Neurotoxicity markers

Williams TI, Lynn BC, Markesbery WR, Lovell MA (2005) Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer s disease. Neurobiol Aging 27(8) 1094—1099 WUquet V, De Strooper B (2004) Amyloid-beta precursor protein processing in neurodegeneration. Curr Opin Neurobiol 14 582-588... 

Maier WE, Costa LG. 1990. Sodium, potassium-ATPase in rat brain and erythrocytes as a possible target and marker, respectively, for neurotoxicity studies with chlordecone, organotins and mercury compounds. Toxicol Lett 51 175-188. 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

The data deseribed above demonstrate that destruction of serotonin axons by MDMA involves the serotonin aetive uptake carrier and that administration of citalopram, a selective serotonin uptake blocker, prior to administration of MDMA, ean prevent the decreases in serotonin markers elicited by MDMA alone. These data are eonsistent with previous reports for other potent serotonin neurotoxins, demonstrating that pretreatment with serotonin uptake blockers can prevent the neurotoxic effects of parachloroamphetamine (Ross 1976 Sanders-Bush and Steranka 1978). Furthermore, it has been shown that MDMA-induced neurotoxicity can be prevented or reversed if a serotonin uptake blocker such as fluoxetine is administered no later than 12 hours after MDMA treatment (Schmidt 1986). 

Long-Term Effects of MDMA on Markers of Neurotoxicity... 

Table 7.3 Effects of MDMA on Established Markers of Neurotoxicity in Rats...

It is well accepted that MDMA produces 5-HT depletions in rat CNS, but much less attention has been devoted to the effects of MDMA on established markers of neurotoxicity such as cell death, silver-positive staining, and reactive gliosis. Support for the hypothesis of MDMA-induced axotomy relies heavily on immunohistochemical analysis of 5-HT levels, which could produce misleading results if not validated by other methods. For example, MDMA-induced loss of 5-HT could be due to persistent adaptive changes in gene expression or protein function, reflecting a state of metabolic quiescence rather than neurotoxic damage. Table 7.3 summarizes the effects of MDMA on hallmark measures of neurotoxicity. 

Fig. 6 Biomonitoring of pollution in the Ebro Delta with Daphnia magna and Corbicula fluminea. (a) Map of sampling sites. Site 1 is out of the figure limits, close to Amposta (see Fig. 1). (b) Assays for neurotoxic activity (ChE and CbE) and D. magna feeding). Note the different pattern for the microcrustacean (sensitive to insecticides), which show a maximal toxic (inhibitory) effect in May and June, and the mollusk (relatively resistant), (c) Oxidative stress markers. These markers showed a similar response for both species with maximal effects (activation) in May (month 5) and August (month 8). Data from [43] and [44], Dm and Cf identify markers from D. magna and C. fluminea, respectively...

Neurodegeneration Alzheimer s Cortical neurons B-amyloid Markers of B-amyloid induced neurotoxicity [271... 

Exposure. The presence of the -hexane metabolite 2,5-hexanedione in the urine is a reasonably reliable marker for exposure to -hexane and has been correlated with air concentrations in the workplace. This is not a specific marker since 2-hexanone is also metabolized to 2,5-hexanedione. The levels of this metabolite in the urine associated with neurotoxicity are not known. A more sensitive marker for exposure may be the presence of pyrolidated proteins in the blood or hair, a result of the reaction of 2,5-hexanedione with the side-chain amino group of lysine (Graham et al. 1995 Johnson et al. 1995). These methods have only been tested after oral exposure to 2,5-hexanedione in the rat model. It would be very useful to know if measurement of pyrrole adducts or cross-linked proteins is also feasible after inhalation exposure to u-hexane in the rat model. Further development and validation of this method in an occupationally exposed population may then be useful. 

Though some very elegant methods are now available to study the biochemistry of the brain and nervous system, none has yet discovered any generalized marker chemicals which will serve as reliable indicators or early warnings of neurotoxic actions or potential actions. There are, however, some useful methods. Before looking at these, however, one should understand the basic problems involved. 

In summary, FAEE protects neuronal cells and synaptosomes against oxidative stress and neurotoxicity as shown by a number of oxidative stress markers. We hypothesize a multifaceted mechanism by which FAEE offers neuroprotection on in vitro models of AD ... 

The fact that the birds developed delayed neurotoxicity under laboratory conditions indicates that the lack of it in the field study was not due to an inability of this mutant to develop the neuropathy. "Early warning" tests for delayed neurotoxicity are lacking. The laboratory data suggest that serum enzymes like CK may be useful markers for organophosphate exposure. However the conditions of this test must be controlled. The increase of CK in all birds taken to Visalia, regardless of their exposure to DEP in the field, suggests that the rigor of the trip may have stressed the birds and increased CK levels. Plasma CK activity in humans is known to increase under stress, such as after heavy exercise (12). 

Julka D, Gill KD. 1995. Development of a possible peripheral marker for aluminum neurotoxicity. Med SciRes 23 311-314. 

Glutamate Decreased presynaptic markers Decreased HC AMPA and kainate receptor expression Minor changes in FC NMDA R sub-units Altered glutamate fibres in cingulate cortex NMDA receptor antagonists produce schizophrenia-like psychosis Roles of NMDA receptors in development and neurotoxicity Partial NMDA receptor agonists have some therapeutic benefits... 

Jarskog et al. (2007) studied the effects of haloperidol, clozapine, and quetiapine on numerous so-called apoptotic markers to study the impact of these drugs on apoptosis. Essentially, they examined the neurotoxicity of neuroleptics, specifically their capacity to induce cell deterioration typical of the process of cell death. They found that the neuroleptics, both the older ones and the atypicals, caused activation of caspase-3, a marker for apoptosis. They tried to reassure their readers that this activity was probably non-lethal. ... 

The number of useful biomarkers to predict neurotoxicity, hepatotoxicity or cardiovascular toxicity is still rather limited and they are not yet well established as tools in pharmaceutical laboratories. Even though some decent correlations between biomarkers and toxicological events have been demonstrated, " a significant amount of validation work still has to be performed. Eor example, while natriuretic peptides and troponin can be clinical markers for cardiovascular toxicity, preclinical use in... 

A critical review of the post-September 11, 2001 literature has resulted in a specific focus on studies that have revealed eritical neural signaling/activity pathways and the identification of primary targets of PAH toxicity, as well as toxicity modifiers. It is hoped that as a result of this review, the interdisciplinary conduct of simultaneous temporal measurements of relevant markers and integrative analysis of critical signaling processes during development will increase two-fold such that a better understanding of the mechanism of PAH exposure-induced neurotoxicity results. 

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