Acute inflammation can represent an effective immune response to the corporeal presence of organisms of exogenous origin or damaged cells of intrinsic origin, both of which are potentially injurious. Very often, such inflammation persists long after the triggering stimulus no longer poses a threat. Such a chronic condition can ultimately be more harmful than the original triggering agent. The means by which metallic compounds can provoke undesirable and extended inflammatory changes within the nervous system are diverse. This short review classifies the likely mechanisms underlying their toxicity by taking into account their known chemical properties and also by reflecting on other injurious events that commonly occur together with inflammation. The brevity of this survey does not allow focusing exhaustively on each individual metal but rather seeks to uncover some intracellular susceptible biochemical loci, based on the chemistry of each class of metals. Developmental and senescence-related characteristics are considered as these stages of life often involve especial vulnerabilities. Another feature addressed is that while research is generally conducted on purified and well-defined agents, exposures in the real world generally involve diverse mixtures in which the individual toxicity of a component can be enhanced or suppressed by the presence of other chemicals.

The axonal migration of nucleic acids and their precursors has been studied following injection of radioactive uridine or thymidine into a single eye of newhatched chicks. After monocular injection of tritiated uridine, a progressive increase was observed in the specific activity of RNA of the optic lobe contralateral to the injected eye. This accumulation was first apparent 18 hours after injection and increased for at least 6 days. There was also a lesser accumulation of trichloracetic acid soluble radioactivity in this contralateral lobe relative to the ipsilateral lobe. RNA was prepared from morphological fractions of optic lobes after differential centrifugation. Radioactive analysis of these RNA fractions suggested that mitochondrial, ribosomal and transfer RNA all migrated axonally to a considerable degree. At neither 4 hours or 4 days after monocular injection of tritiated thymidine, was there any excess of radioactivity in DNA of lobes contralateral to the injected eye relative to DNA of ipsilateral lobes. Thus there was no evidence for the flow of DNA along the axon. The data suggest that a wide variety of RNA species synthesised in the nerve cell body migrate distally and appear at nerve endings. © 1971 Springer-Verlag.

The presence within the brain of metal compounds at toxic levels, has adverse consequences for cerebral function. The type of damage that can be incurred often includes the presence of excessive amounts of inflammation. This event does not enhance cerebral defense systems and is thus not an effective or relevant response. On the contrary, such prolonged neuroinflammation can be disruptive to normal brain metabolism. This review outlines several means by which metals can bring about such extended and inappropriate immune activation within the CNS. Various mechanisms that may enable these changes will be discussed, including the formation of haptens, the production of reactive oxygen and nitrogen species, the sequestering of reducing capacity, and the formation of inflammation-provoking colloids. Emphasis is given to the critical nature of the exact form of the metal exerting harmful effects. This can affect both access to, and subsequent disposition within the brain. The interaction of exposure to toxic metals with normal aging events is also considered.

The current world population contains an ever-increasing increased proportion of the elderly. This is due to global improvements in medical care and access to such care. Thus, a growing incidence of age-related neurodegenerative disorders is to be expected. Increased longevity also allows more time for interaction with adverse environmental factors that have the potential exert a gradual pressure, facilitating the onset of organismic aging. Nearly all neurodegenerative disorders have a relatively minor genetic element and a larger idiopathic component. It is likely that some of the unknown factors promoting neurological disease involve the appearance of some deleterious aspects of senescence, elicited prematurely by low but pervasive levels of toxic materials present in the environment. This review considers the nature of such possible toxicants and how they may hasten neurosenescence. An enhanced rate of emergence of normal age-related changes in the brain can lead to increased incidence of those specific neurological disorders where aging is an essential requirement. In addition, some xenobiotic agents appear to have the capability of engendering specific neurodegenerative disorders and some of these are also considered.

The specific problems related to the study of chemicals that damage the nervous system are discussed. Such damage may be direct or may occur by a series of sequential events. Such a series of events may involve other organs and biochemical targets not confined to nerve tissue. The complexity of investigation of the mode of action of rather nonspecific toxic agents requires that a circumscribed objective be defined and examples of such goals are given. One of these is to attempt to determine which neuronal circuits are damaged by a given toxic agent and how this might cause alterations of behavior. Acrylamide and triethyl lead are used to exemplify the application of neurotransmitter receptor analysis to correlation of deranged nerve activity patterns with modulation of behavior. Such evaluation can set the stage for more detailed biochemical studies of neurotoxic mechanisms.

Aluminum (Al) is a very common component of the earth's mineral composition. It is not essential element for life and is a constituent of rather inert minerals. Therefore, it has often been regarded as not presenting a significant health hazard. As a result, aluminum-containing agents been used in the preparation of many foodstuffs processing steps and also in elimination of particulate organic matter from water. More recently, the reduced pH of bodies of water resulting from acid rain has led to mobilization of aluminum-containing minerals into a more soluble form, and these have thus entered residential drinking water resources. By this means, the body burden of aluminum in humans has increased. Epidemiological and experimental findings indicate that aluminum is not as harmless as was previously thought, and that aluminum may contribute to the inception and advancement of Alzheimer's disease. Epidemiological data is reinforced by indications that aluminum exposure can result in excess inflammatory activity within the brain. Activation of the immune system not initiated by an infectious agent, typifies the aging brain and is even more augmented in several neurodegenerative diseases. The origin of most age-related neurological disorders is generally not known but as they are largely not of genetic derivation, their development is likely triggered by unknown environmental factors. There is a growing and consistent body of evidence that points to aluminum as being one such significant influence. Evidence is presented that reinforces the likelihood that aluminum is a factor speeding the rate of brain aging. Such acceleration would inevitably enlarge the incidence of age-related neurological diseases.

The avian visual system has been used to study the transport of proteins and their precursors along the optic tract. Various labeled compounds were injected into a single eye of new hatched chicks. The radioactivity of components in the optic lobe that was contralateral to, and innervated by, the injected eye was compared to radioactivity in the ipsilateral lobe, not innervated by the treated eye. Proteins migrating from the ganglion cells of the retina to the optic tectum seemed to be relatively stable and may be rich in proline and glycine. Microtubular protein migrated at a rate similar to nonmicrotubule soluble protein, and slower than particulate protein. With the exception of γ-aminobutyric acid, transport of free amino acids occurred to only a minor extent. Following monocular injection of tritiated fucose, a rapid asymmetry in the specific activities of protein from contralateral and ipsilateral lobes, was established. Thus the more rapidly migrating proteins may be attached to glycosidic residues. The carbohydrate moeity of these glycoproteins is attached in the nerve cell body, prior to their axonal transport to the optic tectum. There was no evidence for transneuronal transfer of protein as in no case was a differential in specific activity observed in labeled protein from paired cerebral hemispheres. © 1971 Springer-Verlag.

The evidence for the neurotoxicity of nanoparticles is summarized. The sources of such particles and the ways in which they may enter the brain are listed and discussed. These include the olfactory pathway, the respiratory tract, and the possibility of transport across the blood-brain barrier. However, nanoparticles acting systemically can also be neurotoxic without directly entering the brain. The means by which nanoparticles can be injurious to the central nervous system include both their physical characteristics such as their form and size, and their chemical composition. Particles containing transition metals the possibility of valence flux under biological conditions, may promote prooxidant events in the nervous tissues. Futile activation of astroglial immune responses can initiate chronic inflammatory events. The toxicity of airborne particles includes evidence of oxidative damage and heightened inflammation in the brain. The consequences of these changes may include the advancement of several prevalent neurodegenerative disorders such as Alzheimer's and Parkinson's diseases characterized by excess levels of oxidative damage and inflammatory changes. Conclusive detection of such changes in incidence consequent to particulate exposure remains elusive.

This review explores the processes underlying the deleterious effects of the presence of insoluble or colloidal depositions within the central nervous system. These materials are chemically unreactive and can have a prolonged residence in the brain. They can be composed of mineral or proteinaceous materials of intrinsic or exogenous origin. Such nanoparticulates and colloids are associated with a range of slow-progressing neurodegenerative states. The potential common basis of toxicity of these materials is discussed. A shared feature of these disorders involves the appearance of deleterious inflammatory changes in the CNS. This may be due to extended and ineffective immune responses. Another aspect is the presence of excess levels of reactive oxygen species within the brain. In addition with their induction by inflammatory events, these may be further heightened by the presence of redox active transition metals to the large surface area afforded by nanoparticles and amphipathic micelles.

The mechanisms underlying the toxicity of ethanol have been the subject of much study, but are not well understood. Unlike many selective pharmacological agents, ethanol clearly has several major loci of action. One deleterious factor in ethanol metabolism is the potential for generation of excess amounts of free radicals. The extent to which this activity accounts for the overall toxicity of ethanol is unknown. This review outlines the enzymic steps that have the capacity to generate reactive oxygen species. These steps are likely to differ in acute and extended exposures to ethanol. Acetaldehyde catabolism also has the likelihood of contributing to ethanol-related oxidative stress. The review focuses on the ethanol-induced production of excess amounts of pro-oxidant reactive species in both the liver and the central nervous system. The potential of various stages of ethanol catabolism to involve generation of free radicals is described.