Levente Szalárdy

Kynurenines in the CNS: recent advances and new questions

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntingtons disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders

A mitochondrial dysfunction causes an abatement in ATP production, the induction of oxidative damage and the propagation of cell death pathways. It is additionally closely related to both glutamate excitotoxicity and neuroinflammation. All of these interconnected aspects of a cellular dysfunction are involved in the pathogenesis of numerous neurological disorders, including those with an acute (e.g. ischemic stroke) or a chronic (e.g. Huntingtons disease) onset. Both acute and chronic neurodegenerative disorders have been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism in the pathogenesis of the disease. As regards neuroactive compounds featuring in the pathway, quinolinic acid is a specific agonist of N-methyl-d-aspartate receptors, and a potent neurotoxin with additional and marked free radical-producing and lipid peroxidation-inducing properties. The toxic effects of 3-hydroxy-L-kynurenine are mediated by free radicals. Besides the possibility of increasing brain kynurenic acid concentrations, L-kynurenine may have vasoactive properties, too. Kynurenic acid has proven to be neuroprotective in several experimental settings, but in consequence of its pharmacokinetic properties it is not applicable as systemic administration in human cases. The aim of this short review is to emphasize the common features of cerebral ischemia and Huntingtons disease and to highlight therapeutic strategies targeting the kynurenine pathway.

Glutamatergic Dysfunctioning in Alzheimer's Disease and Related Therapeutic Targets

The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimers disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development.

Mitochondrial disturbances, tryptophan metabolites and neurodegeneration: Medicinal chemistry aspects

Neurodegenerative disorders, e.g. Parkinsons, Huntingtons and Alzheimers diseases are distinct clinical and pathological entities sharing a number of leading features in their underlying processes. These common features involve the disturbances in the normal functioning of the mitochondria and the alterations in the delicate balance of tryptophan metabolism. The development of agents capable of halting the progression of these diseases is in the limelight of neuroscience research. This review highlights the role of mitochondria in the development of neurodegenerative processes with special focus on the involvement of neuroactive kynurenines both as pathological agents and potential targets and tools for future therapeutic approaches by providing a comprehensive summary of the main streams of rational drug design and giving an insight into present clinical achievements.

Evaluating biomarkers of neuronal degeneration and neuroinflammation in CSF of patients with multiple sclerosis-osteopontin as a potential marker of clinical severity

Biomarkers capable of predicting the clinical course and the rate of disease progression in multiple sclerosis are currently unavailable. Our objective was to examine if the levels of proteins associated with axonal and neuronal degeneration (Tau, p-Tau and β-amyloid(1-42)) and T-cell-mediated autoimmunity (osteopontin) are altered in the cerebrospinal fluid (CSF) of MS patients, and to assess their potential in reflecting the clinical severity and predicting the progression and clinical evolution of early MS. The CSF samples collected from patients presenting with different clinical forms of MS were evaluated by enzyme-linked immunosorbent assays. The patients were regularly followed-up and their clinical status was re-evaluated 5 years after sampling. The results demonstrated that while CSF levels of Tau, p-Tau and β-amyloid(1-42) did not differ between MS and Control groups, the levels of osteopontin were significantly elevated in MS patients. This increase was associated with the presence of a relapse and correlated with clinical severity, which findings were independent of age and blood-CSF barrier function. However, none of the examined protein levels differed significantly between groups with different clinical evolutions and no positive correlations with clinical progression could be detected. We conclude that Tau, p-Tau and β-amyloid(1-42) are inappropriate as biomarkers in MS. This is the first report on CSF osteopontin as an independent marker of clinical severity in definite MS.

Association of vitamin D receptor gene polymorphisms and Parkinson's disease in Hungarians

Vitamin D receptor (VDR) gene encodes a transcription factor that influences calcium homeostasis and immunoregulation, and may play a role in neurological disorders including Parkinsons disease (PD). The investigations of the association between VDR and PD in different populations revealed various results. In a present study 100 PD patients and 109 healthy controls from the Hungarian population were genotyped for four polymorphic sites (BsmI, ApaI, FokI and TaqI) in the VDR gene. The polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Our results demonstrate an association between the FokI C allele and PD; the frequency of the C allele was significantly higher in PD patients than in controls, suggesting that this polymorphism may have a role in the development of PD in these patients.

Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction

A number of neurodegenerative diseases have been associated with potentially neurotoxic alterations in the kynurenine pathway. Due to the potent inhibitory effect of kynurenic acid on glutamate receptor function, the potential use of the elevation of its concentrations in the brain in the protection against excitotoxic injury has earned an ever greater interest. The first strong preclinical achievements of protection in transgenic murine models of chronic neurodegenerative diseases by kynurenergic approaches have recently been published. Despite the remarkable neuroprotection provided by these molecules, the potential risk of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be considered. This issue is of particular interest in light of the high affinity of kynurenic acid towards the glycine site of NMDA receptors, the antagonism of which is known to recapitulate key behavioral features of schizophrenia. In the past decade, however, a number of other sites of action have been revealed, most of them being possible contributors of either the neuroprotective or the cognitive deteriorating effects of kynurenic acid. This paper reviews the current understanding about how kynurenic acid can influence cognitive functions in experimental animals, and discusses the possibility of exploiting the neuroprotective potential of kynurenic acid without impairing cognitive functions.

Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics.

Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinsons and Huntingtons diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinsons and Huntingtons disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes.

Elevated levels of PPAR-gamma in the cerebrospinal fluid of patients with multiple sclerosis

Peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcriptional factor involved in the regulation of glucose and lipid metabolism, has gained interest as a potential therapeutic target in multiple sclerosis (MS) due to its potent immunoregulatory properties and the therapeutic efficacy of its ligands in experimental autoimmune encephalitis (EAE). Elevated expression of PPARγ has been observed in the spinal cord of EAE mice and in an in vitro model of antigen-induced demyelination; however, no reports have yet been available on the PPARγ status in the central nervous system of human individuals with MS. Aiming to identify a possible alteration, the present study assessed the levels of PPARγ protein in the cerebrospinal fluid (CSF) of MS patients via ELISA technique. We report a pronounced elevation in the CSF levels of PPARγ in MS patients (n=35) compared to non-inflammatory controls (n=22). This elevation was independent of blood-CSF barrier integrity, but correlated with CSF white blood cell count and IgG index, associating the observed elevation with neuroinflammation. Controlling for potential confounders, the CSF levels of PPARγ further displayed a moderate but significant association with clinical severity. Corroborating with prior experimental findings, these results may contribute to our understanding about the role of PPARγ in MS, and may implicate this protein as a potential CSF biomarker of the disease.

Some molecular mechanisms of dopaminergic and glutamatergic dysfunctioning in Parkinson’s disease

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder with a considerable socioeconomic burden. The pathomechanism of PD clearly involves the synergistic interaction of dopaminergic and glutamatergic dysfunctioning, including maladaptive corticostriatal synaptoplasticity. Most of the available treatment options have the aim of restoration of the physiological dopaminergic activity. Currently, the most widely used treatment is l-3,4-dihydroxyphenylalanine (l-DOPA), which leads to the best symptomatic relief in PD. However, the long-term use of l-DOPA results in abnormal involuntary movements in almost all cases, the development of these dyskinetic movements also involving maladaptive corticostriatal synaptoplasticity. Perhaps chronic l-DOPA treatment has neurotoxic effects as well, but it has not yet been proved in clinical studies. Another important group of dopamine replacement therapy (DRT)-related side-effects consists of disinhibitory psychopathologies. Recent studies revealed that genetic polymorphisms affecting certain dopaminergic and glutamatergic receptors serve as independent risk factors for the development of these pathological conditions in PD patients. The available scientific data demonstrate that alterations in the kynurenine pathway of the tryptophan metabolism can be observed in PD and these alterations may contribute to the disease pathogenesis and to the occurrence of DRT-related side-effects. Therapeutic strategies that target the restoration of the kynurenine metabolism could therefore hold promise.