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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.
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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.
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Cinurenina , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/metabolismo , Cinurenina/metabolismo , Animais , Neuroimunomodulação/fisiologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/fisiopatologiaRESUMO
Migraine is a debilitating neurological disorder characterized by recurring episodes of throbbing headaches that are frequently accompanied by sensory disturbances, nausea, and sensitivity to light and sound [...].
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Transtornos de Enxaqueca , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/terapia , Humanos , Animais , NeurobiologiaRESUMO
OBJECTIVE: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. METHODS: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. RESULTS: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. INTERPRETATION: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.
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Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Humanos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Animais , Transtornos da Cefaleia Primários/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Transtornos de Enxaqueca/metabolismoRESUMO
Welcome to Biomedicines' 10th Anniversary Special Issue, a journey through the human mind's labyrinth and complex neurological pathways [...].
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Translational research in neurological and psychiatric diseases is a rapidly advancing field that promises to redefine our approach to these complex conditions [...].
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Neurologia , Psiquiatria , Pesquisa Translacional Biomédica , Humanos , Pesquisa Translacional Biomédica/tendências , Psiquiatria/métodos , Transtornos Mentais/terapia , Doenças do Sistema Nervoso/terapiaRESUMO
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.
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Ácido Cinurênico , Fármacos Neuroprotetores , Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Fármacos Neuroprotetores/química , Teste de Campo AbertoRESUMO
Neurodegeneration poses a significant challenge for the fields of neuroscience and medicine, as it is the underlying cause of the development and advancement of numerous neurodegenerative and psychiatric disorders [...].
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Neuroscience, neurology, and psychiatry are rapidly evolving fields that aim to understand the complex mechanisms underlying brain function and dysfunction, as well as to develop effective interventions for various neurological and psychiatric disorders [...].
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Memory and learning are essential cognitive processes that enable us to obtain, retain, and recall information [...].
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Aprendizagem , Rememoração Mental , Testes NeuropsicológicosRESUMO
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.
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Microbioma Gastrointestinal , Doenças Mitocondriais , Doenças do Sistema Nervoso , Humanos , Cinurenina/metabolismo , Doenças do Sistema Nervoso/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Ácido Quinolínico/metabolismo , Estresse OxidativoRESUMO
The orexin/hypocretin neuropeptide family has emerged as a focal point of neuroscientific research following the discovery that this family plays a crucial role in a variety of physiological and behavioral processes. These neuropeptides serve as powerful neuromodulators, intricately shaping autonomic, endocrine, and behavioral responses across species. Notably, they serve as master regulators of vigilance and stress responses; however, their roles in food intake, metabolism, and thermoregulation appear complementary and warrant further investigation. This narrative review provides a journey through the evolution of our understanding of the orexin system, from its initial discovery to the promising progress made in developing orexin derivatives. It goes beyond conventional boundaries, striving to synthesize the multifaceted activities of orexins. Special emphasis is placed on domains such as stress response, fear, anxiety, and learning, in which the authors have contributed to the literature with original publications. This paper also overviews the advancement of orexin pharmacology, which has already yielded some promising successes, particularly in the treatment of sleep disorders.
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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.
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Testes Neuropsicológicos , Humanos , Masculino , Feminino , Adulto , Seguimentos , Pessoa de Meia-Idade , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Qualidade de Vida , Estudos Longitudinais , Hungria , Esclerose Múltipla Recidivante-Remitente/psicologia , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla/psicologia , Esclerose Múltipla/complicações , Estudos de Coortes , Cognição/fisiologia , Avaliação da Deficiência , Reprodutibilidade dos TestesRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.
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Esclerose Lateral Amiotrófica , Metilação de DNA , Humanos , Esclerose Lateral Amiotrófica/genética , DNA , Epigenoma , Exoma , Estruturas R-LoopRESUMO
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.
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Cinurenina , Transtornos de Enxaqueca , Humanos , Cinurenina/metabolismo , Transtornos de Enxaqueca/metabolismo , Canais Iônicos/metabolismo , Neurônios/metabolismo , Dor/metabolismoRESUMO
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.
. Methods: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.
. Results: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).
. Conclusion: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.
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Cefaleia , Personalidade , Humanos , Dor , Inventário de Personalidade , AnsiedadeRESUMO
Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.
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Hormônios Gastrointestinais , Transtornos de Enxaqueca , Humanos , Peptídeo Relacionado com Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Secretina/antagonistas & inibidores , Peptídeo Intestinal VasoativoRESUMO
Revealing the underlying pathomechanisms of neurological and psychiatric disorders, searching for new biomarkers, and developing novel therapeutics all require translational research [...].
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Transtornos Mentais , Pesquisa Translacional Biomédica , Humanos , Transtornos Mentais/terapia , Transtornos Mentais/psicologia , Biomarcadores , Ciência Translacional BiomédicaRESUMO
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.
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Hipotermia , Hipóxia-Isquemia Encefálica , Suínos , Animais , Cinurenina/metabolismo , Triptofano/metabolismo , Ácido Cinurênico/metabolismo , Asfixia , Hipóxia-Isquemia Encefálica/terapiaRESUMO
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.