Excitatory amino acids and neurodegeneration: a hypothetical role of calcium precipitation

Abstract

Activation of excitatory amino acid (EAA) receptors can induce neurodegeneration by two major mechanisms of excitotoxicity, one related to the influx of Na(+), Cl(-) and water, and the other to the increase in intracellular calcium concentration ([Ca(2+)](i)). Thus, acute microinjection of EAAs in several areas of the central nervous system (CNS) has been used to produce neurodegenerative models. We studied the excitotoxic pattern associated with acute microinjection of AMPA in rat hippocampus, medial septum-diagonal band of Broca (MS-DBB), prefrontal cortex and retina. In all cases progressive neuronal loss, glial reaction and development of intra- and extracellular calcium concretions were observed. However, a CNS-area differential vulnerability was revealed, as shown by the specific atrophy of MS-DBB and its limited calcification. Whether calcium deposits are a defensive mechanism against the massive increment of free cytoplasmatic calcium is discussed on the basis of ultrastructural data and previous results.

Substance-Related Disorders and Somatic Symptoms: How Should Clinicians Understand the Associations?

“…Although the significance of cellular calcification is unknown, a number of points suggest that it is part of the compensatory mechanisms for excitotoxic 25/48 neurodegeneration. For example, the observation that mitochondria close to Ca 2+ concretions appear normal at the electron microscopy level supports this hypothesis [71], despite the fact that mitochondrial dysfunction constitutes a primary event in NMDA-induced degeneration in cultured hippocampal neurons [117]. This hypothesis is also consistent with the finding that neurons undergoing prolonged stimulation of NMDA receptors can survive in the presence of [Ca 2+ ] i chelators.…”

“…2), a ratio lower than the theoretical apatite value of 1.67. This ratio is also typical of biological crystals which do not have an ideal organization [71]. As biological hydroxyapatites, these deposits are similar to 13/48 those observed in several peripheral human tissues [77;78].…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…In all MPDs, the pathogenic mechanism represents the initial aggregation and CNS deposition of a misfolded protein in specific neurons and/or astroglia that grow following a crystallization-like process [68][69][70] Elaborate systems have evolved to protect cells from misfolded proteins. An example is the ubiquitin-proteasome system, which degrades the newly translated proteins that failed to fold correctly [72,73].…”

Microglia, Calcification and Neurodegenerative Diseases

“…Consequently, astrocyte dysfunction can lead to increased synaptic glutamate levels and glutamate receptor overactivation, combined with reduced neuronal energy, resulting in neuronal damage. Under these conditions of high Ca 2+ and Pi and low ATP, formation of hydroxyapatite precipitates to reduce Ca 2+ cytoplasm activity at low energy costs can occur in neurons and astrocytes (Rodriguez et al, 2000). This new step in calcium homeostasis temporarily helps the cell to resist excessive stimulatory signals and return to basal activity by dissolving paracrystal elements.…”

“…Glutamate analog microinjection in rat CNS leads to an intracellular Ca 2+ precipitation similar to brain calcification in humans (Ramonet et al, 2006(Ramonet et al, , 2002. As these Ca 2+ deposits can be observed in several areas of rat brain after microinjection of different excitotoxins (Bernal et al, 2000b, Rodriguez et al, 2000, Saura et al, 1995, their formation does not depend on the glutamate receptor subtype initially stimulated. However, their size, number and distribution vary with both the activated receptor and the CNS area.…”