26 research outputs found
Is It Lupus? Is It Neuromyelitis Optica Spectrum Disorder (NMOSD)? : Why Not Both?
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are among
the commonly considered differential diagnoses in patients with inflammatory central nervous system (CNS)-diseases. Formerly diagnosed competing autoimmune diseases might impair diagnostics
and treatment. Here, we report on a 41-year-old woman admitted to our hospital with primary
manifestation of NMOSD (paresthesia, paralysis of the lower extremities, and urinary incontinence)
while undergoing treatment for a diagnosed systemic lupus erythematosus (SLE) with hydroxychloroquine. CNS manifestation of the disease was considered. Magnetic resonance imaging (MRI)
of the cranium and spinal cord showed multiple supratentorial lesions of the white matter and
massive intramedullary lesions with contrast enhancement. Cerebrospinal fluid (CSF) showed pleocytosis (20/µL), positive antinuclear antibodies (ANA), antiphospholipid antibodies, and SSA/Ro
antibodies, while formerly positive dsDNA antibodies were negative. Further diagnostics revealed
a 1:10,240 serum titer of Aquaporine-4 antibodies. The patient received intravenous methylprednisolone for three days (2 g per day), which led to an escalation to plasmapheresis and to an improved
EDSS from 8.0 to 4.0. Because of the comorbidity, a combined relapse prophylaxis with satralizumab
and mycophenolate mofetil was established. Rehabilitation and continued treatment improved
EDSS to 1.0 with no impairment of mobilization. Although formerly diagnosed SLE could have
explained the symptoms, it is important to reconsider competitive diseases in order to establish
adequate immunotherap
The Effects of Vitamin D Deficiency on Neurodegenerative Diseases
Approximately 90% of the elderly population in the western countries has at least a mild to moderate vitamin D hypovitaminosis. Besides the well-known function of vitamin D in calcium homeostasis, it has been recently found that several enzymes and receptors involved in its homeostasis are expressed in the nervous system and brain suggesting also an important role in the brain homeostasis. Interestingly, epidemiological and clinical studies found reduced vitamin D level associated with an increased risk of several neurodegenerative disorders. In this chapter, we focus on a potential link between vitamin D and Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, prion disease, and motor neuron disease. Epidemiological studies were summarized, an overview of the known potential underlying pathomolecular mechanisms are given, and results from clinical studies dealing with vitamin D supplementation were presented. As an outlook, recent literature suggesting an impact of vitamin D on autism spectrum disease, depression, and schizophrenia are briefly discussed. In conclusion, the identification of an abundant vitamin D metabolism in the brain and the tight link between the increasing number of several neurological and mental disorders emphasize the need of further research making a clear recommendation of the intake and supplementation of vitamin D in a growing elderly population
Methylxanthines and Neurodegenerative Diseases: An Update
Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally
occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food,
several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in
treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines
are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid
homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine
receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling,
histone deacetylase activation and gene regulation. By affecting several pathways associated with
neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side
effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with
neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative
diseases has been extensively studied and several new aspects have been elucidated. In this review
we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease
and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing
the underlying molecular mechanisms in cell culture experiments and animal studies in order to
assess the neuroprotective potential of methylxanthines in these diseases
Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells
Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood.
As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in
many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism.
However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides
are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many
diseases, such as Alzheimer’s disease, cancer, fatty liver disease and type-2 diabetes, treatment with
gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also
affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently
analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase
in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the
decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common
intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting
that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria
and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which
could be important in diseases, such as Alzheimer’s disease
Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells
Methylxanthines are a group of substances derived from the purine base xanthine with
a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1
and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate
the transcriptional regulation of 83 genes linked to Alzheimer’s disease in the presence of five
methylxanthines, including the most prominent naturally occurring methylxanthines—caffeine,
theophylline and theobromine—and the synthetic methylxanthines pentoxifylline and propentofylline.
Methylxanthine-regulated genes were found in pathways involved in processes including oxidative
stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved
in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene
regulation for caffeine compared to the other methylxanthines, which was further substantiated by
multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results
not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma
wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual
methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the
replacement of single methylxanthines by others could result in unexpected effects, which could not
be anticipated by the comparison to other substances in this substance class
Transorbital sonography and MRI reliability to assess optic nerve sheath diameter in idiopathic intracranial hypertension
Background and Purpose: The purpose of this study was to evaluate the performance of
magnetic resonance imaging (MRI) in measuring the optic nerve sheath diameter (ONSD)
compared to the established method transorbital sonography (TOS) in patients with
idiopathic intracranial hypertension (IIH).
Methods: Twenty-three patients with IIH were prospectively included applying IIH
diagnostic criteria. All patients received a lumbar puncture with assessment of the cerebrospinal fluid (CSF) opening pressure to assure the IIH diagnosis. Measurement of ONSD
was performed 3 mm posterior to inner sclera surface in B-TOS by an expert examiner, while three independent neuroradiologists took measurements in axial T-weighted
MRI examinations. The sella turcica with the pituitary gland (and potential presence of
an empty sella) and the trigeminal cavity were also assessed on sagittal and transversal
T1-weighted MRI images by one independent neuroradiologist.
Results: The means of ONSD between ultrasound and MRI measurements were 6.3 mm
(standard deviation [SD] = 0.6 mm) and 6.2 mm (SD = 0.8 mm). The interrater reliability
between three neuroradiologists showed a high interclass correlation coefficient (ICC)
(confidence interval: .573 < ICC < .8; p < .001). In patients with an empty sella, the ONSD
evaluated by MRI was 6.6 mm, while measuring 6.1 mm in patients without empty sella.
No correlation between CSF opening pressure and ONSD was found.
Conclusions: MRI can reliably measure ONSD and yields similar results compared to
TOS in patients with IIH. Moreover, patients with empty sella showed significantly larger
ONSD than patients without empty sella
Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells
Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine.
Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to
be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial
properties in neurodegenerative diseases, however, the mechanisms of action are not completely
understood. Here we investigate the effect of the naturally occurring caffeine, theobromine
and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in
Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor
protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway.
The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down
the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10,
downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP
expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol
and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism
resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells.
However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a
healthy diet rather than be used exclusively to treat or prevent AD
Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks
of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme
involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here,
we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation
whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which
could not be detected in IDE knock-down cells. Further analysis of the underlying molecular
mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an
elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was
unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme
activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity.
The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet,
revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated
fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for
example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease
The Influence of Acitretin on Brain Lipidomics in Adolescent Mice : Implications for Pediatric and Adolescent Dermatological Therapy
Administration of systemic retinoids such as acitretin has not been approved yet for
pediatric patients. An adverse event of retinoid-therapy that occurs with lower prevalence in children
than in adults is hyperlipidemia. This might be based on the lack of comorbidities in young patients,
but must not be neglected. Especially for the development of the human brain up to young adulthood,
dysbalance of lipids might be deleterious. Here, we provide for the first time an in-depth analysis
of the influence of subchronic acitretin-administration on lipid composition of brain parenchyma of
young wild type mice. For comparison and to evaluate the systemic effect of the treatment, liver lipids
were analogously investigated. As expected, triglycerides increased in liver as well as in brain and a
non-significant increase in cholesterol was observed. However, specifically brain showed an increase
in lyso-phosphatidylcholine and carnitine as well as in sphingomyelin. Group analysis of lipid
classes revealed no statistical effects, while single species were tissue-dependently changed: effects
in brain were in general more subtly as compared to those in liver regarding the mere number of
changed lipid species. Thus, while the overall impact of acitretin seems comparably small regarding
brain, the change in individual species and their role in brain development and maturation has to
be considered
The impact of capsaicinoids on APP processing in Alzheimer's disease in SH-SY5Y cells
The vanilloid capsaicin is a widely consumed spice, known for its burning and "hot" sensation through activation of TRPV1 ion-channels, but also known to decrease oxidative stress, inflammation and influence tau-pathology. Beside these positive effects, little is known about its effects on amyloid-precursor-protein (APP) processing leading to amyloid-β (Aβ), the major component of senile plaques. Treatment of neuroblastoma cells with capsaicinoids (24 hours, 10 µM) resulted in enhanced Aβ-production and reduced Aβ-degradation, leading to increased Aβ-levels. In detailed analysis of the amyloidogenic-pathway, both BACE1 gene-expression as well as protein-levels were found to be elevated, leading to increased β-secretase-activity. Additionally, γ-secretase gene-expression as well as activity was enhanced, accompanied by a shift of presenilin from non-raft to raft membrane-domains where amyloidogenic processing takes place. Furthermore, impaired Aβ-degradation in presence of capsaicinoids is dependent on the insulin-degrading-enzyme, one of the major Aβ-degrading-enzymes. Regarding Aβ-homeostasis, no differences were found between the major capsaicinoids, capsaicin and dihydrocapsaicin, and a mixture of naturally derived capsaicinoids; effects on Ca2+-homeostasis were ruled out. Our results show that in respect to Alzheimer's disease, besides the known positive effects of capsaicinoids, pro-amyloidogenic properties also exist, enhancing Aβ-levels, likely restricting the potential use of capsaicinoids as therapeutic substances in Alzheimer's disease