Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing &... Show moreGlucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing & PRIME; syndrome and neurodegenerative disorders of humans and models of human diseases. ."The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNF & alpha;, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1 & beta; and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1 & beta;, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders. Show less
Dehghani, A.; Schenke, M.; Heiningen, S.H. van; Karatas, H.; Tolner, E.A.; Maagdenberg, A.M.J.M. van den 2023
BackgroundCortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural... Show moreBackgroundCortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation.MethodsCSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor.ResultsIn both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release.ConclusionsCSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine. Show less
Zande, N.A. van de; Bulk, M.; Najac, C.; Weerd, L. van der; Bresser, J. de; Lewerenz, J.; ... ; Bot, S.T. de 2023
IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative... Show moreIntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other. Show less
Amani, H.; Khaboushan, A.S.; Terwindt, G.M.; Tafakhori, A. 2023
Migraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function,... Show moreMigraine is a complicated neurological disorder affecting 6% of men and 18% of women worldwide. Various mechanisms, including neuroinflammation, oxidative stress, altered mitochondrial function, neurotransmitter disturbances, cortical hyperexcitability, genetic factors, and endocrine system problems, are responsible for migraine. However, these mechanisms have not completely delineated the pathophysiology behind migraine, and they should be further studied. The brain microenvironment comprises neurons, glial cells, and vascular structures with complex interactions. Disruption of the brain microenvironment is the main culprit behind various neurological disorders. Neuron-glia crosstalk contributes to hyperalgesia in migraine. In the brain, microenvironment and related peripheral regulatory circuits, microglia, astrocytes, and satellite cells are necessary for proper function. These are the most important cells that could induce migraine headaches by disturbing the balance of the neurotransmitters in the nervous system. Neuroinflammation and oxidative stress are the prominent reactions glial cells drive during migraine. Understanding the role of cellular and molecular components of the brain microenvironment on the major neurotransmitters engaged in migraine pathophysiology facilitates the development of new therapeutic approaches with higher effectiveness for migraine headaches. Investigating the role of the brain microenvironment and neuroinflammation in migraine may help decipher its pathophysiology and provide an opportunity to develop novel therapeutic approaches for its management. This review aims to discuss the neuron-glia interactions in the brain microenvironment during migraine and their potential role as a therapeutic target for the treatment of migraine. Show less
This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several... Show more This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease. Show less
