Quinolinic Acid: An Endogenous Metabolite That Produces Axon-Sparing Lesions in Rat Brain

Schwarcz, Robert; Whetsell, William O.; Mangano, Richard M.

doi:10.1126/science.6849138

Cited by 1,197 publications

(494 citation statements)

References 33 publications

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“…Quinolinic acid (QA) is an agonist of NMDA receptors and is widely used in experiments to induce excitotoxicity. 11 In the literature, we have found reports of reduced susceptibility to neural damage in six mouse HD models. We have also identified studies on an additional six models where susceptibility to excitotoxicity was not different from that seen in wild-type control mice.…”

Section: Huntingtin Mediates Reduced Susceptibility Against Excitotoxmentioning

confidence: 98%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

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Section: Huntingtin Mediates Reduced Susceptibility Against Excitotoxmentioning

confidence: 98%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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“…The magnitude of this death event is increased in both structures after early (PND7) excitotoxic quinolinic acid (QA) injury to the striatum (Macaya et al, 1994). This lesion spares the terminals of the nigrostriatal dopaminergic projection (Schwarcz et al, 1983;Macaya and Burke, 1992). In both structures, the morphology of the induced death event is apoptotic and indistinguishable from natural cell death.…”

mentioning

confidence: 90%

“…This decrease occurs despite the axon-sparing nature of this injury (Schwarcz et al, 1983;Macaya and Burke, 1992) and in the absence of any direct injury to the SN. We have also shown that natural cell death occurs within the SN pars compacta (SNpc) (Janec and Burke, 1993), with the morphology of apoptosis (Kerr et al, 1972), and that this death event is augmented after excitotoxic (Macaya et al, 1994) injury to the striatum during development.…”

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confidence: 92%

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

et al. 1997

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Many developing neural systems with peripheral projections depend on their target for trophic support during a critical period of natural cell death. Much less is known about central systems. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development is suggested by the presence of a natural apoptotic cell death event in these neurons that can be augmented by an early developmental axon-sparing striatal injury. To further assess the target dependence of these neurons, we have used the selective neurotoxin 6-hydroxydopamine to lesion their terminals within the striatum during development, while sparing intrinsic striatal target neurons. This lesion results in an induction of apoptotic cell death in phenotypically defined dopaminergic neurons that appears on the third postlesion day and persists until the tenth. This inducibility of cell death is dependent on developmental age: it is most marked before postnatal day (PND) 14. As late as PND42, inducibility is still detectable but much less so. In addition, at day 42 the morphology of cell death changes and becomes nonapoptotic in some cells. We conclude that terminal injury during a critical period of postnatal development, like axon-sparing target injury, induces augmented apoptotic death in mesencephalic dopaminergic neurons. These results suggest that these neurons have a period of target dependence. Regulation of this dependence is likely to influence the mature adult number of dopaminergic neurons.

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“…[20][21][22] Overstimulation of NMDA receptors leads to neuronal damage. 23 Neurotoxicity of KYN and its metabolites has been demonstrated in animal studies 19,20,24 and studies using human cell cultures. 25,26 KYN is able to pass the BBB 27 and human microglia have been shown capable of metabolizing this substance into its toxic metabolites.…”

mentioning

confidence: 99%

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

et al. 2004

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Studies show that administration of interferon (IFN)-a causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-a-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-a treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-a treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-a-induced depressive symptoms, through its induction of neurotoxic KYN metabolites. Molecular Psychiatry (2005) 10, 538-544.

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Quinolinic Acid: An Endogenous Metabolite That Produces Axon-Sparing Lesions in Rat Brain

Cited by 1,197 publications

References 33 publications

Mutant huntingtin can paradoxically protect neurons from death

Mutant huntingtin can paradoxically protect neurons from death

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

IDO and interferon-α-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity

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