Neurotoxic properties

In light of this, studies of CSF 5-HIAA have been initiated in a cohort of human volunteers with a history of extensive MDMA use. Most participants in the study are individuals who have recently learned of the neurotoxic properties of MDMA and have asked to be evaluated for possible serotonergic damage. To qualify for the study, subjects must (1) have used MDMA on at least 20 to 25 occasions, (2) be drug-free for at least 2 weeks prior to participating in the study, and (3) not have a history of neuropsychiatric illness thought to involve alterations in serotonin metabolism. To date, 34 individuals have participated in the study. The study is now in progress, and completion is anticipated by 1991. At this time, it would be premature to comment on the results. 

As noted above, MDA is a potent stimulator of monoamine release (see Table 7.1), and recent reports indicate that a number of MDMA metabolites are bioactive. For example, Forsling et al.61 showed that the metabolite 4-hydroxy-3-methoxymethamphetamine (HMMA) is more potent than MDMA as a stimulator of vasopressin secretion from rat posterior pituitaries in vitro. The neuroendocrine effects produced by in vivo administration of MDMA metabolites have not been examined. Monks et al.62 demonstrated that catechol metabolites of MDMA and MDA, namely, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), exhibit neurotoxic properties when oxidized and conjugated with glutathione. Further characterization of the biological effects of MDMA metabolites is an important area of research. 

ODAP - nonprotein amino acid with neurotoxic property 121... 

The neurotoxic properties of -hexane are potentiated by exposure to methyl ethyl ketone (qv). Because other compounds may also have this effect, human exposure to mixed solvents containing any neurotoxic hexacarbon compound should be minimized. ... 

There is further analogy with yet "extra concern for toxic chemicals that may also persist in the environment and be transported great distances from their point of entry into the environment. Here the unifying general notion is that unsuspecting individuals are placed at risk, and are thus less able to defend than are the perpetrators. Mercury is a classic example of such a chemical. Mercury is extremely toxic to the CN S. Fetuses, infants, and toddlers are especially sensitive and susceptible to the neurotoxic properties of mercury. Mercury also persists in the environment, and is known to bioaccumulate in the food web and biomagnify up the food chain. 

Pregnant or nursing women exposed to methylmercury through their diet or otherwise also expose their developing fetus or breast-fed infant to the chemical, since methylmercury passes through placental membranes and enters the fetal bloodstream, and also enters breast milk. This is particularly problematic since fetuses and infants (and toddlers) are more susceptible and sensitive to the neurotoxic properties of mercury than are adults. 

While the severe neurotoxic properties of mercury are independent of its ability to persist in the environment and bioaccumulate and biomagnify within the food web, these additional albeit nontoxic properties increase the likelihood of human exposure to mercury and, as such, augment its toxicity. 

In other words, introduction of ortho substitutions into PBDEs or PCDEs does not create a spatial impediment for the two phenyl rings to assume a semi-flat position respect to each other as it does for PCBs or PBBs. This has implications not only for dioxin-type toxicities, but also for nondioxin-type toxicities. For example, studies have shown that mono- and diortho-substituted PCBs exhibit neurotoxic properties and structure-activity relationships for various neurological end points have been established (see Agency for Toxic Substances and Disease Registry 2000 for details). Although structure-activity relationships have not yet been fully examined for PBBs or PBDEs, it is reasonable to speculate that mono-and diortho-substituted PBDEs may not necessarily follow the neurotoxic potency rankings constructed with mono- and diortho-substituted PCBs. 

Neurobehavioral assessment of workers in occupations or industries with chronic exposure to tin and other heavy metals with known neurotoxic properties. 

It is now well known that most of the OC insecticides have neurotoxic properties and cause adverse effects on the CNS. Poisoned animals and humans show symptoms like tremor, eye jerking, changes in gait, convulsions, paralysis, loss of memory, and death. 

Butterfield, D. A., Bush, A. I. Alzheimer s amyloid beta-peptide (1-42) involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide. Neurobiol. Aging 2004, 25 563— 568. 

The neurotoxic properties of Af) have also been shown to be associated with methionine at residue 35 of A (Met35) (Butterfield and Boyd-Kimball, 2005). The substitution of methionine by norleucine from Af) abolishes free radical production, protein oxidation, and toxicity to hippocampal neurons (Butterfield and Boyd-Kimball, 2005). In addition, substitution of a carbon atom for the S atom of methionine completely abrogates A (l-42) neurotoxicity (Yatin et al., 1999 Butterfield and Kanski, 2002), and in vivo studies indicate methionine residue 35 is central for A -induced oxidative damage (Yatin et al., 1999). Studies from our laboratory (Varadarajan et al., 2000) and others (Curtain et al., 2001) showed that Cu bound to Af)(l-42) interacts with Met35 residue to produce free radicals in the absence of methionine in A ( 1 -42) redox metal ions play no role in the oxidative stress and neurotoxicity induced by the peptide (Varadarajan et al., 2000, 2001). Taken together these results are consonant with the notion that Af)-induced protein oxidation may in part account for neurodegeneration in AD brain (Butterfield and Boyd-Kimball,... 

Butterfield DA, Kanski J (2002) Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer s amyloid beta-peptide 1-42. Peptides 23 1299-1309 Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer s disease brain potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32 1050-1060 Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR (2006a) Redox proteomics identification of oxidatively modified hippocampal proteins in mUd cognitive impairment Insights into the development of Alzheimer s disease. Neurobiol Dis 22(2) 223-232... 

The one-pot, three-component synthesis of 1,2,4-triazoles from primary amines, acyl hydrazines and dimethoxy-A(-A(-dimethylmethanamine [84] was utilized for the preparation of compounds 235 (Scheme 41), which were evaluated for their anticonvulsant and neurotoxic properties [85]. The anticonvulsant activity was measured in mice by the maximal electroshock test (MES) and the neurotoxicity in mice by the rotarod neurotoxicity test (Tox). The majority of the compounds... 

Several amphetamines have been shown to have monaminergic neurotoxic properties. Recent studies of PC12 dopaminergic cells have shown increased activity of capsase-3 and mitochondrial cytochrome c release. These findings suggest that amphetamines (particularly substituted amphetamines) may induce apoptosis, possibly via a mitochondrial pathway. 

This comprehensive and useful text provides a broad overview of the neurobiological basis of neurotoxic phenomena in human and veterinary medicine, as well as an alphabetical compendium that describes the neurotoxic properties of over 450 chemicals, drugs, and mixtures, including plants and venoms. It replaces the 1980 edition (available online at http //WWW.ohsu.edu/research/croet/faculty/spen-cer/book/first ed.html), which featured micrographs depicting the neuropathology of neurotoxic agents. 

Chemicals with the potential to disrupt the mammalian nervous system may occur naturally (neurotoxins) or arise by synthesis (neurotoxicants). While chemicals with neurotoxic potential are conveniently termed neurotoxins or neurotoxicants , this is not an intrinsic property but rather the description of an effect that may occur if the tissue concentration exceeds a certain threshold. Biological chemicals with neurotoxic properties often have high target specificity and toxic potency, discrete biological actions, and are among the best understood mechanistically. Examples of chemicals with direct or indirect neurotoxic potential are found in bacteria, algae, fungi, plants, coelenterates, insects, arachnids, moll-usks, amphibians, reptiles, fish, and certain mammals (Table 1). 

The structure of chemicals and their differential access to the nervous system are of critical importance in determining the presence and nature of the neurotoxic response. While access to nervous tissue dictates the possibility of a direct neurotoxic effect, neurotoxicity ultimately depends on the ability of the substance to bind to neural tissue targets and interfere with functional or structural integrity. Structure-activity relationships are therefore of cardinal importance. For example, 1,2-diacetylbenzene but not 1,3-diacetylben-zene induces leg weakness because only the former binds to and crosslinks neuroproteins. Triethyltin targets the myelin sheath, trimethyltin damages neurons, but tributyltin lacks neurotoxic properties - another illustration of the critical importance of chemical structure in determining the presence and nature of the neurotoxic response. 

Spencer PS. 1984. Experimental evaluation of selected petrochemicals for subchronic neurotoxic properties. In MacFarland HN, Holdsworth CE, MacGregor JA, et al., eds. Advances in modern environmental toxicology. Vol. VI Applied toxicology of petroleum hydrocarbon. Princeton, NJ Princeton Scientific Publishers, Inc., 199-211. 

The metabolic pathways leading to the production of these urinary pyridinium metabolites are likely to be mediated by one or more forms of liver cytochrome P450. In vitro metabolic studies with rodent (Igarashi et al., unpublished results) and human (Usuki et al., submitted) microsomal preparations have demonstrated the NADPH-dependent oxidation of both HP and HPTP to HPP. Ongoing studies in the authors laboratory have shown that HPP and related pyridinium metabolites are present in brain tissues obtained from C57 black mice that had been treated with HPTP (Van der Schyf et al. 1994). Additionally, results obtained from intra-cerebral microdialysis, mitochondrial respiration, and rat embryonic mesencephalic cell culture studies suggest that HPP possesses MPP type neurotoxic properties (Rollema et al. 1992, 1994 Bloomquist et al. 1994). 

Recent pharmacological interest in KYN metabolites with respect to CNS diseases has mainly focused on three brain-active molecules 3-HK and QUIN, two molecules with neurotoxic properties, and KYN A, a presumed neuroprotective metabolite. These will be discussed in more detail in the following sections. 

Despite the evidence mentioned above that QUIN may indeed exert its main neurotoxic properties in vivo through the NMDA receptor, and despite synergistic properties with 3-HK, there is still a controversial discussion within the field if the concentration of these metabolites reached in vivo is indeed sufficient to substantially stimulate the NMDA receptor and thus lead to a toxic calcium overload, or whether alternative pathophysiological mechanisms are at work [26]. 

Following the introduction of the boron hydrides in the 1940s as rocket fuels, the neurotoxic properties of diborane, pentaborane, and decaborane became known (Yarbrough et al. 1985). Diborane, a gas, produces mostly pulmonary symptoms. Pentaborane, a liquid, and decaborane, a solid, cause severe cardiac and neurological damage. 

Several synthetic approaches toward the poison-dart frog alkaloids, including pumiliotoxin C (56), ge-phyrotoxin (57) and histrionicotoxin (58), have utilized the Eschenmoser reaction in a variety of distinct applications. These structurally related alkaloids are isolated from skin extracts of various Central and South American frogs in the Dendrohates genus and possess neurotoxic properties. Since their initial isolation and characterization, these toxins have attracted considerable attention for both their synthetic challenge and their interesting biological properties. ... 

Gephyrotoxin (57) is isolated from the frog Dendrohates histrionicus and possesses similar neurotoxic properties. Numerous chemical approaches have been developed to synthesize the parent compound and its hydrogenated analogs. Several of these approaches have incorporated the Eschenmoser reaction, each in a different application. 

Current orthodox medical opinion is that strychnine has no therapeuhc value. However, its selechve neurotoxic properties (see next sechon) are shll widely exploited by researchers stud)dng nerve functions in a variety of neurological condihons including Parkinson s disease, schizophrenia and stroke. 

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