scholarly journals The role of olfactory transport in the penetration of manganese oxide nanoparticles from blood into the brain

2019 ◽  
Vol 23 (4) ◽  
pp. 482-488
Author(s):  
A. V. Romashchenko ◽  
M. B. Sharapova ◽  
К. N. Morozova ◽  
E. V. Kiseleva ◽  
K. E. Kuper ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Manganese Oxide ◽  
Axonal Transport ◽  
Neurological Diseases ◽  
Specific Inhibitor ◽  
Practical Interest ◽  
Submicron Particles ◽  
Neurotropic Viruses ◽  
The Central Nervous System ◽  
The Brain

There is no doubt that various nanoparticles (NPs) can enter the brain from the nasal cavity. It is assumed that NPs can penetrate from blood into the central nervous system (CNS) only by breaking the blood–brain barrier (BBB). The accumulation of NPs in CNS can provoke many neurological diseases; therefore, the understanding of its mechanisms is of both academic and practical interest. Although hitting from the surface of the lungs into the bloodstream, NPs can accumulate in various mucous membranes, including the nasal mucosa. Thus, we cannot rule out the ability of NPs to be transported from the bloodstream to the brain through the olfactory uptake. To test this hypothesis, we used paramagnetic NPs of manganese oxide (Mn3O4-NPs), whose accumulation patterns in the mouse brain were recorded using T1-weighted magnetic resonance imaging. The effect of intranasal application of endocytosis and axonal transport inhibitors on the brain accumulation patterns of intranasally or intravenously injected Mn3O4-NPs was evaluated. A comparative analysis of the results showed that the transport of Mn3O4-NPs from the nasal cavity to the brain is more efficient than their local permeation through BBB into CNS from the bloodstream, for example with the accumulation of Mn3O4NPs in the dentate gyrus of the hippocampus, and through the capture and transport of NPs from the blood by olfactory epithelium cells. Also, experiments with the administration of chlorpromazine, a specific inhibitor of clathrin-dependent endocytosis, and methyl-β-cyclodextrin, inhibitor of the lipid rafts involved in the capture of substances by endothelium cells, showed differences in the mechanisms of NP uptake from the nasal cavity and from the bloodstream. In this study, we show a significant contribution of axonal transport to NP accumulation patterns in the brain, both from the nasal cavity and from the vascular bed. This explains the accumulation of different sorts of submicron particles (neurotropic viruses, insoluble xenobiotics, etc.), unable to pass BBB, in the brain. The results will add to the understanding of the pathogenesis of various neurodegenerative diseases and help studying the side effects of therapeutics administered intravenously.

scholarly journals Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1929 ◽  
Author(s):  
Salman Ul Islam ◽  
Adeeb Shehzad ◽  
Muhammad Bilal Ahmed ◽  
Young Sup Lee
Keyword(s):  
Drug Delivery ◽  
Neurological Disorders ◽  
Neurological Diseases ◽  
Nasal Delivery ◽  
Intranasal Route ◽  
Drug Molecules ◽  
Surface Enhanced ◽  
Effective Delivery ◽  
The Central Nervous System ◽  
The Brain

Although the global prevalence of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, epilepsy, and multiple sclerosis is steadily increasing, effective delivery of drug molecules in therapeutic quantities to the central nervous system (CNS) is still lacking. The blood brain barrier (BBB) is the major obstacle for the entry of drugs into the brain, as it comprises a tight layer of endothelial cells surrounded by astrocyte foot processes that limit drugs’ entry. In recent times, intranasal drug delivery has emerged as a reliable method to bypass the BBB and treat neurological diseases. The intranasal route for drug delivery to the brain with both solution and particulate formulations has been demonstrated repeatedly in preclinical models, including in human trials. The key features determining the efficacy of drug delivery via the intranasal route include delivery to the olfactory area of the nares, a longer retention time at the nasal mucosal surface, enhanced penetration of the drugs through the nasal epithelia, and reduced drug metabolism in the nasal cavity. This review describes important neurological disorders, challenges in drug delivery to the disordered CNS, and new nasal delivery techniques designed to overcome these challenges and facilitate more efficient and targeted drug delivery. The potential for treatment possibilities with intranasal transfer of drugs will increase with the development of more effective formulations and delivery devices.

scholarly journals Systemic Delivery of Tyrosine-Mutant AAV Vectors Results in Robust Transduction of Neurons in Adult Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Asako Iida ◽  
Naomi Takino ◽  
Hitomi Miyauchi ◽  
Kuniko Shimazaki ◽  
Shin-ichi Muramatsu
Keyword(s):  
Transgene Expression ◽  
Neurological Diseases ◽  
Systemic Delivery ◽  
Adeno Associated Virus ◽  
Gene Therapies ◽  
Adult Mice ◽  
The Central Nervous System ◽  
Foreign Dna ◽  
The Brain ◽  
Limited Usefulness

Recombinant adeno-associated virus (AAV) vectors are powerful tools for both basic neuroscience experiments and clinical gene therapies for neurological diseases. Intravascularly administered self-complementary AAV9 vectors can cross the blood-brain barrier. However, AAV9 vectors are of limited usefulness because they mainly transduce astrocytes in adult animal brains and have restrictions on foreign DNA package sizes. In this study, we show that intracardiac injections of tyrosine-mutant pseudotype AAV9/3 vectors resulted in extensive and widespread transgene expression in the brains and spinal cords of adult mice. Furthermore, the usage of neuron-specific promoters achieved selective transduction of neurons. These results suggest that tyrosine-mutant AAV9/3 vectors may be effective vehicles for delivery of therapeutic genes, including miRNAs, into the brain and for treating diseases that affect broad areas of the central nervous system.

Effects of Neuroinflammation on Neural Stem Cells

2016 ◽  
Vol 23 (1) ◽  
pp. 27-39 ◽  
Author(s):  
Ruxandra Covacu ◽  
Lou Brundin
Keyword(s):  
Immune Responses ◽  
Subventricular Zone ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Adaptive Immune ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
And Migration ◽  
The Brain ◽  
Proliferation And Migration

Neural stem/progenitor cells (NSCs/NPCs) are present in different locations in the central nervous system. In the subgranular zone (SGZ) there is a constant generation of new neurons under normal conditions. New neurons are also formed from the subventricular zone (SVZ) NSCs, and they migrate anteriorly as neuroblast to the olfactory bulb in rodents, whereas in humans migration is directed toward striatum. Most CNS injuries elicit proliferation and migration of the NSCs toward the injury site, indicating the activation of a regenerative response. However, regeneration from NSC is incomplete, and this could be due to detrimental cues encountered during inflammation. Different CNS diseases and trauma cause activation of the innate and adaptive immune responses that influence the NSCs. Furthermore, NSCs in the brain react differently to inflammatory cues than their counterparts in the spinal cord. In this review, we have summarized the effects of inflammation on NSCs in relation to their origin and briefly described the NSC activity during different neurological diseases or experimental models.

Regional susceptibilities to mitochondrial dysfunctions in the CNS

2012 ◽  
Vol 393 (4) ◽  
pp. 275-281 ◽  
Author(s):  
Milena Pinto ◽  
Alicia M. Pickrell ◽  
Carlos T. Moraes
Keyword(s):  
Mitochondrial Function ◽  
Neurological Diseases ◽  
Mitochondrial Diseases ◽  
Biochemical Properties ◽  
Specific Cell ◽  
Mitochondrial Dysfunctions ◽  
Common Features ◽  
Age Related ◽  
The Central Nervous System ◽  
The Brain

Abstract Mitochondrial dysfunctions are very common features of age-related neurological diseases such as Parkinson’s, Alzheimer’s and Huntington’s disease. Several studies have shown that bioenergetic impairments have a major role in the degeneration of the central nervous system (CNS) in these patients. Accordingly, one of the main symptoms in many mitochondrial diseases is severe encephalopathy. The heterogeneity of the brain in terms of anatomic structures, cell composition, regional functions and biochemical properties makes the analysis on this organ very complex and difficult to interpret. Humans, in addition to animal models, exposed to toxins that affect mitochondrial function, in particular oxidative phosphorylation, exhibit degeneration of specific regions within the brain. Moreover, mutations in ubiquitously expressed genes that are involved in mitochondrial function also induce regional-specific cell death in the CNS. In this review, we will discuss some current hypotheses to explain the regional susceptibilities to mitochondrial dysfunctions in the CNS.

scholarly journals Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

2021 ◽  
Vol 22 (12) ◽  
pp. 6442
Author(s):  
Aida Kouhi ◽  
Vyshnavi Pachipulusu ◽  
Talya Kapenstein ◽  
Peisheng Hu ◽  
Alan L. Epstein ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Neurological Diseases ◽  
High Specificity ◽  
Biochemical Properties ◽  
Antibody Engineering ◽  
Stage Of Development ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
The Brain

Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer’s, and Parkinson’s disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood–brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1–0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.

scholarly journals Novel Technologies in Studying Brain Immune Response

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Li Li ◽  
Cameron Lenahan ◽  
Zhihui Liao ◽  
Jingdong Ke ◽  
Xiuliang Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Neurological Diseases ◽  
Structural Complexity ◽  
Innate Immune ◽  
Brain Repair ◽  
Novel Technologies ◽  
Novel Treatments ◽  
The Central Nervous System ◽  
Immunomodulatory Therapies ◽  
The Brain

Over the past few decades, the immune system, including both the adaptive and innate immune systems, proved to be essential and critical to brain damage and recovery in the pathogenesis of several diseases, opening a new avenue for developing new immunomodulatory therapies and novel treatments for many neurological diseases. However, due to the specificity and structural complexity of the central nervous system (CNS), and the limit of the related technologies, the biology of the immune response in the brain is still poorly understood. Here, we discuss the application of novel technologies in studying the brain immune response, including single-cell RNA analysis, cytometry by time-of-flight, and whole-genome transcriptomic and proteomic analysis. We believe that advancements in technology related to immune research will provide an optimistic future for brain repair.

scholarly journals Central nervous system diseases associated with blood brain barrier breakdown - A Comprehensive update of existing literatures

2020 ◽  
Vol 4 (2) ◽  
pp. 053-062
Author(s):  
Dutta Rajib
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Barrier Breakdown ◽  
The Brain ◽  
Blood Brain Barrier Breakdown

Blood vessels that supply and feed the central nervous system (CNS) possess unique and exclusive properties, named as blood–brain barrier (BBB). It is responsible for tight regulation of the movement of ions, molecules, and cells between the blood and the brain thereby maintaining controlled chemical composition of the neuronal milieu required for appropriate functioning. It also protects the neural tissue from toxic plasma components, blood cells and pathogens from entering the brain. In this review the importance of BBB and its disruption causing brain pathology and progression to different neurological diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) etc. will be discussed.

scholarly journals Burkholderia pseudomallei Rapidly Infects the Brain Stem and Spinal Cord via the Trigeminal Nerve after Intranasal Inoculation

2016 ◽  
Vol 84 (9) ◽  
pp. 2681-2688 ◽  
Author(s):  
James A. St. John ◽  
Heidi Walkden ◽  
Lynn Nazareth ◽  
Kenneth W. Beagley ◽  
Glen C. Ulett ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Nasal Cavity ◽  
Brain Stem ◽  
Trigeminal Nerve ◽  
Burkholderia Pseudomallei ◽  
Content Type ◽  
Intranasal Inoculation ◽  
Stem Infection ◽  
The Central Nervous System ◽  
The Brain

Infection withBurkholderia pseudomalleicauses melioidosis, a disease with a high mortality rate (20% in Australia and 40% in Southeast Asia). Neurological melioidosis is particularly prevalent in northern Australian patients and involves brain stem infection, which can progress to the spinal cord; however, the route by which the bacteria invade the central nervous system (CNS) is unknown. We have previously demonstrated thatB. pseudomalleican infect the olfactory and trigeminal nerves within the nasal cavity following intranasal inoculation. As the trigeminal nerve projects into the brain stem, we investigated whether the bacteria could continue along this nerve to penetrate the CNS. After intranasal inoculation of mice,B. pseudomalleicaused low-level localized infection within the nasal cavity epithelium, prior to invasion of the trigeminal nerve in small numbers.B. pseudomalleirapidly invaded the trigeminal nerve and crossed the astrocytic barrier to enter the brain stem within 24 h and then rapidly progressed over 2,000 μm into the spinal cord. To rule out that the bacteria used a hematogenous route, we used a capsule-deficient mutant ofB. pseudomalleithat does not survive in the blood and found that it also entered the CNS via the trigeminal nerve. This suggests that the primary route of entry is via the nerves that innervate the nasal cavity. We found that actin-mediated motility could facilitate initial infection of the olfactory epithelium. Thus, we have demonstrated thatB. pseudomalleican rapidly infect the brain and spinal cord via the trigeminal nerve branches that innervate the nasal cavity.

scholarly journals Does hemofiltration protect the brain after head trauma? An experimental study in rabbits

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Enrique Martinez-Gonzalez ◽  
Dolores Garcia-Olmo ◽  
Empar Mayordomo-Aranda ◽  
Maria Granada-Picazo ◽  
Monica Gomez-Juarez ◽  
...  
Keyword(s):  
Experimental Study ◽  
Renal Failure ◽  
Head Trauma ◽  
Neurological Diseases ◽  
Renal Replacement Therapies ◽  
Continuous Renal Replacement Therapies ◽  
The Central Nervous System ◽  
New Treatments ◽  
The Brain ◽  
Experimental Group

Abstract Background Traumatic brain injury (TBI) is one of the most frequent and severe neurological diseases. In the last few decades, significant advances have been made in TBI pathophysiology and monitoring, however new treatments have not emerged. Although the central nervous system (CNS) has been historically defined as an immunologically privileged organ, recent studies show the increasingly predominant role of inflammatory and apoptotic phenomena in the pathogenesis of TBI. Inflammatory response mediators can be eliminated with continuous renal replacement therapies (CRRT). Our aim was to investigate whether hemofiltration protects the brain after head trauma in an experimental study in animals. Methods and results A model of TBI and CVVH was performed in anesthetized New Zealand white rabbits without acute renal failure. The experimental group TBI ( +)-CVVH ( +) was compared with a TBI ( +)-CVVH (−) and a TBI (−)-CVVH ( +) control groups. Rabbits were assessed immediately (NES1) and 24 h hours after (NES2) TBI and/or CVVH using a functional Neurological Evaluation Score (NES) and histology of the brains after sacrifice. There was evidence to support a difference of NES1 comparing with the TBI (−)-CVVH ( +), but not with TBI ( +)-CVVH (−) with only 15% of the rabbits treated with CVVH and TBI showing a favorable neurological course. The final neurological outcome (mortality at 24 h) was 0%, 22% and 53% in the TBI(−) + CVVH( +), TBI( +)-CVVH(−) and TBI( +)-CVVH( +) groups respectively. The use of hemofiltration before or after TBI did not make a difference in regards the outcome of the rabbits. There was evidence in the histology to support an increase of mild ischemia, hemorrhage and edema in the experimental group compared with the other two groups. Conclusions CVVH in rabbits without renal failure used with the intention to protect the brain may worsen the prognosis in TBI.

Respiratory viral infections and associated neurological manifestations

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shirin Hosseini ◽  
Kristin Michaelsen-Preusse ◽  
Martin Korte
Keyword(s):  
Viral Infections ◽  
Neurological Diseases ◽  
Animal Health ◽  
Respiratory Viruses ◽  
Target Tissue ◽  
Direct Invasion ◽  
Spanish Flu ◽  
The Central Nervous System ◽  
Respiratory Viral Infections ◽  
The Brain

Abstract Respiratory viruses as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target tissue of these viruses is the lung, they can induce immediate or delayed neuropathological manifestations in humans and animals. Already after the Spanish flu (1918/20) evidence accumulated that neurological diseases can be induced by respiratory viral infections as some patients showed parkinsonism, seizures, or dementia. In the recent outbreak of COVID-19 as well patients suffered from headache, dizziness, nausea, or reduced sense of smell and taste suggesting that SARS-CoV2 may affect the central nervous system (CNS). It was shown that different respiratory viral infections can lead to deleterious complications in the CNS by a direct invasion of the virus into the brain and/or indirect pathways via proinflammatory cytokine expression. Therefore, we will discuss in this review mechanisms how the most prevalent respiratory viruses including influenza and coronaviruses in humans can exert long-lasting detrimental effects on the CNS and possible links to the development of neurodegenerative diseases as an enduring consequence.

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