Current Medicinal Chemistry - Volume 26, Issue 34, 2019

Background: Migraine is the most common neurological disorder and the second most disabling human condition, whose pathogenesis is favored by a combination of genetic, epigenetic, and environmental factors. In recent years, several efforts have been made to identify reliable biomarker(s) useful to monitor disease activity and/or ascertain the response to a specific treatment. Objective: To review the current evidence on the potential biological markers associated with migraine. Methods: A structured search of peer-reviewed research literature was performed by searching major publications databases up to December 2017. Results: Several circulating biomarkers have been proposed as diagnostic or therapeutic tools in migraine, mostly related to migraine’s inflammatory pathophysiological aspects. Nonetheless, their detection is still a challenge for the scientific community, reflecting, at least in part, disease complexity and clinical diagnostic limitations. At the present time, calcitonin generelated peptide (CGRP) represents probably the most promising candidate as a diagnostic and/or therapeutic biomarker, as its plasma levels are elevated during migraine attack and decrease during successful treatment. Other molecules (including some neuropeptides, cytokines, adipokines, or vascular activation markers) despite promising, do not possess the sufficient prerequisites to be considered as migraine biomarkers. Conclusion: The characterization of migraine-specific biomarkers would be fundamental in a perspective of precision medicine, enabling risk assessment and tailored treatments. However, speculating on the clinical validity of migraine biomarkers may be premature and controlled clinical trials are presently needed to investigate both the diagnostic and therapeutic value of these biomarkers in migraine.

Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.

Background: Despite pain being its most prominent feature, migraine is primarily a disorder of sensory processing. Electrophysiology-based research in the field has consistently developed over the last fifty years. Objective: To summarize the current knowledge on the electrophysiological characteristics of the migraine brain, and discuss perspectives. Methods: We critically reviewed the literature on the topic to present and discuss articles selected on the basis of their significance and/or novelty. Results: Physiologic fluctuations within time, between-subject differences, and methodological issues account as major limitations of electrophysiological research in migraine. Nonetheless, several abnormalities revealed through different approaches have been described in the literature. Altogether, these results are compatible with an abnormal state of sensory processing. Perspectives: The greatest contribution of electrophysiological testing in the future will most probably be the characterization of sub-groups of migraine patients sharing specific electrophysiological traits. This should serve as strategy towards personalized migraine treatment. Incorporation of novel methods of analysis would be worthwhile.

Background: In current migraine clinical practice, conventional neuroimaging examinations are often sought to exclude possible causes of secondary headaches or migraineassociated disorders. Contrariwise, although advanced Magnetic Resonance Imaging (MRI) has improved tremendously our understanding of human brain processes in migraine patients, to the state of the art they have not superseded the conventional neuroimaging techniques in the migraine clinical setting. Methods: A comprehensive review was conducted of PubMed citations by entering the keyword “marker” and/or “biomarker” combined with “migraine” and/or “headache”. Other keywords included “imaging” or “neuroimaging”, “structural” or “functional”. The only restriction was English-language publication. The abstracts of all articles meeting these criteria were reviewed, and the full text was retrieved and examined for relevant references. Results: Several authors tried to identify imaging biomarkers able to identify different migraine phenotypes or, even better, to follow-up the same migraine patients during the course of the disease, to predict the evolution into more severe phenotypes and, finally, the response to specific treatment. Conclusion: The identification of diagnostic, prognostic and therapeutic advanced neuroimaging biomarkers in the migraine clinical setting, in order to approach to patients in a more and more rational and “tailored” way, is extremely intriguing and futuristic. Unfortunately, reliable and robust neuroimaging biomarkers are still lacking for migraine, probably due to both not completely understood pathogenesis and clinical and neuroimaging heterogeneity. Although further longitudinal advanced neuroimaging studies, aimed to identify effective neuroimaging biomarkers, are needed, this review aims to collect the main and most recent works on this topic.

Migraine is a common disabling neurological disorder which is characterised by a recurring headache associated with a variety of sensory and autonomic symptoms. The pathophysiology of migraine remains not entirely understood, although many mechanisms involving the central and peripheral nervous system are now becoming clear. In particular, it is widely accepted that migraine is associated with energy metabolic impairment of the brain. The purpose of this review is to present an updated overview of the energy metabolism involvement in the migraine pathophysiology. Several biochemical, morphological and magnetic resonance spectroscopy studies have confirmed the presence of energy production deficiency together with an increment of energy consumption in migraine patients. An increment of energy demand over a certain threshold creates metabolic and biochemical preconditions for the onset of the migraine attack. The defect of oxidative energy metabolism in migraine is generalized. It remains to be determined if the mitochondrial deficit in migraine is primary or secondary. Riboflavin and Co-Enzyme Q10, both physiologically implicated in mitochondrial respiratory chain functioning, are effective in migraine prophylaxis, supporting the hypothesis that improving brain energy metabolism may reduce the susceptibility to migraine.

Background: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. Objective: The present study is a review of the current literature regarding new therapeutic lines in migraine research. Methods: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. Results: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Conclusion: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.

RNAi, post-transcriptional gene silencing mechanism, could be considered as one of the most important breakthroughs and rapidly growing fields in science. Researchers are trying to use this discovery in the treatment of various diseases and cancer is one of them although there are multiple treatment procedures for treatment-resistant cancers, eradication of resistance remain as an unsolvable problem yet. The current review summarizes both transcriptional and post-transcriptional gene silencing mechanisms, and highlights mechanisms leading to drug-resistance such as, drug efflux, drug inactivation, drug target alteration, DNA damages repair, and the epithelial-mesenchymal transition, as well as the role of tumor cell heterogeneity and tumor microenvironment, involving genes in these processes. It ultimately points out the obstacles of RNAi application for in vivo treatment of diseases and progressions that have been achieved in this field.

Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealing with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage.

Stem cell transplantation is an advanced medical technology, which brings hope for the treatment of some difficult diseases in the clinic. Attributed to its self-renewal and differential ability, stem cell research has been pushed to the forefront of regenerative medicine and has become a hot topic in tissue engineering. The surrounding extracellular matrix has physical functions and important biological significance in regulating the life activities of cells, which may play crucial roles for in situ inducing specific differentiation of stem cells. In this review, we discuss the stem cells and their engineering application, and highlight the control of the fate of stem cells, we offer our perspectives on the various challenges and opportunities facing the use of the components of extracellular matrix for stem cell attachment, growth, proliferation, migration and differentiation.