL-1β, IL-8, TNF-α, and caspase-1. The concentrations of proinflammatory cytokines, but not of caspase-1, were reduced in the supernatants from Mos stimulated by MSU crystals in the presence of melanocortin peptides. Overnight incubation of neutrophils with the peptides significantly inhibited their ability to migrate toward chemotactic supernatants and their capacity to be primed in terms of ROI production.Conclusions: α-MSH and (CKPV)2 have a dual effect on MSU crystal-induced inflammation, inhibiting the Mos' ability to produce neutrophil chemoattractants and activating compounds and preventing the neutrophil responses to these proinflammatory substances. These findings reinforce previous observations on the potential role of α-MSH and related peptides as a new class of drugs for treatment of inflammatory arthritis. © 2009 Capsoni et al.; licensee BioMed Central Ltd
Getting Into the Brain: The Intranasal Approach to Enhance the Delivery of Nerve Growth Factor and Its Painless Derivative in Alzheimer’s Disease and Down Syndrome
No full textThe neurotrophin Nerve Growth Factor (NGF) holds a great potential as a therapeutic candidate for the treatment of neurological diseases. However, its safe and effective delivery to the brain is limited by the fact that NGF needs to be selectively targeted to the brain, to avoid severe side effects such as pain and to bypass the blood brain barrier. In this perspective, we will summarize the different approaches that have been used, or are currently applied, to deliver NGF to the brain, during preclinical and clinical trials to develop NGF as a therapeutic drug for Alzheimer’s disease. We will focus on the intranasal delivery of NGF, an approach that is used to deliver proteins to the brain in a non-invasive, safe, and effective manner minimizing systemic exposure. We will also describe the main experimental facts related to the effective intranasal delivery of a mutant form of NGF [painless NGF, human nerve growth factor painless (hNGFp)] in mouse models of Alzheimer’s disease and compare it to other ways to deliver NGF to the brain. We will also report new data on the application of intranasal delivery of hNGFp in Down Syndrome mouse model. These new data extend the therapeutic potential of hNGFp for the treatment of the dementia that is progressively associated to Down Syndrome. In conclusion, we will show how this approach can be a promising strategy and a potential solution for other unmet medical needs of safely and effectively delivering this neuroprotective neurotrophin to the brain
Design of novel inverse analysis methodology for exact estimation of elasticity parameters in thermoelastic stress model
No full textThis paper presents general outlines of the research conducted in the applied mathematics field, -the theory of inverse problems, specifically utilized for the thermoelastic stress analysis model for exact estimation of thermoelasticity parameters. We present formulation of the well posed direct mathematical model that depicts general interconnections between physically governed fields for thermally heated plate subjected to fixed constrains on the boundaries with small deformations from thermal expansion over the homogeneous multilayered medium domain. Applying elements of variational calculus, functional analysis and fractional order derivatives, we demonstrate the derivation of the conjugate problem and analytical expressions used for exact estimation of structural material thermoelastic properties. The novelty of proposed methodology lies in derivation of exact estimators that could be utilized for general homogenized thermoelastic model with finite amount of sampled temperature measurements on the domain outlets. It also opens curtains over the key issues and some important aspects aroused in the derivation procedures of exact estimators for general problem statement. There were posed and discussed necessary conditions in a form of a working hypothesizes. Results may be utilized as an experimental technique designed to obtain an essential information on the surface stress field along with the thermoelastic material properties
BDNF intranasal administration rescues visual memory deficits in a mouse model of Alzheimer disease (AD), the AD11 mouse
No full textWe have recently demonstrated that environmental enrichment (EE) starting after the onset of behavioural deficits and the appearance of AD neuropathological hallmarks rescues visual memory (VM) deficits in aged AD11 mice (Berardi et al., 2006). AD11 mice, which express anti nerve growth factor (NGF) antibodies, develop an age dependent neurodegeneration which encompasses all hallmarks of human AD and appear to be a comprehensive mouse model for sporadic AD (Capsoni et al., 2000). The mechanisms underlying these beneficial effects of EE in AD11 mice are still unknown. It has been suggested that a crucial component of EE effects is the increase in neurotrophin (NT) expression found in the brain of EE animals. NT are considered potentially useful therapeutic agents in neurodegenerative diseases, given their control of cortical plasticity and their neuroprotective actions. A non invasive intranasal route to administer a NT, NGF, to the brain of AD11 mice has been recently employed, leading to a rescue of neuropathological markers (Capsoni et al 2002), as well as of VM deficits (De Rosa et al., 2005) in AD11 mice. We now tested whether BDNF intranasal administration, starting after the onset of cognitive and anatomical deficits, could rescue VM deficits in aged AD11 mice. We found that intranasal administration of BDNF for two weeks rescues VM deficits both at the 1 h and 24 hours retention interval. All BDNF treated animals showed a strong increase in their performance with respect to the ”before treatment” assessement. By converse, PBS treated, control AD11 mice showed no improvement, remaining at the very low performance levels typical of 7 months old AD11 mice. These results show that it is possible to revert the progression of cognitive decline in a mouse model of AD by non invasive intranasal administration of BDNF and suggest that BDNF increase found in EE animals is a crucial factor for the beneficial effects of EE in AD animal models. Telethon grant GGP030416
Cholinesterase inhibitors with a nicotinic mode of action: Neuroprotection in anti-NGF mice
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