Nordihydroguaiaretic Acid Affects Undifferentiated and Differentiated Neuroblastoma Cells Differently through Mechanisms that Impact on Cell Viability.

Aim: We aimed to investigate the mechanisms involved in the neurotoxic effects of NDGA on differentiated and undifferentiated human neuroblastoma cells (MSN), assessing cell viability, changes in the actin cytoskeleton, cell migration and the expression of the 5-LOX enzyme and the inhibitor of cell cycle progression p21.

Background: High expression and activity of the lipoxygenase enzyme (LOX) have been detected in several tumors, including neuroblastoma samples, suggesting the use of LOX inhibitors as potential therapy molecules. Among these, the natural compound nordihydroguaiaretic acid (NDGA) has been extensively tested as an antiproliferative drug against diverse types of cancer cells.

Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production.

The high consumption of saturated lipids has been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance in peripheral tissues. However, how neurons develop insulin resistance in response to lipid overload is not fully understood.

Nonsteroidal anti-inflammatory drugs attenuate amyloid-β protein-induced actin cytoskeletal reorganization through Rho signaling modulation.

Amyloid-β protein (Aβ) neurotoxicity occurs along with the reorganization of the actin-cytoskeleton through the activation of the Rho GTPase pathway. In addition to the classical mode of action of the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin, and ibuprofen have Rho-inhibiting effects. In order to evaluate the role of the Rho GTPase pathway on Aβ-induced neuronal death and on neuronal morphological modifications in the actin cytoskeleton, we explored the role of NSAIDS in human-differentiated neuroblastoma cells exposed to Aβ.

Lovastatin Differentially Affects Neuronal Cholesterol and Amyloid-β Production in vivo and in vitro.

Background And Aims: Epidemiological and experimental studies indicate that high cholesterol may increase susceptibility to age-associated neurodegenerative disorders, such as Alzheimer's disease (AD). Thus, it has been suggested that statins, which are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), may be a useful therapeutic tool to diminish the risk of AD. However, several studies that analyzed the therapeutic benefits of statins have yielded conflicting results.

Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus.

Chronic consumption of high-fat-and-fructose diets (HFFD) is associated with the development of insulin resistance (InsRes) and obesity. Systemic insulin resistance resulting from long-term HFFD feeding has detrimental consequences on cognitive performance, neurogenesis, and long-term potentiation establishment, accompanied by neuronal alterations in the hippocampus. However, diet-induced hippocampal InsRes has not been reported.

Interplay between cholesterol and homocysteine in the exacerbation of amyloid-β toxicity in human neuroblastoma cells.

Amyloid-β (Aβ) plays an important role in Alzheimer's disease (AD) progression and is associated with synaptic damage and neuronal death. Epidemiological and experimental studies indicate that hypercholesterolemia and hyperhomocysteinemia increase susceptibility to AD; however, the exact impact and mechanisms involved are largely unknown. Few studies have addressed the combined effects of the above compounds, which are considered to be risk factors for developing AD, on Aβ-induced neurotoxicity.

Amyloid-β protein modulates insulin signaling in presynaptic terminals.

Synaptic loss is a major neuropathological correlate of memory decline as a result of Alzheimer's disease (AD). This phenomenon appears to be aggravated by soluble amyloid-β (Aβ) oligomers causing presynaptic terminals to be particularly vulnerable to damage. Furthermore, insulin is known to participate in synaptic plasticity through the activation of the insulin receptor (IR) and the PI3K signaling pathway, while low concentrations of soluble Aβ and Aβ oligomers aberrantly modulate IR function in cultured neurons.

Caspase-12 activation is involved in amyloid-β protein-induced synaptic toxicity.

Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer's disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER)-stress depending of amyloid-β protein (Aβ). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction.

Cholesterol potentiates beta-amyloid-induced toxicity in human neuroblastoma cells: involvement of oxidative stress.

Alterations in brain cholesterol concentration and metabolism seem to be involved in Alzheimer's disease (AD). In fact, several experimental studies have reported that modification of cholesterol content can influence the expression of the amyloid precursor protein (APP) and amyloid beta peptide (Abeta) production. However, it remains to be determined if changes in neuronal cholesterol content may influence the toxicity of Abeta peptides and the mechanism involved.

Sequential expression of cell-cycle regulators and Alzheimer's disease-related proteins in entorhinal cortex after hippocampal excitotoxic damage.

Growing evidence suggests that one of the earliest events in the neuronal degeneration of Alzheimer's disease (AD) is aberrant cell-cycle activation in postmitotic neurons, which may, in fact, be sufficient to initiate the neurodegenerative cascade. In the present study we examined whether cyclins and cyclin-dependent kinases, molecules normally associated with cell-cycle control, may be involved in delayed expression of altered Alzheimer's proteins in two interconnected areas, the entorhinal cortex (EC) and the dentate gyrus (DG), after a hippocampal excitotoxic lesion. Several cell-cycle proteins of the G1 and S phases and even of the G2 phase were found to be up-regulated in the EC after kainic acid evoked neuronal death in the hippocampus.

Histopathologic changes induced by the microtubule-stabilizing agent Taxol in the rat hippocampus in vivo.

Microtubules and their associated proteins play a prominent role in neuronal morphology, axonal transport, neuronal plasticity, and neuronal degeneration. It has been proposed that microtubule damage is sufficient to induce neuronal death. In this regard, the microtubule-stabilizing agent Taxol could be a useful tool to reproduce some aspects of neurodegenerative diseases associated with disturbances of the cytoskeleton and alterations in axonal transport.

Changes in the content and distribution of microtubule associated protein 2 in the hippocampus of the rat during the estrous cycle.

The molecular mechanisms involved in the regulation of synaptic plasticity in the hippocampus during the estrous cycle of the rat are not completely understood. Because this process implicates changes in neuronal cytoskeleton organization, we analyzed the content of microtubule associated protein 2 (MAP2) and Tau in the hippocampus and the frontal cortex of the rat by Western blot, as well as the hippocampal distribution of MAP2 during the estrous cycle by immunohistochemistry. In the hippocampus the lowest content of MAP2 was found on diestrus day, and it significantly increased at proestrus.

Okadaic acid induces epileptic seizures and hyperphosphorylation of the NR2B subunit of the NMDA receptor in rat hippocampus in vivo.

Overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors is closely related to epilepsy and excitotoxicity, and the phosphorylation of these receptors may facilitate glutamate-mediated synaptic transmission. Here we show that in awake rats the microinjection into the hippocampus of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A, induces in about 20 min intense electroencephalographic and behavioral limbic-type seizures, which are suppressed by the systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine hydrogen maleate and by the intrahippocampal administration of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, an inhibitor of protein kinases. Two hours after okadaic acid, when the EEG seizures were intense, an increased serine phosphorylation of some hippocampal proteins, including an enhancement of the serine phosphorylation of the NMDA receptor subunit NR2B, was detected by immunoblotting.

Estradiol and progesterone modify microtubule associated protein 2 content in the rat hippocampus.

The molecular mechanisms involved in the regulation of synaptic plasticity and neuroprotection by estradiol (E(2)) and progesterone (P(4)) are unknown. Because these processes involve changes in cytoskeleton organization, we studied the effects of E(2) and P(4) in the expression of two cytoskeletal proteins: microtubule associated protein 2 (MAP2) and tau in the hippocampus and the frontal cortex of ovariectomized adult rats. While tau expression was unaffected by E(2) and P(4), an increase in MAP2 protein content in the hippocampus but not in the cortex was observed after E(2) and P(4) treatments.

beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine.

In Alzheimer's disease (AD), loss of synapses exceeds neuronal loss and some evidence suggests a role of beta-amyloid protein (Abeta) in synaptic degeneration through a mechanism which may involve intraneuronal Ca2+ dyshomeostasis. Emerging evidence points to the participation of the internal Ca2+ stores in the pathophysiology of neurodegeneration in AD. To test the involvement of intrasynaptic Ca2+ mobilization in A toxicity, we explored the role of ryanodine receptor activation in rat cortical synaptosomes taken as a model system for the central presynapses.