Neuronal toxicity

Bruijn, L. I., Houseweart, M. K., Kato, S. et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD 1. Science 281 1851-1854, 1998. 

Multiple single-point modification of both halves of the bisindole framework provided vinepidine (144), a bisindole alkaloid that exhibited experimental antitumor activity similar to vincristine without demonstrating the acute neuronal toxicity of this alkaloid. Ultimately, the vinepidine experience was both educational and an exercise in humility, since the compound showed promise in preclinical neurotoxicology models yet demonstrated considerable neurotoxicity in clinical trials. Nevertheless, vinepidine brings a rich example of the combined effects of ring D conformation (with its associated effect on N-6 basicity) and the presence of an N-1 formyl group. 

Metabolic differences also account for the great species variability in methyl alcohol toxicity with humans and nonhuman primates being uniquely sensitive. (A relatively poor ability to metabolize the methanol-metabolized formate in these species leads to increased blood formate levels and subsequent metabolic acidosis and neuronal toxicity.)... 

Persistent excitatory glutamatergic stimulation of postsynaptic NMDA receptors, which may cause neuronal toxicity by allowing excessive calcium entry into neurons, has been implicated in the symptomatology of dementia of the Alzheimer s type (Farber et al. 1998). Memantine is a moderate-affinity, noncompetitive inhibitor of NMDA receptors (Danysz et al. 2000). 

Copper is essential for some of the enzymes that have a role in brain metabolism. Sophisticated mechanisms balance copper import and export to ensure proper nutrient levels (homeostasis) while minimizing toxic effects. Several neurodegenerative diseases including AD are characterized by modified copper homeostasis. This change seems to contribute either directly or indirectly to increased oxidative stress, an important factor in neuronal toxicity. The association of misfolded proteins and modified copper homeostasis appears to be important in the pathological progression of AD [Donnelly et al., 2007],... 

Rothstein J. D. andKuncl R. W. (1995). Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. J. Neurochem. 65 643-651. 

Bouldin TW, Goines ND, Bagnell CR, et al. 1981. Pathogenesis of trimethyltin neuronal toxicity Ultrastructural and cytochemical observations. Am J Pathol 104 237-249. 

Bouldin, T.W., Goines, N.D., Bagnell, R.C., Krigman, M.R. (1981). Pathogenesis of trimethyltin neuronal toxicity. Ultra-structural and cytochemical observations. Am. J. Pathol. 104 237 9. 

In contrast to HTV-1 coreceptors, some chemokine ligands have the ability to reduce or ablate neuron toxicity. High levels of chemokines RANTES, MIP-la, and others have been shown to reduce neuron death (Meucci et al., 1998 Kaul and Lipton, 1999), while SDF-1, at higher concentrations may actually promote neuronal death (Hesselgesser et al., 1998 Kaul and Lipton, 1999 Zheng et al., 1999b). The mechanism is not yet completely understood, but may rely upon simple competitive inhibition, receptor expression changes on the cell surface, or other unknown mechanisms. 

New pharmacological treatments have been developed for the treatment of obesity. These include the combination of phentermine and fenfluramine (phen-fen) and, alternatively, dexfenfluramine (Redux). Phentermine (Fastin, lonamin) is a stimulant and fenfluramine (Pondimin) is a serotonin agonist. In combination they have persistent appetite suppression and weight loss effects. These medications can cause anxiety and insomnia and must be used with extreme caution if taken with antidepressants, especially SSRIs. Dexfenfluramine works similarly, but avoids the side effect of increased anxiety, and instead tends to cause diarrhea, dry mouth, and somnolence. There have also been reports of pulmonary hypertension, a potentially fatal condition, especially when taken for longer than three months. Some researchers (Ricuarte et al. 1991 McCann et al. 1994) have expressed concern because rats given these medications showed evidence of neuronal toxicity. Thus, they are effective medications, but must be used with caution. 

Treatment of cell cultures containing both neuronal and glial cells derived from fetal rat brain with low concentrations of both organic and inorganic mercury compounds leads to cell death. In cell cultures derived from a more mature fetal stage, the organic form of mercury was more toxic and showed specific neuronal toxicity. Below the cytotoxic concentration of mercury (>lpmoll ), pronounced gliosis was... 

Aschner, M Wake Forest University Winston-Salem, NC Mechanisms of methylmercury induced neuronal toxicity. NIEHS... 

AD. Park et al. [530] investigated the effects of surfactin, a surfactant from Bacillus subtilis, on oligomeric Ap-induced microglial activation and neurotoxicity. Surfactin suppressed expression of MMP-9, iNOS, and COX-2, as well as production of ROS, NO, PGE2, TNF-a, IL-ip, IL-6, and MCP-1 in Ap-stimulated BV-2 microglial cells. Surfactin also inhibited Ap-induced nuclear translocation and activation of NF-kB as well as phosphorylation of JNK and p38 MAPK, and protected hippocampal HT22 cells from indirect neuronal toxicity mediated by A(3-treated microglial cells. 

Fabian, R. H. and Rea, H. C., Neuronal toxicity by macrophages in mixed brain cell culture is augmented by antineuronal IgG and dependent upon nitric oxide synthesis, J. Neuroimmunol., 44, 95, 1993. 

Neurosteroids appear to mainly function as neurotransmitters in a paracrine and autocrine fashion in the modulation of many brain functions including myelination, inhibition of neuronal toxicity and ischemia, behavioral aspects, and neuronal survival, growth, and differentiation (Griffin et ah, 2004 Mellon et ah, 2004 Mellon, 2007 Mukai et ah, 2006). Such neurosteroids include progesterone, pregnenolone, allopregnanolone, DHEA, their sulfate esters, and 5ot/5p-tetrahydroprogesterone, some of which were previously viewed as inactive metabolites or steroid precursors (Plassart-Schiess and Baulieu, 2001 Sakamoto et ah, 2007). 

In summary, therefore, there are a variety of ways in which domoic acid appears to produce neuronal toxicity, but aU involve either direct or indirect "over-stimulation" of post-s)maptic receptors leading to the influx of excessive amounts of Ca. The differential sensitivity of different neuronal populations in different regions of the brain, is probably determined both by which of these mechanisms is present, as well as by how many of them are actively involved at the time of toxic insult. Let us now consider the nature of the toxicity produced by DOM, and learn why it s something you want to avoid. 

Optimal CTA imaging is dependent on the concentration of intravascular iodine, which in turn is dependent on both choice of contrast and injection strategy. Nonionic CT contrast agents have been shown to be safe in an animal model of MCA stroke, without significant neuronal toxicity, even to already ischemic neurons [41, 42], There are several forms of nonionic contrast, with varying concentrations of iodine. The relationship between concentration and enhancement is demonstrated graphically in Fig. 4.6 [43,44]. 

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