A synthetic NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo

Protein Laboratory, Institute of Molecular Pathology, Panum Institute, University of Copenhagen, Blegdamsvej 3C, bld. 6.2, DK-2200 Copenhagen N, Denmark.
European Journal of Neuroscience (Impact Factor: 3.18). 11/2005; 22(7):1589-96. DOI: 10.1111/j.1460-9568.2005.04345.x
Source: PubMed


There is a major unmet need for development of innovative strategies for neuroprotection against ischemic brain injury. Here we show that FGL, a neural cell adhesion molecule (NCAM)-derived peptide binding to and inducing phosphorylation of the fibroblast growth factor receptor (FGFR), acts neuroprotectively after an ischemic insult both in vitro and in vivo. The neuroprotective activity of FGL was tested in vitro on dissociated rat hippocampal neurons and hippocampal slice cultures, using a protocol of oxygen-glucose deprivation (OGD). FGL protected hippocampal neurons from damage and maintained or restored their metabolic and presynaptic activity, both if employed as a pretreatment alone to OGD, and if only applied after the insult. In vivo 24 h pretreatment with a single suboccipital injection of FGL significantly protected hippocampal CA1 neurons from death in a transient global ischemia model in the gerbil. We conclude that FGL promotes neuronal survival after ischemic brain injury.

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    • "FGL has been shown to be neuroprotective in a range of pathological situations in vitro [24], and in vivo in the aged rodent [25]–[27], the ischemic male Mongolian gerbil model [28] and, of particular interest for the current study, in the cingulate cortex and CA3 of the amyloid beta25–35 (Aβ25–35-)-injected rat brain [21]. The NCAM-derived peptide has also been shown to be anti-inflammatory both in vitro and in vivo, particularly in the aged rat hippocampus [26], [29], [30], and a cognitive enhancer [28], [31], [32]. All the effects of FGL have been dependent on the activation of FGFR1 and FGFR2 rather than NCAM-induced signalling [24]. "
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    ABSTRACT: Increased levels of neurotoxic amyloid-beta in the brain are a prominent feature of Alzheimer's disease. FG-Loop (FGL), a neural cell adhesion molecule-derived peptide that corresponds to its second fibronectin type III module, has been shown to provide neuroprotection against a range of cellular insults. In the present study impairments in social recognition memory were seen 24 days after a 5 mg/15 µl amyloid-beta(25-35) injection into the right lateral ventricle of the young adult rat brain. This impairment was prevented if the animal was given a systemic treatment of FGL. Unbiased stereology was used to investigate the ability of FGL to alleviate the deleterious effects on CA1 pyramidal cells of the amyloid-beta(25-35) injection. NeuN, a neuronal marker (for nuclear staining) was used to identify pyramidal cells, and immunocytochemistry was also used to identify inactive glycogen synthase kinase 3beta (GSK3β) and to determine the effects of amyloid-beta(25-35) and FGL on the activation state of GSK3β, since active GSK3β has been shown to cause a range of AD pathologies. The cognitive deficits were not due to hippocampal atrophy as volume estimations of the entire hippocampus and its regions showed no significant loss, but amyloid-beta caused a 40% loss of pyramidal cells in the dorsal CA1 which was alleviated partially by FGL. However, FGL treatment without amyloid-beta was also found to cause a 40% decrease in CA1 pyramidal cells. The action of FGL may be due to inactivation of GSK3β, as an increased proportion of CA1 pyramidal neurons contained inactive GSK3β after FGL treatment. These data suggest that FGL, although potentially disruptive in non-pathological conditions, can be neuroprotective in disease-like conditions.
    PLoS ONE 08/2013; 8(8):e71479. DOI:10.1371/journal.pone.0071479 · 3.23 Impact Factor
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    • "Cultured embryonic rat neurons constitute an accepted and relevant model system in the scientific community and have been widely used to evaluate the effects of pharmacologic and genetic interventions. Moreover, well-described culturing protocols and procedures for phenotypic characterization of cultures of embryonal rat neurons exist (Araujo et al. 2004; Burkarth et al. 2007; Busciglio et al. 1995; Cambon et al. 2004; Maar et al. 1997; Neiiendam et al. 2004; Skibo et al. 2005; Walicke et al. 1986). The following morphometric parameters were measured: the number of viable neurons, neurite outgrowth and synaptic connectivity. "
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    ABSTRACT: The recently described therapeutic benefits of the hemodialysate actovegin on neuropathic symptoms in diabetic patients with symptomatic polyneuropathy suggest a neuroprotective activity of the drug. To elucidate the possible cellular mechanism of the pharmacological effects of actovegin, we investigated its effects on cultured primary rat neurons in vitro. Primary neurons were cultured for up to 10 days in the presence of increasing doses of actovegin (0.3-1,000 mg/l). Total cell number, dendrite length and the number of excitatory synapses, i.e., the amount of the synaptic V-Glut1 protein, were measured by immunocytochemistry followed by fluorescence microscopy. The apoptotic level in neurons after induction of apoptosis by amyloid peptide Aβ(25-35) was assessed by the level of activated caspase-3. In addition, the capability of the neurons to diminish oxidative stress was assessed by measuring the cellular level of reactive oxygen species ROS in the presence of actovegin. Actovegin treatment yielded an increased maintenance of neuronal cells and total number of synapses and could lower the level of activated caspase-3 in a dose-dependent manner. Dendrite lengths were not significantly affected. In addition, actovegin reduced the cellular level of ROS in cultured neurons. The cellular effects observed suggest neuroprotective and anti-oxidative effects of the drug Actovegin(®), which could at least partially explain its therapeutic benefits.
    Neuromolecular medicine 12/2011; 13(4):266-74. DOI:10.1007/s12017-011-8157-7 · 3.68 Impact Factor
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    • "Our results provide convincing evidence to support a role for FGL in inhibiting age-related glial cell activation within the aged brain. FGL has been shown to restore cognitive function, enhance memory and avert neuropathology in models of ageing and age-related diseases (Cambon et al., 2004; Downer et al., 2010; Klementiev et al., 2007; Neiiendam et al., 2004; Popov et al., 2008; Skibo et al., 2005; Stewart et al., 2010). Together with its anti-inflammatory properties (Downer et al., 2009, 2010) our data highlight the potential for FGL to combat age-related changes in the brain, warranting further investigation into its therapeutic potential to alleviate age-related cognitive dysfunction . "
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    ABSTRACT: Neuroglial activation is a typical hallmark of ageing within the hippocampus, and correlates with age-related cognitive deficits. We have used quantitative immunohistochemistry and morphometric analyses to investigate whether systemic treatment with the Neural Cell Adhesion Molecule (NCAM)-derived peptide FG Loop (FGL) specifically alters neuroglial activation and population densities within the aged rat hippocampus (22 months of age). A series of 50 μm paraformaldehyde/acrolein-fixed sections taken throughout the dorsal hippocampus (5 animals per group) were immunostained to detect astrocytes (GFAP and S100ß) and microglial cells (CD11b/OX42 and MHCII/OX6), and analysed using computerised image analysis and optical segmentation (Image-Pro Plus, Media Cybernetics). FGL treatment reduced the density of CD11b+ and MHCII+ microglia in aged animals, concomitant with a reduction in immunoreactivity for these phenotypic markers. FGL treatment also markedly reduced GFAP immunoreactivity within all hippocampal subfields in aged animals, without exerting an appreciable effect on the density of S100ß+ cells. These results demonstrate that FGL can indeed regulate neuroglial activation and reduce microglial cell density in the aged hippocampus, and support its potential use as a therapeutic agent in age-related brain disorders.
    Experimental Neurology 12/2011; 232(2):318-28. DOI:10.1016/j.expneurol.2011.09.025 · 4.70 Impact Factor
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