Circadian Variation of Migraine Attack Onset: A Review of Clinical Studies.

Several studies suggested that migraine attack onset shows a circadian variation; however, there has not been an overview and synthesis of these findings. A PubMed search with keywords "migraine" AND "circadian" resulted in ten studies directly investigating this topic. Results of these studies mostly show that migraine attacks follow a monophasic 24-hour cyclic pattern with an early morning or late night peak while other studies reported an afternoon peak and also a biphasic 24-hour cycle of attacks. The identified studies showed methodological variation including sample size, inclusion of medication use, comorbidities, and night or shift workers which could have contributed to the contradictory results. Several theories emerged explaining the diurnal distribution of migraine attacks suggesting roles for different phenomena including a morning rise in cortisol levels, a possible hypothalamic dysfunction, a circadian variation of migraine triggers, sleep stages, and a potentially different setting of the circadian pacemaker among migraineurs. At the moment, most studies show an early morning or late night peak of migraine attack onset, but a significant amount of studies reveals contradictory results. Further studies should investigate the arising hypotheses to improve our understanding of the complex mechanism behind the circadian variation of migraine attacks that can shed light on new targets for migraine therapy.

Mitochondrial dysfunctioning and neuroinflammation: Recent highlights on the possible mechanisms involved in Traumatic Brain Injury.

Traumatic brain injury (TBI) is the injury to the vasculature of brain while trauma caused by physical, chemical and biological stimuli. TBI is the leading cause of mortality and morbidity around the world. In this, primary insult leads to secondary injury through the involvement and initiation of various pathological processes. The most citable includes excitotoxicity, Blood Brain Barrier (BBB) dysfunction, inflammation, mitochondrial dysfunction, oxidative stress, calcium efflux, microglial mediated release of proinflammatory mediators (cytokine, chemokines, interleukin, tissue necrosis factor etc.). The morphological changes in TBI are proportional to mitochondrial dysfunctioning and microglial activation, which play an assorted role in neurodegeneration following traumatic brain injury. It is also assumed that the release of nitric oxide, activation of microglial cells plays a diversive role in maintaining the physiological and pathological balance. This review cites different pathophysiological mechanisms that are involved in progenesis of secondary injury after primary insult. These targets further are useful to explore the deep molecular mechanisms and to analyse the effectiveness of available drugs. Moreover, the present review reflects the underlying inflammatory cascade responsible for neuronal loss and neurological deficit in TBI.

[Anxiety and depression - the role of blood-brain barrier integrity]. / Szorongás és depresszió ­ a vér-agy gát integritásának szerepe.

Among mental illnesses, anxiety disorders represent the second most frequent disorder. According to WHO Survey 2017, 264 million people suffer from their different types globally. The emergence of anxiety disorders can often increase the likelihood of developing other psychiatric illnesses such as depression, which is the most common mental illness with 300 million people affected worldwide. Although the two diseases mentioned above are widespread throughout the world, the exact physiological causes of their development and the way they are connected are not well understood. However, in order to be able to use right treatment it would be important to know the physiological background in their development. The use of anxiolytics and antidepressants is not always effective and safe, which may be due to the subtypes of these mental disorders with different etiologies. Identifying the right therapeutic strategies could be also challenging because of the phenotypic overlap between anxiety disorders and depression. Their comorbidity has been confirmed by many studies, but their exact physiological relationship is still unclear. Previous studies suggested that blood-brain barrier proteins play an important role in the development of depression and anxiety disorders and might partially explain their comorbidities. In our summary we review the current literature related to this topic.

Transcriptomic changes following chronic administration of selective serotonin reuptake inhibitors: a review of animal studies.

The review focuses on transcriptomic changes following treatment with serotonin reuptake inhibitor (SSRI) antidepressants. We aimed to overview results of the most established methods for the investigation of the gene expression alterations including northern blotting, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray and RNAseq in various brain regions and after chronic treatment protocols. In spite of some measurable changes in serotonin system mRNA expression, serotonin transporter levels remained mostly unaltered following various treatment protocols. In contrast, tryptophan hydroxylase 2 appeared to be downregulated in serotonergic nuclei, and upregulated in the midbrain regions. Alterations in serotonin receptors lack clear conclusions and changes probably reflect animal strain/substance related- and brain region dependent effects. Brain derived neurotrophic factor was upregulated following many, but not all chronic treatment regimens. GABA and glutamate genes also showed heterogeneous changes, with a surprising NMDA receptor downregulation in areas including the striatum and amygdala, known to be involved in depressive states and stress reactions. The review of the above studies suggests alterations in multiple processes, reflecting the heterogeneity of the action depending on brain area and type of SSRI, and raises the possibility of a novel grouping of antidepressant medications based on their chronic molecular profile rather than on their initial actions.

Downregulation of the Vitamin D Receptor Regulated Gene Set in the Hippocampus After MDMA Treatment.

The active ingredient of ecstasy, ±3,4-methylenedioxymethamphetamine (MDMA), in addition to its initial reinforcing effects, induces selective and non-selective brain damage. Evidences suggest that the hippocampus (HC), a central region for cognition, may be especially vulnerable to impairments on the long-run, nevertheless, transcription factors that may precede and regulate such chronic changes remained uninvestigated in this region. In the current study, we used gene-set enrichment analysis (GSEA) to reveal possible transcription factor candidates responsible for enhanced vulnerability of HC after MDMA administration. Dark Agouti rats were intraperitoneally injected with saline or 15 mg/kg MDMA. Three weeks later HC gene expression was measured by Illumina whole-genome beadarrays and GSEA was performed with MSigDB transcription factor sets. The number of significantly altered genes on the genome level (significance < 0.001) in up/downregulated sets was also counted. MDMA upregulated one, and downregulated 13 gene sets in the HC of rats, compared to controls, including Pax4, Pitx2, FoxJ2, FoxO1, Oct1, Sp3, AP3, FoxO4, and vitamin D receptor (VDR)-regulated sets (q-value <0.05). VDR-regulated set contained the second highest number of significantly altered genes, including among others, Camk2n2, Gria3, and Grin2a. Most identified transcription factors are implicated in the response to ischemia confirming that serious hypoxia/ischemia occurs in the HC after MDMA administration, which may contribute to the selective vulnerability of this brain region. Moreover, our results also raise the possibility that vitamin D supplementation, in addition to the commonly used antioxidants, could be a potential alternative method to attenuate MDMA-induced chronic hippocampal impairments.