Homocysteine, a risk factor for atherosclerosis, biphasically changes the endothelial production of kynurenic acid

Stążka, Janusz; Luchowski, Piotr; Urbańska, Ewa M.

doi:10.1016/j.ejphar.2005.04.048

Cited by 21 publications

(13 citation statements)

References 40 publications

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“…Taking into account that the effects of 100 μM Hcy were mediated by NMDA and VDCC Ca 2+ channels and RyR (Loureiro et al, 2008), while the effects of 500 μM Hcy were mediated only by NMDA Ca 2+ channels and RyR, we could propose that different Ca 2+ oscillations would be generated from the different intensities of the insult, activating distinct signaling mechanisms, such as the differential activation of calmodulin, a Ca 2+ binding protein responsible for mediating many of the actions of Ca 2+ , including activation of Ca 2+ /calmodulin‐dependent protein kinases or phosphatases (Selvakumar and Sharma, 2006). In this context, dual action of Hcy has been previously described for other biochemical parameters (Lee et al, 2002; Luchowska et al, 2005; Panganamala et al, 1986; Stazka et al, 2005; Zhang et al, 2005). The high susceptibility of hippocampus to the Hcy insult could be ascribed to the highest level of plasticity of this structure in the brain.…”

Section: Discussionmentioning

confidence: 85%

Hyperhomocysteinemia selectively alters expression and stoichiometry of intermediate filament and induces glutamate‐ and calcium‐mediated mechanisms in rat brain during development

Loureiro

Heimfarth

Pelaez

et al. 2009

Intl J of Devlp Neuroscience

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The aim of the present work was to investigate the actions of a chemically induced chronic hyperhomocysteinemia model on intermediate filaments (IFs) of cortical and hippocampal neural cells and explore signaling mechanisms underlying such effects. Results showed that in hyperhomocysteinemic rats the expression of neural IF subunits was affected. In cerebral cortex, glial fibrillary acidic protein (GFAP) expression was donwregulated while in hippocampus high and middle molecular weight neurofilament subunits (NF-H and NF-M, respectively) were up-regulated. Otherwise, the immunocontent of IF proteins was unaltered in cerebral cortex while in hippocampus the immunocontent of cytoskeletal-associated low molecular weight neurofilament (NF-L) and NF-H subunits suggested a stoichiometric ratio consistent with a decreased amount of core filaments enriched in lateral projections. These effects were not accompanied by an alteration in IF phosphorylation. In vitro results showed that 500muM Hcy-induced protein phosphatases 1-, 2A- and 2B-mediated hypophosphorylation of NF subunits and GFAP in hippocampal slices of 17-day-old rats without affecting the cerebral cortex, showing a window of vulnerability of cytoskeleton in developing hippocampus. Ionotropic and metabotropic glutamate receptors were involved in this action, as well as Ca(2+) release from intracellular stores through ryanodine receptors. We propose that the mechanisms observed in the hippocampus of 17-day-old rats could support the neural damage observed in these animals.

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Section: Discussionmentioning

confidence: 85%

Hyperhomocysteinemia selectively alters expression and stoichiometry of intermediate filament and induces glutamate‐ and calcium‐mediated mechanisms in rat brain during development

Loureiro

Heimfarth

Pelaez

et al. 2009

Intl J of Devlp Neuroscience

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“…Hansen et al [21] demonstrated that vascular endothelial cells were the primary sites of IDO expression in murine malaria infection, and that this response was systemic and INF-γ-dependent. Moreover, it has been demonstrated that vascular endothelium is able to produce and liberate of KYNA [22], and that homocysteine, a risk factor for atherosclerosis, can change its endothelial production [23,24]. Much less is known about the function of KYNA in the periphery.…”

Section: Discussionmentioning

confidence: 99%

Kynurenine pathway – a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients

Pawlak

Myśliwiec

Pawlak

2010

Advances in Medical Sciences

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“…The possible link between vascular function and neuromodulation (central or peripheral) is supported by the ability of glutamate to inhibit kynurenic acid generation. In addition, L‐homocysteine or S‐adenosyl‐homocysteine can exert biphasic effects on kynurenic acid synthesis depending on concentration (Stazka et al ., ). This has in turn led to proposals that endothelial kynurenines may contribute to arterial vessel relaxation and the control of blood pressure.…”

Section: Peripheral Kynurenines and The Cnsmentioning

confidence: 97%

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Stone

Darlington

2013

British J Pharmacology

222

179

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Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition -glutamate and acetylcholine. Since this pathway -the kynurenine pathway of tryptophan metabolism -is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures. The neurochemistry of cognitionThe neural complexity of cognitive function makes it exceptionally difficult to identify specific neurochemical substrates, especially those that could provide pharmacologically relevant targets for the prevention or treatment of cognitive dysfunction (Millan et al., 2012). Most of the recognized neurotransmitters in the CNS have been linked with some aspect of cognition either as primary factors or as systems whose activity is modified as a secondary consequence of a neurochemically distinct previous event. Among the major candidates with a putatively primary role in cognition are the monoamines norepinephrine, dopamine and 5-hydroxytryptamine (5HT) (Dalley et al., 2004;Sarter et al., 2007;Robert and Benoit, 2008;Tadaiesky et al., 2008), although dopamine has received most attention because of its potential links to the cognitive dysfunction seen in schizophrenia and Parkinson's disease (Tadaiesky et al., 2008;Xu et al., 2012), with roles in executive functioning and perceptual response speed that are affected in both disorders (Backman et al., 2010). Several other neurotransmitter systems, such as those releasing histamine and neuropeptides have been implicated in cognitive performance or its modification by drugs (Minzenberg and Carter, 2008).The two systems which have received by far the greatest attention to date are those releasing glutamate or acetylcholine as their transmitters. Both these systems have wellestablished roles in various aspects of cognitive function, with the focus of interest being on glutamate receptors sensitive to the synthetic ligand NMDA (Castellano et al., 2001;Newcomer and Krystal, 2001;Neill et al., 2010). These systems are of particular relevance to this review since the primary compounds of interest -quinolinic acid and kynurenic acid -both have prominent actions on them. Conversely, little is known of the possible interactions between the kynurenine pathway and other systems contributing to cognitive function, so the focus of this review will be limited to glutamatergic and cholinergi...

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Homocysteine, a risk factor for atherosclerosis, biphasically changes the endothelial production of kynurenic acid

Cited by 21 publications

References 40 publications

Hyperhomocysteinemia selectively alters expression and stoichiometry of intermediate filament and induces glutamate‐ and calcium‐mediated mechanisms in rat brain during development

Hyperhomocysteinemia selectively alters expression and stoichiometry of intermediate filament and induces glutamate‐ and calcium‐mediated mechanisms in rat brain during development

Kynurenine pathway – a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

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