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Flavonoids and chalcones are known for their manifold biological activities, of which many affect the central nervous system. Pyranochalcones were recently shown to have a great neurogenic potential, which is partly due to a specific structural motif-the pyran ring. Accordingly, we questioned if other flavonoid backbones with a pyran ring as structural moiety would also show neurogenic potential. Different semi-synthetic approaches starting with the prenylated chalcone xanthohumol, isolated from hops, led to pyranoflavanoids with different backbones. We identified the chalcone backbone as the most active backbone with pyran ring using a reporter gene assay based on the promoter activity of doublecortin, an early neuronal marker. Pyranochalcones therefore appear to be promising compounds for further development as a treatment strategy for neurodegenerative diseases.

Given the financial constraints in public healthcare, we investigated the monthly out-of-pocket expenses for non-pharmacological treatments among individuals with multiple sclerosis (MS), a chronic neurological disorder that primarily affects individuals of working age. This cross-sectional study employed an online questionnaire to evaluate the expenses and utilization of non-pharmacological treatments, as well as the weekly working hours among 104 individuals with relapsing-remitting MS (RRMS, 79%), secondary progressive MS (SPMS, 12%), and primary progressive MS (PPMS, 10%). Non-pharmacological treatments were used by 82% of participants (vitamin D (43%), physiotherapy (31%), massage (21%), magnesium (19%)). The average monthly out-of-pocket expenses were 136 EUR (SD ± 218) and significantly higher among individuals with PPMS (337 EUR SD ± 354) compared to RRMS (110 EUR SD ± 195; p  = 0.01). The average weekly working hours were 26 and significantly lower among individuals with PPMS (11 h/week, SD ± 16; p  = 0.008) and SPMS (13 h/week, SD ± 16; p  = 0.001) compared to the RRMS cohort (30 h/week, SD ± 15). Working hours were not related to individual monthly costs. This study reveals substantial expenses incurred by individuals with MS in Austria, particularly those with PPMS, highlighting the willingness to actively participate in their disease management. Physicians should be aware of the financial resources and inform about available evidence on non-pharmacological treatment approaches.

Local inflammation plays a pivotal role in the process of secondary damage after spinal cord injury. We recently reported that acute intravenous application of extracellular vesicles (EVs) secreted by human umbilical cord mesenchymal stromal cells dampen the induction of inflammatory processes following traumatic spinal cord injury. However, systemic application of EVs is associated with delayed delivery to the site of injury and the necessity for high doses to reach therapeutic levels locally. To resolve these two constraints, we injected EVs directly at the lesion site acutely after spinal cord injury. We report here that intralesional application of EVs resulted in a more robust improvement of motor recovery, assessed with the BBB score and sub-score, as compared to the intravenous delivery. Moreover, intralesional application was more potent in reducing inflammation and scarring after spinal cord injury than intravenous administration. Hence, development of EV-based therapy for spinal cord injury should aim at an early application of vesicles close to the lesion.

The neuropeptide galanin (GAL), which is expressed in limbic brain structures, has a strong impact on the regulation of mood and behavior. GAL exerts its effects via three G protein-coupled receptors (GAL1–3-R). Little is known about the effects of aging and loss of GAL-Rs on hippocampal-mediated processes connected to neurogenesis, such as learning, memory recall and anxiety, and cell proliferation and survival in the dorsal dentate gyrus (dDG) in mice. Our results demonstrate that loss of GAL3-R, but not GAL2-R, slowed learning and induced anxiety in older (12–14-month-old) mice. Lack of GAL2-R increased cell survival (BrdU incorporation) in the dDG of young mice. However, normal neurogenesis was observed in vitro using neural stem and precursor cells obtained from GAL2-R and GAL3-R knockouts upon GAL treatment. Interestingly, we found sub-strain differences between C57BL/6J and C57BL/6N mice, the latter showing faster learning, less anxiety and lower cell survival in the dDG. We conclude that GAL-R signaling is involved in cognitive functions and can modulate the survival of cells in the neurogenic niche, which might lead to new therapeutic applications. Furthermore, we observed that the mouse sub-strain had a profound impact on the behavioral parameters analyzed and should therefore be carefully considered in future studies.

Transcranial alternating current stimulation (tACS) is the application of subthreshold, sinusoidal current to modulate ongoing brain rhythms related to sensory, motor and cognitive processes. Electrophysiological studies suggested that the effect of tACS applied at an alpha frequency (8-12 Hz) was state-dependent. The effects of tACS, that is, an increase in parieto-occipital electroencephalography (EEG) alpha power and magnetoencephalography (MEG) phase coherence, was only observed when the eyes were open (low alpha power) and not when the eyes were closed (high alpha power). This state-dependency of the effects of alpha tACS might extend to the aging brain characterized by general slowing and decrease in spectral power of the alpha rhythm. We additionally hypothesized that tACS will influence the motor cortex, which is involved in motor skill learning and consolidation. A group of young and old healthy adults performed a serial reaction time task (SRTT) with their right hand before and after the tACS stimulation. Each participant underwent three sessions of stimulation: sham, stimulation applied at the individual participant's alpha peak frequency or individual alpha peak frequency (iAPF; α-tACS) and stimulation with iAPF plus 2 Hz (α2-tACS) to the left motor cortex for 10 min (1.5 mA). We measured the effect of stimulation on general motor skill (GMS) and sequence-specific skill (SS) consolidation. We found that α-tACS and α2-tACS improved GMS and SS consolidation in the old group. In contrast, α-tACS minimally improved GMS consolidation but impaired SS consolidation in the young group. On the other hand, α2-tACS was detrimental to the consolidation of both skills in the young group. Our results suggest that individuals with aberrant alpha rhythm such as the elderly could benefit more from tACS stimulation, whereas for young healthy individuals with intact alpha rhythm the stimulation could be detrimental.

Extracellular Vesicles (EVs) from Mesenchymal Stromal Cells (MSCs) are promising cell‐free therapeutics due to their ability to modulate immune responses, promote tissue repair and replicate many benefits of their parental cells. However, developing standardised, clinically translatable MSC‐EV preparations remains difficult because of biological and technical variability. Factors such as cell source, donor differences, passage number and culture conditions affect EV yield and function, while enrichment methods, purity and media composition further complicate interpretation of EV‐specific effects. Although prior studies have explored isolation methods and serum contaminants, the impact of different collection media on EV bioactivity is poorly understood. Here, we used hTERT‐immortalised MSCs, which preserve the therapeutic properties of primary MSCs, to minimise cellular variability. EVs were collected in four different xeno‐free media, enriched via Tangential Flow Filtration (TFF) and assessed in terms of their anti‐inflammatory, anti‐fibrotic, gap closure and proliferative potential compared with unconditioned, TFF processed collection media. Our results demonstrate that collection media significantly affect MSC‐EV biological and functional properties, highlighting the need to carefully select media for standardised EV production. This study advances standardisation in EV research and supports the development of consistent, clinically relevant MSC‐EV products.

Several clinical trials address demyelinating diseases via transplantation of mesenchymal stromal cells (MSCs). Published reports detail that administration of MSCs in patients may provide a beneficial immunomodulation, and that factors secreted by MSCs are potent inducers of oligodendrogenesis. Dimethylsulfoxide (DMSO) is widely used in life science and medicine as solvent, vehicle or cryoprotectant for cells used in transplantation. Importantly, most transplantation protocols do not include the removal of DMSO before injecting the cell suspension into patients. This indifferent application of DMSO is coming under increasing scrutiny following reports investigating its potential toxic side-effects. While the impact of DMSO on the central nervous system (CNS) has been partially studied, its effect on oligodendrocytes and oligodendrogenesis has not been addressed yet. Consequently, we evaluated the influence of DMSO on oligodendrogenesis, and on the pro-oligodendrogenic effect of MSCs' secreted factors, using adult rat neural stem and progenitor cells (NSPCs). Here, we demonstrate that a concentration of 1% DMSO robustly suppressed oligodendrogenesis and drove the fate of differentiating NSPCs toward astrogenesis. Furthermore, the pro-oligodendrogenic effect of MSC-conditioned medium (MSCCM) was also nearly completely abolished by the presence of 1% DMSO. In this condition, inhibition of the Erk1/2 signal transduction pathway and high levels of Id2 expression, a specific inhibitor of oligodendrogenic differentiation, were detected. Furthermore, inflammatory demyelinating diseases may even potentiate the impact of DMSO on oligodendrogenesis. Our results demonstrate the imperative of considering the strong anti-oligodendrogenic activity of DMSO when designing future clinical trial protocols.

Restoration of neuronal connectivity after lesion of the central nervous system, such as spinal cord injury, is one of the biggest challenges in modern medicine. In particular, the accumulation of axon growth inhibitory factors at the site of injury constitutes a major obstacle to structural and thus functional repair. We previously investigated a group of prenylflavonoids derived from hops for their capacity to promote neuroregeneration. We identified a molecule called ENDF1 that was very potent to enhance regrowth and branching of neurites from dorsal root ganglion neurons in culture on growth promoting substrates. In the present study, we investigated ENDF1's capacity to promote regeneration of rat dorsal root ganglion neurons in the presence of three main components of the extracellular matrix acting as axon growth inhibitors: Semaphorin 3A, Ephrin A4 and mixed chondroitin sulfate proteoglycans. We report that ENDF1 application significantly promoted the percentages of sensory neurons able to regrow their neurites regardless of the presence of those inhibitors, and this to an extent similar to the one obtained after NGF treatment. Moreover, ENDF1 strongly enhanced the total neurite length and the complexity of neurites extending from neurons challenged with axon growth inhibitors. Although the impact of NGF and ENDF1 on the regeneration of neurons was similar, the activity of ENDF1 was not mediated by signaling through the TrkA receptor, indicating that each molecule act through different signaling pathways. In addition, ENDF1 did not decrease the phosphorylation of cofilin, a downstream effector of the regeneration-associated RhoA/ROCK signaling pathway. Hence, ENDF1 is a potent pro-neuroregenerative factors that could help in identifying new efficient targets for regenerative therapies of the nervous system.

BackgroundEfficacy of vaccines and disease activity linked to immunization are major concerns among people with multiple sclerosis (pwMS).ObjectiveTo assess antibody responses to seasonal influenza antigens and vaccine-associated neuroaxonal damage utilizing serum neurofilament light chain (sNfL) in pwMS receiving dimethyl fumarate (DMF).MethodsIn this prospective study, the 2020/2021 seasonal tetravalent influenza vaccine was administered to 20 pwMS treated with DMF and 15 healthy controls (HCs). The primary endpoints were responder rate of strain-specific antibody production (seroconversion or significant (4-fold) increase in influenza-antibody titers for ≥2/4 strains) at 30 days post-vaccination and changes in sNfL levels.ResultsAll patients treated with DMF fulfilled the responder criteria for immunization compared with 53% of the controls. However, higher proportions of HCs already had influenza-antibody titers ≥1:40 at baseline (53% vs. 41%, p = 0.174). sNfL levels were comparable among both groups at baseline and did not increase 34 days after vaccination. In addition, no clinical or radiological disease reactivation was found.ConclusionDMF-treated patients mount an adequate humoral immune response to influenza vaccines. Within the limits of the small cohort investigated, our data suggest that influenza immunization is not associated with clinical or subclinical disease reactivation.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). In recent years, vitamin D has gained attention, as low serum levels are suspected to increase the risk for MS. Cholecalciferol supplementation has been tested in several clinical trials, since hypovitaminosis D was linked to higher disease activity and may even play a role in long-term outcome. Here, we review the current understanding of the molecular effects of vitamin D beyond calcium homeostasis, the potential beneficial action in MS and hazards including complications of chronic and high-dose therapy. In clinical trials, doses of up to 40,000 IU/day were tested and appeared safe as add-on therapy for short-term periods. A recent meta-analysis of a randomized, double-blind, placebo-controlled clinical trial investigating vitamin D as add-on therapy in MS, however, suggested that vitamin D had no therapeutic effect on disability or relapse rate. We recognize a knowledge gap for chronic and high-dose therapy, which can lead to life-threatening complications related to vitamin D toxicity including renal failure, cardiac arrythmia and status epilepticus. Moreover, vitamin D toxicity may manifest as fatigue, muscle weakness or urinary dysfunction, which may mimic the natural course of progressive MS. Given these limitations, vitamin D supplementation in MS is a sensitive task which needs to be supervised by physicians. While there is strong evidence for vitamin D deficiency and the development of MS, the risk-benefit profile of dosage and duration of add-on supplementation needs to be further clarified.