Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The drugs don't work-or do they? Pharmacological and transgenic studies of the contribution of NMDA and GluR-A-containing AMPA receptors to hippocampal-dependent memory.

OBJECTIVE: The aim of this article is to provide a review of studies using N-methyl-D-aspartate (NMDA) receptor antagonists to assess the hippocampal long-term potentiation (LTP)/learning hypothesis. DISCUSSION: In particular, we will re-examine the validity of both (1) the original hippocampal LTP/spatial learning hypothesis of Morris and (2) the sensorimotor account put forward by Cain, among others, both from the point of view of the pharmacological studies on which they were based and with regard to recent studies with genetically modified mice. More specifically, we will review the pharmacological studies in the light of recent work on the glutamate receptor A (GluR-A or GluR1) L-alpha-amino-3-hydroxy-5-methyl-4-isoxazelopropionate (AMPA) receptor sub-unit knockout mouse. We will argue that neither the original hippocampal LTP/spatial learning hypothesis nor a sensorimotor account can adequately explain all of the available data. We argue instead that hippocampal synaptic plasticity, which requires NMDA receptors for its induction and GluR-A-containing AMPA receptors for its continued expression, contributes to a process whereby appropriate behavioural responses are selected rapidly on the basis of conditional information provided by the context. These contextual cues could include not only the spatial context (i.e. the 'where') and the temporal context (the 'when'), but also other aspects of context, such as internal state cues (hunger and fear state), and can be used to rapidly and flexibly alter valences of specific response options. RECOMMENDATIONS: We also suggest that there is a separate, distinct, NMDA/GluR-A-independent mechanism through which the context can gradually (incrementally or decrementally) alter the valence of a particular response option