Mechanisms of CNS injury in behavioral dysfunction

Advances in the neurosciences have led to a greater understanding of the anatomical, biochemical, and molecular loci involved in injury to, and adaptation of, the central nervous system. Recent research has permitted the elucidation of the mechanisms for some neurotoxicants whose actions have been studied for decades, as in the example of the pyrethroid insecticides. In contrast, the mechanism of the neurotoxicity of the organophosphate insecticides and nerve gases has been known for many years, but our understanding of the many resulting sequelae has been markedly increased by recent discoveries. Two examples illustrate the strengths and weaknesses of such methods in predicting neurotoxicity. Studies of the parkinsonian-like toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (a by-product of synthesis of illicit opiates) exemplify the best application of current methods in neurotoxicology. It has been shown that the expression of MPTP toxicity requires both metabolism of MPTP to the proximal toxicant 1-methyl-4-phenylpyridinium (MPP⁺) and active uptake into central dopamine neurons. The discovery of binding sites of MPP⁺ in these cells has clarified how dopamine neurons are destroyed, thereby causing neurological signs. This illustrates two key concepts: first, the bioconversion of compounds to proximal toxicants is often ignored, and second, these events are unlikely to be detectable by in vitro studies that focus on a few biochemical endpoints. Another useful example was that of erythrosin (FD&C Red No. 3), in which numerous in vitro studies suggested that this food color was a potential neurotoxicant. However, this was shown to be an artifact of the ability of this color to disrupt biomembranes at high in vitro concentrations, and this idea was supported by negative data from both behavioral and clinical studies. Thus, the plethora of possible molecular and biochemical targets in the central nervous system (receptors, second messenger events, transmitter-modulator synthesis, storage and release, membrane maintenance, etc.) preclude the likelihood of developing a single test or a battery of neurochemical or biochemical tests that will be able to screen for neurotoxicants randomly or efficiently. Use of in vitro methods is likely to detect both false positives and negatives. While the availability of theoretical or phenomenological data provides the best start to the application of available biochemical and molecular techniques, predictions of neurotoxicity best can come from theoretical comparison of the structure of suspect compounds (and hypothesized metabolites) with known target sites in the CNS. Such a comprehensive structure-activity examination, while apparently an heroic task, can be made quite manageable by the availability of modern computer modeling, storage, and retrieval systems. Coupled with behavioral, pathological, and physiological screening in intact target organisms, it could provide the most efficient manner to predict neurotoxicity.