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Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides., Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year's promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multiple sclerosis is a common chronic, disabling autoimmune neurological disease affecting mainly young adults. In its pathomechanism, neurodegenerative and acute inflammatory characteristics are both involved. Disease-modifying therapies aim to reduce relapse-rate and slow down the deterioration in neurological functions. The currently available therapies fail to exert neuroprotective effects and most of them are associated with potentially toxic side-effects, therefore, ongoing research aims to develop novel drug candidates to cover these therapeutic gaps. The kynurenine pathway has been implicated in both the physiological processes of the central nervous system and in the pathomechanism of several neurological disorders as well. Alterations of the kynurenine pathway metabolites have been detected in multiple sclerosis and a number of potential therapeutic targets related to this metabolic route have been already identified. Laquinimod is a quinoline carboxamide showing structural similarities with kynurenic acid, which proved to have beneficial effects on reduction of brain atrophy and disability progression. The kynurenine pathway is therefore a promising target for the development of future drugs for the treatment of autoimmune diseases such as multiple sclerosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Parkinson's disease (PD) is a progressive neurodegenerative disorder with prominent motor and non-motor symptoms. Psychosis develops in over 40% of PD patients and it is one of the most distressing symptoms for patients and caregivers alike. Until recently, atypical antipsychotics, clozapine and quetiapine were used to treat psychotic symptoms, but treatment was associated with substantial concerns for side-effects of clozapine and unfounded efficacy for quetiapine. Extensive research has shown that the antipsychotic effect of these drugs could be attributed to serotonin 2a receptor (5-HT2A) triggered mechanisms. A selective 5-HT2A inverse agonist, pimavanserin, has been developed, investigated and has gained approval in April 2016 in the US for the treatment of hallucinations and delusions in PD. In this review we primarily focus on psychosis in PD, the current treatment possibilities and the new, emerging therapy, pimavanserin, a selective 5-HT2A inverse agonist. All articles were reviewed in this topic and indexed in PubMed with keywords: Parkinson's disease psychosis, serotonin 2a receptor inverse agonist, clozapine, quetiapine, pimavanserin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Migraine is a highly disabling neurovascular primary headache disorder, with its exact pathomechanism being still unrevealed. The current leading hypotheses are based on the sensitization and activation of the trigeminovascular system., Objective: To review the literature with focus on the effects of kynurenines (L-kynurenine and kynurenic acid) and pituitary adenylate cyclase-activating polypeptide on the regulation of the trigeminovascular system., Method: A literature search was conducted to identify preclinical and clinical publications (198 references) by using the keywords 'kynurenines', 'pituitary adenylate cyclase-activating polypeptide', and 'migraine' in the database of MEDLINE/PubMed up to 10 September 2016 for topical review. Additional filters used included 'review', 'systematic review', 'original article', and 'English language'., Results: L-kynurenine and kynurenic acid act on the glutamatergic system at the level of the second-order nociceptive neurons in the trigeminal nucleus caudalis. Pituitary adenylate cyclase- activating polypeptide is released from the peripheral nerve endings of the trigeminal pseudounipolar neurons and causes vasodilation and mast cell degranulation, leading to consequent peripheral sensitization of the dural nociceptors. Centrally released pituitary adenylate cyclase-activating polypeptide in the trigeminal nucleus caudalis results in the central sensitization of the second-order neurons. The sensitization process leads to the characteristic features of migraine., Conclusion: L-kynurenine, kynurenic acid, and pituitary adenylate cyclase-activating polypeptide may have fundamental roles in the initiation of migraine headache attacks., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential., Objective: To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials., Method: A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'., Results: MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well., Conclusion: Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms., Objective: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation., Method: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published until January 2017., Results: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant results compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC1), and kynurenic acid (KYNA) analogues., Conclusion: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Alzheimer's disease (AD) is an age-related neurodegenerative disease and the most common cause of dementia. The etiology of AD is not entirely clear and despite the increasing knowledge regarding the pathomechanism, no effective disease-modifying therapy is yet available. Astrocytes earlier presumed to serve merely supportive roles for the neuronal network, have recently been shown to play an active role in the synaptic dysfunction, impairment of homeostasis, inflammation as well as excitotoxicity in relation to AD pathology. This review focuses on the pathomechanism of AD with special attention to the role of the astrocytes, excitotoxicity and the alterations in the kynurenine metabolism in the development of the disease. The correction of the neuroprotective/neurotoxic imbalance in the kynurenine pathway may represent a novel target for pharmaceutical interventions in dementia related to neurodegenerative disorders.

Though migraine and neurodegenerative disorders have a high socioeconomic impact, their therapeutic management has not been fully addressed. Their pathomechanisms are not completely understood, but glutamateinduced excitotoxicity, mitochondrial disturbances and oxidative stress all seem to play crucial roles. The overactivation of glutamate receptors contributes to the hyperexcitability observed in migraine and also to the neurodegenerative process. The kynurenine pathway of the tryptophan metabolism produces the only known endogenous Nmethyl- D-aspartate receptor antagonist, kynurenic acid, which has been proven in different preclinical studies to exert a neuroprotective effect. Influencing the kynurenine pathway might be beneficial in migraine and neurodegenerative diseases, and in the normalization of glutamatergic neurotransmission and the prevention of excitotoxic neuronal damage. The synthesis of kynurenic acid analogues may offer a valuable tool for drug development.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are widely distributed at different levels of the pain-processing pathway. Its action at the peripheral sensory nerve terminals has been found to be divergent; it can exert both pro- and anti-nociceptive effects, depending on the mode of administration (local or systemic) and the mechanism of the pain process (acute or chronic, inflammatory or neuropathic). In the central nervous system it exerts mainly neuronal excitation, leading to increased nociceptive signalling. Since the clinical data strongly suggest the involvement of PACAP in the pathophysiology of migraine, special emphasis is placed on examinations of its role and the mechanisms of activation of the trigeminovascular system. The intravenous administration of PACAP to migraineurs induces migraine-like headache and extracranial arterial dilatation. Furthermore, an increased PACAP concentration has been detected in the peripheral blood of patients during a migraine attack. Animal experiments have also revealed that PACAP elicits peripheral and central sensitization of the neuronal elements of the trigeminovascular system and evokes meningeal vasodilatation. This review summarizes data relating to the expression of PACAP and its receptors, and the main effects and mechanisms in the nociceptive pathways, with special emphasis on migraine. It is clear that PACAP plays an excitatory role in migraine, but its target and signalling pathways have not yet been elucidated due to the lack of non-peptide, selective agonists and antagonists. Identification of its up- and downstream regulations and receptorial molecular mechanisms might open up future perspectives for the development of novel analgesic drugs.

There is an increasing number of evidence showing analgesic properties of the kynurenic acid (KYNA), and also some studies demonstrate that kynurenine might interact with the opioid system. Therefore in this study, for the first time we investigated the direct binding affinity of KYNA and its structural analog KYNA-1 towards mu, kappa and delta opioid receptor in competition binding experiments applying opioid receptor specific radioligands. The binding affinity measurements were performed in Chinese hamster ovary cell lines overexpressing the corresponding opioid receptor (mu and kappa opioid receptor were rat, delta opioid receptor were mouse sequence). Additionally we also examined the chronic effect of these compounds on mu, kappa and delta opioid receptor and also nociceptin peptide receptor mediated G-protein activity in [(35)S]GTPγS binding assays performed in mouse cortex and striatum membranes. Our results showed that KYNA and KYNA-1 had no affinity towards any of the three classic opioid receptors. On the other hand the compounds significantly decreased opioid and nociceptin receptor mediated G-protein activity or in some cases enhanced the potency of the activating ligand. Moreover, the alterations were receptor and brain region specific. Accordingly, we conclude that KYNA and KYNA-1 do not interact directly with the opioid receptors, but more likely alter the receptor functions intracellularly.

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.

Substantial evidence indicates that neuroactive kynurenine metabolites play a role in the normal physiology of the human brain, and are involved in the pathology of neurodegenerative disorders such as Parkinson's disease and Huntington's disease. A side-arm product of the pathway, kynurenic acid (KYNA), which is synthesized by the irreversible transamination of kynurenine (KYN) by kynurenine aminotransferases (KAT I and KAT II), is an excitatory amino acid receptor antagonist. In the present study, we measured the level of KYNA and the activities of the biosynthetic enzyme isoforms KAT I and KAT II in the plasma and in the erythrocytes (RBCs) of patients with cervical dystonia or blepharospasm and in age-matched controls. The KAT I and KAT II activities were significantly lower in the plasma of the patients in both subgroups. In the RBCs, only the KAT I activity was elevated significantly. The KYNA concentration was unchanged in both type of patients. These data support the contribution of an altered kynurenine metabolism to the pathogenesis of focal dystonia.