scholarly journals Exosomal delivery of therapeutic modulators through the blood–brain barrier; promise and pitfalls

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morteza Heidarzadeh ◽  
Yasemin Gürsoy-Özdemir ◽  
Mehmet Kaya ◽  
Aysan Eslami Abriz ◽  
Amir Zarebkohan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Large Population ◽  
Drug Carriers ◽  
The Elderly ◽  
Brain Parenchyma ◽  
Main Question ◽  
Inflammatory Conditions ◽  
Degenerative Disorders ◽  
Delivery Strategies ◽  
The Brain

AbstractNowadays, a large population around the world, especially the elderly, suffers from neurological inflammatory and degenerative disorders/diseases. Current drug delivery strategies are facing different challenges because of the presence of the BBB, which limits the transport of various substances and cells to brain parenchyma. Additionally, the low rate of successful cell transplantation to the brain injury sites leads to efforts to find alternative therapies. Stem cell byproducts such as exosomes are touted as natural nano-drug carriers with 50–100 nm in diameter. These nano-sized particles could harbor and transfer a plethora of therapeutic agents and biological cargos to the brain. These nanoparticles would offer a solution to maintain paracrine cell-to-cell communications under healthy and inflammatory conditions. The main question is that the existence of the intact BBB could limit exosomal trafficking. Does BBB possess some molecular mechanisms that facilitate the exosomal delivery compared to the circulating cell? Although preliminary studies have shown that exosomes could cross the BBB, the exact molecular mechanism(s) beyond this phenomenon remains unclear. In this review, we tried to compile some facts about exosome delivery through the BBB and propose some mechanisms that regulate exosomal cross in pathological and physiological conditions.

scholarly journals Gangliosides Contribute to Vascular Insulin Resistance

2019 ◽  
Vol 20 (8) ◽  
pp. 1819 ◽  
Author(s):  
Norihiko Sasaki ◽  
Yoko Itakura ◽  
Masashi Toyoda
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Vascular Function ◽  
Molecular Mechanisms ◽  
The Elderly ◽  
Necrosis Factor Alpha ◽  
Aortic Endothelial Cells ◽  
Inflammatory Conditions ◽  
Factor Alpha

Insulin in physiological concentrations is important to maintain vascular function. Moreover, vascular insulin resistance contributes to vascular impairment. In the elderly, other factors including hypertension, dyslipidemia, and chronic inflammation amplify senescence of vascular endothelial and smooth muscle cells. In turn, senescence increases the risk for vascular-related diseases such as arteriosclerosis, diabetes, and Alzheimer’s disease. Recently, it was found that GM1 ganglioside, one of the glycolipids localized on the cell membrane, mediates vascular insulin resistance by promoting senescence and/or inflammatory stimulation. First, it was shown that increased GM1 levels associated with aging/senescence contribute to insulin resistance in human aortic endothelial cells (HAECs). Second, the expression levels of gangliosides were monitored in HAECs treated with different concentrations of tumor necrosis factor-alpha (TNFα) for different time intervals to mimic in vivo acute or chronic inflammatory conditions. Third, the levels of insulin signaling-related molecules were monitored in HAECs after TNFα treatment with or without inhibitors of ganglioside synthesis. In this review, we summarize the molecular mechanisms of insulin resistance in aged/senescent and TNFα-stimulated endothelial cells mediated by gangliosides and highlight the possible roles of gangliosides in vascular insulin resistance-related diseases.

Age-related changes in microglial physiology: the role for healthy brain ageing and neurodegenerative disorders

e-Neuroforum ◽  
2017 ◽  
Vol 23 (4) ◽  
Author(s):  
Olga Garaschuk
Keyword(s):  
Neurodegenerative Disorders ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Brain Parenchyma ◽  
Immune Defense ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Age Related ◽  
Brain Ageing ◽  
The Brain

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.

scholarly journals Neurotrophins and Neurotrophic Therapy (Based on the Cerebrolysin Model) in the Treatment of Elderly Patients with Cognitive Disorders and Depression. Part 2

Psychiatry ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 80-89
Author(s):  
S. I. Gavrilova ◽  
T. P. Safarova
Keyword(s):  
Molecular Mechanisms ◽  
Common Mental Disorders ◽  
Cognitive Disorders ◽  
The Elderly ◽  
Therapeutic Approaches ◽  
Neurodegenerative Process ◽  
Target Drug ◽  
Higher Doses ◽  
The Brain ◽  
Neurotrophic Therapy

Background: сognitive impairment and late depression, along with dementia, are the most common mental disorders in elderly and senile patients. Currently, more and more attention is being paid to preventive therapeutic approaches in the treatment of these conditions and to the study of drugs with multimodal neuroprotective and neurotrophic properties that contribute to the strengthening of the so-called endogenous system of protection and recovery of the brain, which is a kind of barrier to the incipient neurodegeneration. Objective: to present a review of domestic and foreign modern studies devoted to the study of the multimodal effects of the drug cerebrolysin, which has neurotrophin-like properties, and the results of its use in the treatment of cognitive disorders that do not reach the degree of dementia, as well as late depression. Material and methods: using the keywords “late age, mild cognitive disorders, depression, MCI syndrome, therapy, cerebrolysin”, we searched for scientifi c articles in the MEDLINE and PubMed databases for the period 2000–2020. Conclusion: the data presented in the review showed that cerebrolysin, acting as a multi-target drug, affects multiple molecular mechanisms of the pathogenesis of pre-dementia cognitive disorders and late-age depression. The drug detects a neurotrophin-like effect, improves the processes of neuroplasticity and can help enhance the protection and restoration of the brain under various pathological infl uences. Neurobiological studies and the results of a pilot prospective study indicate the preventive potential of cerebrolysin in preventing the development or slowing the progression of the neurodegenerative process of Alzheimer’s type. In the studies presented in the review, the ability of cerebrolysin to increase the effectiveness of modern antidepressant therapy (with second-generation drugs) in the elderly has been shown, presumably by potentiating the therapeutic effect of antidepressants or by improving their tolerability, which makes it possible to safely use higher doses of antidepressants in the elderly and senile patients.

Gut Microbiota and Alzheimer’s Disease: Experimental Evidence and Clinical Reality

2021 ◽  
Vol 18 ◽  
Author(s):  
Sarama Saha ◽  
Sukhpal Singh ◽  
Suvarna Prasad ◽  
Amit Mittal ◽  
Anil Kumar Sharma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Experimental Evidence ◽  
Molecular Mechanisms ◽  
Bacterial Flora ◽  
Experimental Studies ◽  
The Elderly ◽  
The Impact ◽  
The Brain

: Alzheimer’s disease (AD) is characterized by progressive death of neuronal cells in the regions of the brain concerned with memory and cognition, and is the major cause of dementia in the elderly population. Various molecular mechanisms, metabolic risk factors and environmental triggers contributing to the genesis and progression of AD are under intense investigations. The present review has dealt with the impact of a highly discussed topic of gut microbiota affecting the neurodegeneration in the AD brain. A detailed description of the composition of gut bacterial flora and its interaction with the host has been presented, followed by an analysis of key concepts of bi- directional communication between gut microbiota and the brain. The substantial experimental evidence of gut microbiota affecting the neurodegenerative process in experimental AD models has been described next in this review, and finally, the limitations of such experimental studies vis-a- vis the actual disease and the paucity of clinical data on this topic have also been mentioned.

scholarly journals Molecular mechanisms of sleep–wake regulation: a role of prostaglandin D 2

2000 ◽  
Vol 355 (1394) ◽  
pp. 275-280 ◽  
Author(s):  
Osamu Hayaishi
Keyword(s):  
Basal Forebrain ◽  
Molecular Mechanisms ◽  
Brain Parenchyma ◽  
Immunoperoxidase Staining ◽  
Major Protein ◽  
Sleep Regulation ◽  
Tissue Samples ◽  
Intracerebroventricular Infusion ◽  
Fos Expression ◽  
The Brain

Prostaglandin (PG) D 2 is a major prostanoid in the brains of rats and other mammals, including humans. When PGD synthase (PGDS), the enzyme that produces PGD 2 in the brain, was inhibited by the intracerebroventricular infusion of its selective inhibitors, i.e. tetravalent selenium compounds, the amount of sleep decreased both time and dose dependently. The amount of sleep of transgenic mice, in which the human PGDS gene had been incorporated, increased several fold under appropriate conditions. These data indicate that PGDS is a key enzyme in sleep regulation. In situ hybridization, immunoperoxidase staining and direct enzyme activity determination of tissue samples revealed that PGDS is hardly detectable in the brain parenchyma but is localized in the membrane systems surrounding the brain, namely, the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid (CSF) to become β–trace, a major protein component of the CSF. PGD 2 exerts its somnogenic activity by binding to PGD 2 receptors exclusively localized at the ventrorostral surface of the basal forebrain. When PGD 2 was infused into the subarachnoid space below the rostral basal forebrain, striking expression of proto–oncogene Fos immunoreactivity (FosIR) was observed in the ventrolateral preoptic area (VLPO), a putative sleep centre, concurrent with sleep induction. Fos expression in the VLPO was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus (TMN), a putative wake centre. These observations suggest that PGD 2 may induce sleep via leptomeningeal PGD 2 receptors with subsequent activation of the VLPO neurons and downregulation of the wake neurons in the TMN area. Adenosine may be involved in the signal transduction associated with PGD 2 .

scholarly journals 4R-Cembranoid Treatment Alters Gene Expression of RAW264.7 Macrophages in Basal and Inflammatory Conditions

2020 ◽  
Author(s):  
Maxine N. Gonzalez-Vega ◽  
Sandeep sreerama ◽  
Kelvin Carrasquillo-Carrion ◽  
Abiel Roche-Lima ◽  
Susan Corey Best ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Parenchyma ◽  
Inflammatory Conditions ◽  
Raw264.7 Macrophages ◽  
Blood Brain Barrier Model ◽  
Peripheral Immune Response ◽  
Anti Inflammatory ◽  
Macrophage Adhesion ◽  
The Brain ◽  
Inflammatory Effect

Inflammation is considered an important target for stroke therapy because it induces secondary brain damage after the initial ischemic insult. Peripheral monocytes migrate to the brain parenchyma after a central insult. They then differentiate to macrophages in a positive feedback fashion contributing to damage instead of ischemic resolution and inflammation control. A cyclic diterpenoid, (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R), decreases neurodegeneration after ischemia with central anti-inflammatory activity. This study aims to determine whether the central anti-inflammatory effect of 4R is effective against peripheral inflammation triggered by brain ischemia. To investigate the anti-inflammatory effect of 4R, we treated macrophages with lipopolysaccharide (LPS) as an inflammatory model, followed by treatment with 4R. Microarray transcriptome analysis of over 30,000 genes identified the differential expression of 393 genes. Genes related to inflammation, cell adhesion, and transcription were validated with qPCR, and reduced expression was determined. Quantification of NF-kB phosphorylation served as a marker for the modulation of inflammation through gene transcription. Our results show that 4R was associated with a reduction in NFKB1 and ITGB5 gene expression, increased phosphorylation of NF-kB, and a decrease in macrophage adhesion in a blood-brain barrier model. These results indicate that 4R can partially modulate the peripheral immune response, making 4R a potential drug against post-ischemic inflammation.

scholarly journals Sublethal Exposure Effects of the Neonicotinoid Clothianidin Strongly Modify the Brain Transcriptome and Proteome in the Male Moth Agrotis ipsilon

Insects ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 152
Author(s):  
Camille Meslin ◽  
Françoise Bozzolan ◽  
Virginie Braman ◽  
Solenne Chardonnet ◽  
Cédric Pionneau ◽  
...  
Keyword(s):  
Sex Pheromone ◽  
Molecular Mechanisms ◽  
Insect Pest ◽  
Agrotis Ipsilon ◽  
Positive Effects ◽  
Male Moth ◽  
Hormetic Effect ◽  
Pest Insects ◽  
Neuronal Processes ◽  
The Brain

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids such as clothianidin. The residual accumulation of low concentrations of these insecticides can have positive effects on target pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction and olfactory synaptic transmission is cholinergic, neonicotinoid residues could indeed modify chemical communication. We recently showed that treatments with low doses of clothianidin could induce hormetic effects on behavioral and neuronal sex pheromone responses in the male moth, Agrotis ipsilon. In this study, we used high-throughput RNAseq and proteomic analyses from brains of A. ipsilon males that were intoxicated with a low dose of clothianidin to investigate the molecular mechanisms leading to the observed hormetic effect. Our results showed that clothianidin induced significant changes in transcript levels and protein quantity in the brain of treated moths: 1229 genes and 49 proteins were differentially expressed upon clothianidin exposure. In particular, our analyses highlighted a regulation in numerous enzymes as a possible detoxification response to the insecticide and also numerous changes in neuronal processes, which could act as a form of acclimatization to the insecticide-contaminated environment, both leading to enhanced neuronal and behavioral responses to sex pheromone.

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

scholarly journals Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

2021 ◽  
Vol 22 (8) ◽  
pp. 4269
Author(s):  
Simona Gribaudo ◽  
Daniele Saraulli ◽  
Giulia Nato ◽  
Sara Bonzano ◽  
Giovanna Gambarotta ◽  
...  
Keyword(s):  
Associative Memory ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Large Population ◽  
Adult Life ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Knock Out ◽  
Memory Impairments ◽  
Dependent Learning

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

scholarly journals Molecular mechanisms of metabotropic GABAB receptor function

2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Neurological Diseases ◽  
Activation Mechanism ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmitter ◽  
Therapeutic Drugs ◽  
G Protein Coupled ◽  
The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

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