Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable.

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Toxic Potential of Materials at the Nanolevel

Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo

/pdf/the-capsaicin-receptor-a-heat-activated-ion-channel-in-the-57mhjl9hkd.pdf

The capsaicin receptor: a heat-activated ion channel in the pain pathway

Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death

In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death. Although much is known about the control of cell proliferation, less is known about the control of cell death. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. The decision of a cell to undergo apoptosis can be influenced by a wide variety of regulatory stimuli. Recent evidence suggests that alterations in cell survival contribute to the pathogenesis of a number of human diseases, including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (acquired immunodeficiency syndrome). Treatments designed to specifically alter the apoptotic threshold may have the potential to change the natural progression of some of these diseases.

https://science.sciencemag.org/content/sci/267/5203/1456.full.pdf

Apoptosis in the pathogenesis and treatment of disease

Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .

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Protective and Damaging Effects of Stress Mediators

The neurotoxicity of 3 non-NMDA glutamate receptor agonists--kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and quisqualate--was investigated quantitatively in dissociated murine cortical cultures Five minute exposure to 500 microM kainate, but not AMPA, produced widespread acute neuronal swelling Kainate-induced swelling was resistant to 2-amino-5-phosphonovalerate (APV) or replacement of extracellular sodium with choline but attenuated by either kynurenate or low concentrations of quisqualate Unlike NMDA agonists, kainate or AMPA did not produce much late neuronal loss after a 5 min exposure In contrast, 5 min exposure to 500 microM quisqualate produced both acute neuronal swelling and widespread late neuronal degeneration This acute swelling was blocked by APV or by replacement of extracellular sodium by choline, consistent with mediation by NMDA receptors; we speculate that high concentrations of quisqualate may directly activate NMDA receptors or induce the release of endogenous glutamate Quisqualate-induced late neuronal degeneration may be due to another unexpected process: cellular quisqualate uptake and delayed release, converting brief addition into prolonged exposure Hours after thorough washout of exogenously added quisqualate, micromolar concentrations could be detected in the bathing medium by high performance liquid chromatography With lengthy exposure (20-24 hr), all 3 non-NMDA agonists were potent neurotoxins, able to destroy neurons with EC50's of about 20 microM for kainate, 4 microM for AMPA, and 1 microM for quisqualate Kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not APV or L-glutamate diethyl ester, were effective in attenuating the neuronal degeneration induced by these agonists CNQX was about 3 times more selective than kynurenate against kainate-induced neuronal injury, but CNQX was still nearly equipotent with APV against NMDA-induced injury Gamma-D-glutamylaminomethyl sulfonate exhibited partial antagonist specificity for AMPA-induced toxicity

https://www.jneurosci.org/content/jneuro/10/2/693.full.pdf

Non-NMDA receptor-mediated neurotoxicity in cortical culture

The ability of several glutamate receptor antagonists to reduce hypoxic cortical neuronal injury was quantitatively examined in cell cultures derived from fetal mice. Cultures exposed to hypoxia for 8 hr showed by the following day widespread neuronal injury, which was substantially attenuated by addition of the specific N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). The protective effect of APV was concentration dependent (ED50 about 2 microM) and stereospecific (D-APV approximately 100 times more potent that L-APV). Neuron-protective effects were also observed with several other NMDA antagonists: 2-amino-7-phosphonoheptanoate, phencyclidine and (+)-SKF 10,047 [(+)-N-allylnormetazocine]--as well as with the nonspecific glutamate antagonists D-glutamylglycine and kynurenate. In addition, a similar antagonist profile was observed with a chemical model of hypoxic neuronal injury, produced by brief exposure to high concentrations of cyanide. In contrast, 1 mM concentrations of glutamate diethylester and gamma-aminomethyl sulfonate, compounds reported in some studies to preferentially antagonize non-NMDA glutamate receptors, failed to protect neurons against either hypoxia or cyanide. These results are consistent with the hypothesis that NMDA receptors are preferentially involved in the pathogenesis of hypoxic cortical neuronal injury and suggest that cortical cell culture may be a useful system in which to quantitatively characterize the pharmacology of that injury.

N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.

Quantitative concentration-toxicity relationships were determined for the injury of cultured murine cortical neurons by several excitatory amino acid (EAA) agonists. All tested agonists produced concentration- dependent neuronal injury at concentrations between 1 and 1000 microM. With 5 min exposure, glutamate, aspartate, N-methyl-D-aspartate (NMDA), L-homocysteate (HCA), and quisqualate all had similar potencies, destroying half of the neuronal population (LD50) at concentrations of 50–200 microM, and similar efficacies, with 88–92% neuronal loss produced by exposure to high agonist concentrations. Quinolinate and kainate were substantially weaker toxins, producing only 20–30% neuronal loss after 5 min exposure to 3 mM concentrations; with prolonged (24 hr) exposure, 85–95% neuronal loss could be attained. The comparative EAA vulnerability of a specific cortical neuronal subpopulation containing high concentrations of the enzyme, reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), was also examined. Glutamate had no differential toxicity on these cells, damaging them at all concentrations in proportion to the general population; however, other, more selective, agonists produced strikingly differential injuries. These NADPH-d-containing [NADPH- d(+)]neurons were selectively resistant to damage by low concentrations of the NMDA agonists quinolinate, HCA, aspartate, or NMDA itself. By contrast, NADPH-d(+)neurons were selectively destroyed by concentrations of quisqualate or kainate too low to produce much general neuronal injury. The differential susceptibility of these neurons was not absolute, as high concentrations of all tested agonists produced nonselective neuronal injury. In light of recent evidence that forebrain NADPH-d(+)neurons are selectively spared in Huntington's disease, the present study continues to support the hypothesis that neuronal loss in Huntington's disease might result from excessive NMDA- receptor stimulation by any selective NMDA agonist. Furthermore, the demonstration that the differential susceptibility of NADPH-d(+)neurons is agonist concentration-dependent, rather than absolute, could provide a basis for explaining some existing conflicting experimental data.

https://www.jneurosci.org/content/jneuro/8/6/2153.full.pdf

Vulnerability of cultured cortical neurons to damage by excitotoxins: differential susceptibility of neurons containing NADPH-diaphorase

https://www.cell.com/neuron/pdf/0896-6273(94)90362-X.pdf

Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS.

Recent data have indicated that the divalent cation Zn2+ can selectively block central neuronal excitation mediated by N-methyl-D- aspartate (NMDA) receptors. The present experiments were conducted to determine the action of Zn2+ at the single-channel level. Outside-out membrane patches were prepared from cultured murine cortical neurons. Glutamate, 3 microM, in the presence of 5 microM glycine activated channels with a main conductance state of about 50 pS which were blocked in a voltage-dependent manner by Mg2+. Zn2+ appeared to have 2 effects on these NMDA receptor-activated channels. First, at concentrations as low as 1–10 microM, Zn2+ produced a concentration- dependent reduction in channel open probability, insensitive to membrane voltage between -60 and +40 mV; about 50% reduction in open probability was produced by 3 microM Zn2+. This reduction was mostly due to a decrease in opening frequency and only weakly mimicked by Mg2+. Second, at higher concentrations (10–100 microM) and negative membrane voltages, Zn2+ additionally produced an apparent reduction in single-channel amplitude, associated with an increase in channel noise, suggestive of a fast channel block. The amplitude reduction was voltage- dependent, with a delta of 0.51; amplitude distribution analysis suggested that this voltage dependence was primarily contributed by the “on” blocking rate constant, with little contribution from the “off” rate constant. The channel block produced by Zn2+ was faster than that of Mg2+, which at 100 microM and negative membrane voltages induces flickering of the NMDA receptor-activated channel without changing apparent channel amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)

https://www.jneurosci.org/content/jneuro/10/1/108.full.pdf

Dennis W. Choi

Papers

Non-NMDA receptor-mediated neurotoxicity in cortical culture

N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.

Vulnerability of cultured cortical neurons to damage by excitotoxins: differential susceptibility of neurons containing NADPH-diaphorase

Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS.

Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.