Excitotoxins constitute a group of agents that are capable of activating excitatory amino acid receptors and producing axon-sparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid and ibotenic acid result in depletion of neurotransmitter markers in neuronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave as excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin. In the mammalian brain QUIN has been localized to glial and immune cells, and its content increases with age. The neuro-excitatory and neurotoxic actions of QUIN are mediated via the Mg2+-sensitive N-methyl-D-aspartate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate–aspartate afferent input to the target area. Focal injections of QUIN into the nucleus basalis magnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas, produce sustained loss of cholinergic neuron markers in the neocortex and amygdala. The neurotoxic action of QUIN on nbM results in an impairment of performance on memory-related tasks. Cortical and amygdaloid projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the reported discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of certain excitotoxins. Cortical muscarinic receptor function is not significantly influenced by QUIN injections into the nbM producing loss of cortical cholinergic neurons. In the striatum, focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease, an inherited movement disorder. Intrastriatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the adjacent transition zone. QUIN is also highly damaging to the striatopallidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce significant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yielding QUIN produces a number of intermediates that act as excitotoxin antagonists. Kynurenic acid, the most potent of these endogenous agents, blocks the action of QUIN and other excitotoxins that act on NMDA and non-NMDA receptors. Picolinic acid, a pyridine monocarboxylic acid, also attenuates QUIN toxicity. However, it only influences excitotoxins that require an intact glutamatergic afferent input to the target area for the expression of their neurotoxic action. Although picolinic acid modulates presynaptic glutamate release in vitro, this action does not entirely explain its restricted anti-excitotoxic action. The presence of several endogenous excitotoxin antagonists in the CNS has important implications for neuron survival. A balance between endogenous excitotoxins and their built-in antagonists may influence the viability of neuronal groups in the CNS. It also suggests a novel strategy for influencing excitotoxicity through elevations in levels of endogenous antagonists. Nicotinylalanine, an enzyme inhibitor, elevates brain kynurenate levels and exhibits potential for anticonvulsant and anti-excitotoxic action. The study of QUIN and related agents holds promise of understanding factors that underlie neuronal damage and developing novel agents to reduce or prevent this damage in areas of the CNS affected in neurodegenerative disease.Key words: quinolinic acid, brain, neurotransmitters, deficits, excitotoxin, antagonists.
Why the Reactive Oxygen Species of the Fenton Reaction Switches from Oxoiron(IV) Species to Hydroxyl Radical in Phosphate Buffer Solutions? A Computational Rationale
