Kynurenic acid protects against ischemia/reperfusion injury by modulating apoptosis in cardiomyocytes.

Acute myocardial infarction, often associated with ischemia/reperfusion injury (I/R), is a leading cause of death worldwide. Although the endogenous tryptophan metabolite kynurenic acid (KYNA) has been shown to exert protection against I/R injury, its mechanism of action at the cellular and molecular level is not well understood yet. Therefore, we examined the potential involvement of antiapoptotic mechanisms, as well as N-methyl-D-aspartate (NMDA) receptor modulation in the protective effect of KYNA in cardiac cells exposed to simulated I/R (SI/R). KYNA was shown to attenuate cell death induced by SI/R dose-dependently in H9c2 cells or primary rat cardiomyocytes. Analysis of morphological and molecular markers of apoptosis (i.e., membrane blebbing, apoptotic nuclear morphology, DNA double-strand breaks, activation of caspases) revealed considerably increased apoptotic activity in cardiac cells undergoing SI/R. The investigated apoptotic markers were substantially improved by treatment with the cytoprotective dose of KYNA. Although cardiac cells were shown to express NMDA receptors, another NMDA antagonist structurally different from KYNA was unable to protect against SI/R-induced cell death. Our findings provide evidence that the protective effect of KYNA against SI/R-induced cardiac cell injury involves antiapoptotic mechanisms, that seem to evoke independently of NMDA receptor signaling.

Revolutionizing our understanding of Parkinson's disease: Dr. Heinz Reichmann's pioneering research and future research direction.

Millions of individuals around the world are afflicted with Parkinson's disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann's work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann's findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.

The 7-year follow-up of the Hungarian BICAMS validation cohort implies that cognitive performance may improve in multiple sclerosis patients.

BACKGROUND: Cognitive impairment (CI) is a frequent symptom of multiple sclerosis (MS) and has a great impact on the patients' quality of life, so screening is essential. The brief international cognitive assessment for multiple sclerosis (BICAMS) was developed for this purpose. However, longitudinal data is lacking with the use of the battery. OBJECTIVE: This study is to assess the performance of patients after 5 and 7 years of the original BICAMS validation study and to identify any influencing factors. METHODS: BICAMS was used to measure cognitive function of 52 relapsing-remitting MS patients (RRMS) from the original validation study after 5 years (n = 43) and again, after 7 years (n = 42). Patients filled out the fatigue impact scale (FIS) and multiple sclerosis quality of life-54 (MSQoL-54) questionnaire, and we evaluated expanded disability status scale (EDSS). RESULTS: There was an improvement in the BVMT-R and the CVLT-II assessments at both the 5-year (p<0.001 and p=0.025) and the 7-year retest (p<0.001 and p=0.002). The prevalence of CI significantly decreased at the 5-year mark (p=0.021) but remained stable after that. There was no deterioration in MSQoL scores during the study. The basic cognitive performance is the most important influencing factor, but the duration of the disease, the EDSS score, and the escalation of the therapy also affect the cognitive scores. CONCLUSION: This is the longest longitudinal study utilizing the BICAMS battery, reinforcing its feasibility as a clinical screening tool. It seems that cognitive performance may improve in the long term and early initiation of effective therapy may influence this outcome.

Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora.

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.

Neural Correlates and Molecular Mechanisms of Memory and Learning.

Memory and learning are essential cognitive processes that enable us to obtain, retain, and recall information [...].

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain.

The central nervous system (CNS) is the final frontier in drug delivery because of the blood-brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions, and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain-modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically, SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open-field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 µmol/4 µL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 µmol/4 µL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior.

The role of kynurenines in migraine-related neuroimmune pathways.

Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.

Smouldering Lesion in MS: Microglia, Lymphocytes and Pathobiochemical Mechanisms.

Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Immune cell infiltration can lead to permanent activation of macrophages and microglia in the parenchyma, resulting in demyelination and neurodegeneration. Thus, neurodegeneration that begins with acute lymphocytic inflammation may progress to chronic inflammation. This chronic inflammation is thought to underlie the development of so-called smouldering lesions. These lesions evolve from acute inflammatory lesions and are associated with continuous low-grade demyelination and neurodegeneration over many years. Their presence is associated with poor disease prognosis and promotes the transition to progressive MS, which may later manifest clinically as progressive MS when neurodegeneration exceeds the upper limit of functional compensation. In smouldering lesions, in the presence of only moderate inflammatory activity, a toxic environment is clearly identifiable and contributes to the progressive degeneration of neurons, axons, and oligodendrocytes and, thus, to clinical disease progression. In addition to the cells of the immune system, the development of oxidative stress in MS lesions, mitochondrial damage, and hypoxia caused by the resulting energy deficit and iron accumulation are thought to play a role in this process. In addition to classical immune mediators, this chronic toxic environment contains high concentrations of oxidants and iron ions, as well as the excitatory neurotransmitter glutamate. In this review, we will discuss how these pathobiochemical markers and mechanisms, alone or in combination, lead to neuronal, axonal, and glial cell death and ultimately to the process of neuroinflammation and neurodegeneration, and then discuss the concepts and conclusions that emerge from these findings. Understanding the role of these pathobiochemical markers would be important to gain a better insight into the relationship between the clinical classification and the pathomechanism of MS.

Ion Channel Disturbances in Migraine Headache: Exploring the Potential Role of the Kynurenine System in the Context of the Trigeminovascular System.

Migraine is a primary headache disorder, which is an enormous burden to the healthcare system. While some aspects of the pathomechanism of migraines remain unknown, the most accepted theory is that activation and sensitization of the trigeminovascular system are essential during migraine attacks. In recent decades, it has been suggested that ion channels may be important participants in the pathogenesis of migraine. Numerous ion channels are expressed in the peripheral and central nervous systems, including the trigeminovascular system, affecting neuron excitability, synaptic energy homeostasis, inflammatory signaling, and pain sensation. Dysfunction of ion channels could result in neuronal excitability and peripheral or central sensitization. This narrative review covers the current understanding of the biological mechanisms leading to activation and sensitization of the trigeminovascular pain pathway, with a focus on recent findings on ion channel activation and modulation. Furthermore, we focus on the kynurenine pathway since this system contains kynurenic acid, which is an endogenous glutamate receptor antagonist substance, and it has a role in migraine pathophysiology.

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain.

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP.

Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models.

Revealing the underlying pathomechanisms of neurological and psychiatric disorders, searching for new biomarkers, and developing novel therapeutics all require translational research [...].

Differential Effects of Hypothermia and SZR72 on Cerebral Kynurenine and Kynurenic Acid in a Piglet Model of Hypoxic-Ischemic Encephalopathy.

Kynurenic acid (KYNA), an endogenous neuroprotectant with antiexcitotoxic, antioxidant, and anti-inflammatory effects, is synthesized through the tryptophan-kynurenine (KYN) pathway. We investigated whether brain KYN or KYNA levels were affected by asphyxia in a translational piglet model of hypoxic-ischemic encephalopathy (HIE). We also studied brain levels of the putative blood-brain barrier (BBB) permeable neuroprotective KYNA analogue SZR72, and whether SZR72 or therapeutic hypothermia (TH) modified KYN or KYNA levels. KYN, KYNA, and SZR72 levels were determined using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry in five brain regions 24 h after 20 min of asphyxia in vehicle-, SZR72- and TH-treated newborn piglets (n = 6-6-6) and naive controls (n = 4). Endogenous brain KYN levels (median range 311.2-965.6 pmol/g) exceeded KYNA concentrations (4.5-6.0 pmol/g) ~100-fold. Asphyxia significantly increased cerebral KYN and KYNA levels in all regions (1512.0-3273.9 and 16.9-21.2 pmol/g, respectively), increasing the KYN/Tryptophan-, but retaining the KYNA/KYN ratio. SZR72 treatment resulted in very high cerebral SZR72 levels (13.2-33.2 nmol/g); however, KYN and KYNA levels remained similar to those of the vehicle-treated animals. However, TH virtually ameliorated asphyxia-induced elevations in brain KYN and KYNA levels. The present study reports for the first time that the KYN pathway is altered during HIE development in the piglet. SZR72 readily crosses the BBB in piglets but fails to affect cerebral KYNA levels. Beneficial effects of TH may include restoration of the tryptophan metabolism to pre-asphyxia levels.

Cluster headache and kynurenines.

BACKGROUND: The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements. FINDINGS: Significantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid. CONCLUSIONS: Our results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH.

[Headache registry in Szeged: Experiences regarding to migraine patients]. / Fejfájásregiszter kialakításával szerzett szegedi tapasztalataink migrénes betegek vonatkozásában.

Background and purpose:

Using patient registries is essential both in clinical research and in medical practice. Headaches, more specifically migraines are one of the most common complaints that can detract the quality of a patient’s life and these complaints also have a significant socio-econo­mic effect. Our goal is to create a national Headache Registry and to also provide the pre-analysis of the registry’s database.

Our research is based on the national Multiple Sclerosis Registry, which we modified using the latest version of diagnostic criteria published by the International Headache Society. This clinical study contains data collected from patients suffering from migraines and currently receiving care at the Headache Outpatient Department at the Neurologic Clinic of the University of Szeged.

The data of 412 patients (363 wo­men and 49 men) suffering from migraine (migraine without aura: n = 313 and migraine with aura: n = 99) were added to the Headache Registry. The average age of participants was 44.1 ± 12.5 SD years. Regarding the attributes of migraine headaches we examined the following characteristics: localization, quality and intensity (based on the Visual Analogue Scale) of the pain, frequency (the number of headache days per month), medications (acute or prophylactic), comorbidities (depression, anxiety, hypertension, asthma, epilepsy and others), family history and the occurrence of stroke among patients.

Based on international expe­rience, patient registries are the most optimal systems for structured patient mo­nitoring. For high level management and long-term follow up of the patients the application of registries is essential. The registries include the detailed medical history and the diagnostic and therapeutic data of the patients, and they trace the changes during the follow up medical visits. Registries are able to record the entire course of the disease in digital way. The numerous data can be set out any time from the digital database. Extensive spread of patients’ registries is fundamental not only in every day clinical practice, but also in clinical research.

Personality traits and psychological complaints under patients suffering from headaches.

Background and purpose:

Although headaches are often comorbid with psychological symptoms, the underlying psychological processes, e.g. the role of personality dimensions as headache determinants remains unclear. Studies found associations between headaches and various personality traits; according to the Big Five model of personality, persons suffering from headaches exhibit a higher rate in neuroticism, while a lower rate in extraversion, openness to experiences and positive emotions. This is the first study to clarify the associations among duration, intensity, and frequency of headaches and personality dimensions. Through this study we could get into the personality dimensions in the background of pain experience and that which personality dimensions bear a part in the behaviour of the persons, who suffered from headache, but do not seek treatment through this complaint. 

Treated (Group1) and untreated (Group2) headache patients and healthy controls (Group3) were investigated (total of 360 participants). The main headache components of intensity, duration, and frequency were used as dependent variables with personality dimensions in the Big Five concept investigated by the NEO-PI-R Personality Inventory.

Employing multiple regression analysis, facets of personality described 14.7% of headache intensity, 10.9 % of duration, and 18.7 % of frequency variance. Group1 and Group2 reached significantly higher values on the dimension of anxiety, depression, and vulnerability to stress than Group3. Group1 showed a significantly higher value on trust personality dimension than Group3 and Group2. Group3 exhibited a significantly higher value in the trust dimension than Group2. Concerning vulnerability to stress, the highest value was yielded by the “treated and suffering from headaches” group and there was a significant difference also with the “untreated and suffering from headaches” group and with the control group. In this dimension, the “untreated and suffering from headaches” group’s point value was significantly higher than the control group’s (p<0.01, U=-4.501).

Our study demonstrates that the three headache components are not independent from personality traits, and personality traits may interact with treatment seeking behavior even in the presence of significant headache complaints. The role of the personality traits are significant in the intensity, duration and frequency of headaches. 

Modelling the neurodevelopmental pathogenesis in neuropsychiatric disorders. Bioactive kynurenines and their analogues as neuroprotective agents-in celebration of 80th birthday of Professor Peter Riederer.

Following introduction of the monoamine oxidase type B inhibitor selegiline for the treatment of Parkinson's disease (PD), discovery of the action mechanism of Alzheimer's disease-modifying agent memantine, the role of iron in PD, and the loss of electron transport chain complex I in PD, and development of the concept of clinical neuroprotection, Peter Riederer launched one of the most challenging research project neurodevelopmental aspects of neuropsychiatric disorders. The neurodevelopmental theory holds that a disruption of normal brain development in utero or during early life underlies the subsequent emergence of neuropsychiatric symptoms during later life. Indeed, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and the International Classification of Diseases, 11th Revision categorize autism spectrum disorder and attention deficit hyperactivity disorder in neurodevelopmental disorders (NDDs). More and more evidence, especially from preclinical studies, is revealing that neurodevelopmental pathology is not limited to the diagnostic class above, but also contributes to the development of other psychiatric disorders such as schizophrenia, bipolar disorder, and obsessive-compulsive disorder as well as neurodegenerative diseases such as PD and Huntington's disease. Preclinical animal research is taking a lead in understanding the pathomechanisms of NDDs, searching for novel targets, and developing new neuroprotective agents against NDDs. This narrative review discusses emerging evidence of the neurodevelopmental etiology of neuropsychiatric disorders, recent advances in modelling neurodevelopmental pathogenesis, potential strategies of clinical neuroprotection using novel kynurenine metabolites and analogues, and future research direction for NDDs.

Rare co-occurrence of multiple sclerosis and Wilson's disease - case report.

BACKGROUND: Wilson's disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). The co-occurrence of these two, although not unheard of in literature, is still considered to be very rare and can give rise to diagnostic difficulties. Also, comorbidity in MS highly influences quality of life and disease progression, which makes the timely diagnosis and treatment of these conditions essential. CASE PRESENTATION: The aim of this study is to present a patient exhibiting symptoms of both MS and Wilson's disease, as well as to conduct a detailed review of previously reported cases. The patient's neurological symptoms (sensory disorder) as well as MRI and CSF findings were characteristic for MS. The diagnosis of MS preceded that of Wilson's disease and was relatively mild in course. Currently, the patient receives cladribine as an immunomodulatory treatment after escalation from glatiramer acetate therapy. Apart from one episode of acute hepatic decompensation, during which transfusion, albumin supplementation and diuretic treatment was necessary, Wilson's disease manifested as chronic impairment of liver function. The diagnosis of Wilson's disease was established by the analysis of serum coeruloplasmin levels, histological examination and genetic findings. Continuous oral penicillamine therapy led to the slow normalization of hepatic function and significant amelioration of the patient's symptoms. Correlating with cases previously reported, the course of MS was relatively mild, and like in three out of four other known cases, the symptoms of Wilson's disease were mostly restricted to hepatic dysfunction. CONCLUSION: The case presented in our report is similar to those reported before. The co-occurrence of the two diseases seems to be more a coincidence than a sharing of common factors in their pathogenesis; however, they are considered to influence one another. Regarding rare co-occurrences such as this one, every new case is of high importance, as it enables a better evaluation and understanding of the clinical presentations that are more characteristic of these cases, thus aiding the estimation of disease course as well as possible therapeutic choices.

Editorial of Special Issue 'Dissecting Neurological and Neuropsychiatric Diseases: Neurodegeneration and Neuroprotection'.

This Special Issue has focused on dissecting the neuroprotective and neurodegenerative components of neurological and neuropsychiatric diseases, highlighting the latest advance in understanding the etiology, pathomechanism, biomarkers, imaging techniques, and novel therapeutic targets of neurodegenerative diseases (NDDs) [...].

TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine.

Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.

Proteomics in Multiple Sclerosis: The Perspective of the Clinician.

Multiple sclerosis (MS) is the inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the last decade, a new era was heralded in by a new phenotypic classification, a new diagnostic protocol and the first ever therapeutic guideline, making personalized medicine the aim of MS management. However, despite this great evolution, there are still many aspects of the disease that are unknown and need to be further researched. A hallmark of these research are molecular biomarkers that could help in the diagnosis, differential diagnosis, therapy and prognosis of the disease. Proteomics, a rapidly evolving discipline of molecular biology may fulfill this dire need for the discovery of molecular biomarkers. In this review, we aimed to give a comprehensive summary on the utility of proteomics in the field of MS research. We reviewed the published results of the method in case of the pathogenesis of the disease and for biomarkers of diagnosis, differential diagnosis, conversion of disease courses, disease activity, progression and immunological therapy. We found proteomics to be a highly effective emerging tool that has been providing important findings in the research of MS.