scholarly journals Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1745
Author(s):  
Noriyasu Kamei ◽  
Susumu Suwabe ◽  
Kenji Arime ◽  
Hidemi Bando ◽  
Kaho Murata ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Subcutaneous Administration ◽  
Perivascular Space ◽  
Peptide Drugs ◽  
Olfactory Pathway ◽  
Bottom Part ◽  
Transport Pathways ◽  
Brain Drug Delivery ◽  
Trigeminal Nerves ◽  
The Brain

We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas.

scholarly journals Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.

1990 ◽  
Vol 172 (4) ◽  
pp. 1127-1132 ◽  
Author(s):  
S Perlman ◽  
G Evans ◽  
A Afifi
Keyword(s):  
Olfactory Bulb ◽  
Hepatitis Virus ◽  
Anterior Commissure ◽  
Olfactory Pathway ◽  
Surgical Ablation ◽  
Viral Transport ◽  
The Central Nervous System ◽  
Trigeminal Nerves ◽  
The Brain

Previous results suggested that, after intranasal inoculation, mouse hepatitis virus (MHV), a neurotropic coronavirus, entered the central nervous system (CNS) via the olfactory and trigeminal nerves. To prove this hypothesis, the effect of interruption of the olfactory pathway on spread of the virus was studied using in situ hybridization. Unilateral surgical ablation of this pathway prevented spread of the virus via the olfactory tract on the side of the lesion. MHV RNA could be detected, however, at distal sites on the operated side, indicating that the virus spread via well-described circuits involving the anterior commissure from the control (intact) side of the brain. Viral transport via the trigeminal nerve was not affected by removal of the olfactory bulb, showing that the surgical procedure was specific for the olfactory pathway. These results prove conclusively that MHV gains entry to the CNS via a transneuronal route, and spreads to additional sites in the brain via known neuroanatomic pathways.

scholarly journals An Evolutionary Microcircuit Approach to the Neural Basis of High Dimensional Sensory Processing in Olfaction

2021 ◽  
Vol 15 ◽  
Author(s):  
Gordon M. Shepherd ◽  
Timothy B. Rowe ◽  
Charles A. Greer
Keyword(s):  
Olfactory Bulb ◽  
Receptor Gene ◽  
Olfactory Cortex ◽  
High Dimensional ◽  
Gene Duplications ◽  
Olfactory Pathway ◽  
Neural Basis ◽  
Property A ◽  
Fundamental Understanding ◽  
The Brain

Odor stimuli consist of thousands of possible molecules, each molecule with many different properties, each property a dimension of the stimulus. Processing these high dimensional stimuli would appear to require many stages in the brain to reach odor perception, yet, in mammals, after the sensory receptors this is accomplished through only two regions, the olfactory bulb and olfactory cortex. We take a first step toward a fundamental understanding by identifying the sequence of local operations carried out by microcircuits in the pathway. Parallel research provided strong evidence that processed odor information is spatial representations of odor molecules that constitute odor images in the olfactory bulb and odor objects in olfactory cortex. Paleontology provides a unique advantage with evolutionary insights providing evidence that the basic architecture of the olfactory pathway almost from the start ∼330 million years ago (mya) has included an overwhelming input from olfactory sensory neurons combined with a large olfactory bulb and olfactory cortex to process that input, driven by olfactory receptor gene duplications. We identify a sequence of over 20 microcircuits that are involved, and expand on results of research on several microcircuits that give the best insights thus far into the nature of the high dimensional processing.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

Polymeric Nanoparticles for Brain Drug Delivery - A Review

2020 ◽  
Vol 21 (9) ◽  
pp. 649-660
Author(s):  
Subashini Raman ◽  
Syed Mahmood ◽  
Ayah R. Hilles ◽  
Md Noushad Javed ◽  
Motia Azmana ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Surface Modification ◽  
Polymeric Nanoparticles ◽  
Drug Loading ◽  
Preparation Methods ◽  
Brain Drug Delivery ◽  
Polymeric Nanoparticle ◽  
Relationship Of ◽  
The Relationship ◽  
The Brain

Background: Blood-brain barrier (BBB) plays a most hindering role in drug delivery to the brain. Recent research comes out with the nanoparticles approach, is continuously working towards improving the delivery to the brain. Currently, polymeric nanoparticle is extensively involved in many therapies for spatial and temporal targeted areas delivery. Methods: We did a non-systematic review, and the literature was searched in Google, Science Direct and PubMed. An overview is provided for the formulation of polymeric nanoparticles using different methods, effect of surface modification on the nanoparticle properties with types of polymeric nanoparticles and preparation methods. An account of different nanomedicine employed with therapeutic agent to cross the BBB alone with biodistribution of the drugs. Results: We found that various types of polymeric nanoparticle systems are available and they prosper in delivering the therapeutic amount of the drug to the targeted area. The effect of physicochemical properties on nanoformulation includes change in their size, shape, elasticity, surface charge and hydrophobicity. Surface modification of polymers or nanocarriers is also vital in the formulation of nanoparticles to enhance targeting efficiency to the brain. Conclusion: More standardized methods for the preparation of nanoparticles and to assess the relationship of surface modification on drug delivery. While the preparation and its output like drug loading, particle size, and charge, permeation is always conflicted, so it requires more attention for the acceptance of nanoparticles for brain delivery.

scholarly journals Odor hedonics coding in the vertebrate olfactory bulb

2021 ◽  
Vol 383 (1) ◽  
pp. 485-493 ◽  
Author(s):  
Florence Kermen ◽  
Nathalie Mandairon ◽  
Laura Chalençon
Keyword(s):  
Social Interaction ◽  
Olfactory Bulb ◽  
Physicochemical Properties ◽  
Olfactory Perception ◽  
Hedonic Value ◽  
Odor Hedonics ◽  
The Brain

AbstractWhether an odorant is perceived as pleasant or unpleasant (hedonic value) governs a range of crucial behaviors: foraging, escaping danger, and social interaction. Despite its importance in olfactory perception, little is known regarding how odor hedonics is represented and encoded in the brain. Here, we review recent findings describing how odorant hedonic value is represented in the first olfaction processing center, the olfactory bulb. We discuss how olfactory bulb circuits might contribute to the coding of innate and learned odorant hedonics in addition to the odorant’s physicochemical properties.

scholarly journals Murine Olfactory Bulb Interneurons Survive Infection with a Neurotropic Coronavirus

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
D. Lori Wheeler ◽  
Jeremiah Athmer ◽  
David K. Meyerholz ◽  
Stanley Perlman
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Olfactory Bulb ◽  
Hepatitis Virus ◽  
Large Fraction ◽  
Acute Infection ◽  
Virus Antigen ◽  
Host Cells ◽  
Virulent Virus ◽  
The Brain

ABSTRACT Viral infection of the central nervous system (CNS) is complicated by the mostly irreplaceable nature of neurons, as the loss of neurons has the potential to result in permanent damage to brain function. However, whether neurons or other cells in the CNS sometimes survive infection and the effects of infection on neuronal function is largely unknown. To address this question, we used the rJHM strain (rJ) of mouse hepatitis virus (MHV), a neurotropic coronavirus that causes acute encephalitis in susceptible strains of mice. To determine whether neurons or other CNS cells survive acute infection with this virulent virus, we developed a recombinant JHMV that expresses Cre recombinase (rJ-Cre) and infected mice that universally expressed a silent (floxed) version of tdTomato. Infection of these mice with rJ-Cre resulted in expression of tdTomato in host cells. The results showed that some cells were able to survive the infection, as demonstrated by continued tdTomato expression after virus antigen could no longer be detected. Most notably, interneurons in the olfactory bulb, which are known to be inhibitory, represented a large fraction of the surviving cells. In conclusion, our results indicated that some neurons are resistant to virus-mediated cell death and provide a framework for studying the effects of prior coronavirus infection on neuron function. IMPORTANCE We developed a novel recombinant virus that allows the study of cells that survive an infection by a central nervous system-specific strain of murine coronavirus. Using this virus, we identified neurons and, to a lesser extent, nonneuronal cells in the brain that were infected during the acute phase of the infection and survived for approximately 2 weeks until the mice succumbed to the infection. We focused on neurons and glial cells within the olfactory bulb because the virus enters the brain at this site. Our results show that interneurons of the olfactory bulb were the primary cell type able to survive infection. Further, these results indicate that this system will be useful for functional and gene expression studies of cells in the brain that survive acute infection.

scholarly journals Histological study of the drug PEG-Filstim sub-acute toxicity

2018 ◽  
pp. 80-88
Author(s):  
V. L. Karbovskyy ◽  
I. A. Shevchuk ◽  
O. V. Kurkina ◽  
T. Ye. Makovska
Keyword(s):  
Defect Formation ◽  
Histological Study ◽  
Subcutaneous Administration ◽  
Toxic Effects ◽  
Internal Organs ◽  
Brain Vessels ◽  
Laboratory Rats ◽  
Applied Dose ◽  
Reticular Tissue ◽  
The Brain

One of the critical steps in development of safe and efficient drugs during their pre-clinical trials are toxicity studies. Therefore, the aim of our work was to study PEG-Filstim toxic effects on animal internal organs and tissues. Toxicity study of PEG-Filstim was performed in 50 white wild-type rats of both sexes with body weight of 170 to 230 g on daily (28 days) subcutaneous administration in the doses of 0.5, 1.0 and 2.0 mg/kg. In all groups of animals, after completing the experiment careful pathomorphologic and histological examination was performed. PEG-Filstim has been shown to possess no toxic effects on internal organs of laboratory rats and does not cause specific changes in the heart, kidneys and mucous coat of stomach on daily subcutaneous administration in the doses of 0.5, 1.0, and 2.0 mg/kg within 28 days. In the maximum applied dose of 2.0 mg/kg, the studied drug causes pronounced acute splenic hyperplasia, related to hyper-proliferation of the reticular tissue, leads to functional strain of the liver due to formation of hematopoietic foci in it, as well as impaired integrity of the respiratory epithelium and congestive signs in the lungs, swelling of the brain tissues, abnormalities in the gray matter structure and hyperemia of the brain vessels. These effects were not observed in the animals, to which the drug was administered in the doses of 0.5 and 1.0 mg/kg. Administration of PEG-Filstim (in all studied doses) results in increasing the size of the ankle joint in rats, which is related to hyper-proliferation of the reticular tissue, leading to bone defect formation in the form of perforation with subsequent filling the periosteum with reticular tissue and formation of hematopoietic foci within its boundaries.

Expression patterns of nicotinic subunits α2, α7, α8, and β1 affect the kinetics and pharmacology of ACh-induced currents in adult bee olfactory neuropiles

2011 ◽  
Vol 106 (4) ◽  
pp. 1604-1613 ◽  
Author(s):  
Julien Pierre Dupuis ◽  
Monique Gauthier ◽  
Valérie Raymond-Delpech
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Expression Patterns ◽  
Insect Brain ◽  
Olfactory Pathway ◽  
Excitatory Neurotransmitter ◽  
Kenyon Cells ◽  
Inward Currents ◽  
Induced Currents ◽  
The Brain

Acetylcholine (ACh) is the main excitatory neurotransmitter of the insect brain, where nicotinic acetylcholine receptors (nAChRs) mediate fast cholinergic synaptic transmission. In the honeybee Apis mellifera, nAChRs are expressed in diverse structures including the primary olfactory centers of the brain, the antennal lobes (ALs) and the mushroom bodies (MBs), where they participate in olfactory information processing. To understand the nature and properties of the nAChRs involved in these processes, we performed a pharmacological and molecular characterization of nAChRs on cultured Kenyon cells of the MBs, using whole cell patch-clamp recordings combined with single-cell RT-PCR. In all cells, applications of ACh as well as nicotinic agonists such as nicotine and imidacloprid induced inward currents with fast desensitization. These currents were fully blocked by saturating doses of the antagonists α-bungarotoxin (α-BGT), dihydroxy-β-erythroidine (DHE), and methyllycaconitine (MLA) (MLA ≥ α-BGT ≥ DHE). Molecular analysis of ACh-responding cells revealed that of the 11 nicotinic receptor subunits encoded within the honeybee genome, α2, α8, and β1 subunits were expressed in adult Kenyon cells. Comparison with the expression pattern of adult AL cells revealed the supplementary presence of subunit α7, which could be responsible for the kinetic and pharmacological differences observed when comparing ACh-induced currents from AL and Kenyon cells. Together, our data demonstrate the existence of functional nAChRs on adult MB Kenyon cells that differ from nAChRs on AL cells in both their molecular composition and pharmacological properties, suggesting that changing receptor subsets could mediate different processing functions depending on the brain structure within the olfactory pathway.

Expression of IGF-I and -II mRNA in the brain and craniofacial region of the rat fetus

Development ◽  
1991 ◽  
Vol 111 (1) ◽  
pp. 105-115 ◽  
Author(s):  
C. Ayer-le Lievre ◽  
P.A. Stahlbom ◽  
V.R. Sara
Keyword(s):  
Nervous System ◽  
Olfactory Bulb ◽  
Endocrine Function ◽  
Target Cells ◽  
Pars Intermedia ◽  
Sensory Ganglia ◽  
Rat Fetus ◽  
Amino Terminal ◽  
Igf I ◽  
The Brain

Insulin-like growth factors (IGF-I and -II) are present in the brain during development, with high levels of both being also found in the periphery particularly in the embryo. IGFs in the brain are believed to stimulate the proliferation of neuronal and glial precursors and their phenotypic differentiation. Using in situ hybridization, we have investigated the distribution of cells producing IGF-I and -II in the rat fetus during the second half of prenatal development with special emphasis on the peripheral and central nervous system. High levels of IGF-I mRNA were found in the olfactory bulb and in discrete neurons of the cranial sensory ganglia, notably in the trigeminal ganglion, as early as 13 days of gestation, in the pineal primordium of 18 day old fetuses, and in discrete groups of cells in the cochlear epithelium located laterally outside the forming spiral organ, in day 13 to 21 fetuses. High levels of IGF-II mRNA in the brain, besides the choroid plexus and the leptomeninges, were detected in hypothalamus, in the floor of the 3rd ventricle at all stages studied, in the pineal primordium at 18 days and in the pars intermedia of the pituitary or in the Rathke's pouch epithelium from which it is derived, with progressive fading towards the end of the gestation. In the peripheral nervous system the IGF-II mRNA was only found in association with the vascular endothelia of the ganglia. IGF-II mRNA in the nervous system was found in highly vascularized areas, meninges, blood vessels and choroid plexuses. It is thus associated with structures involved in the production of extracellular fluids and/or substrate transport and supply in the nervous tissues. A more specific role in the differentiation or fetal endocrine function should be considered for IGF-II in cells producing melatonin and melanocyte stimulating hormone (MSH) in the pineal and pituitary glands, respectively. The presence of IGF-I mRNA in the nervous system could be associated with fiber outgrowth and synaptogenesis in the cases of olfactory bulb and developing iris. The role of IGF-I in restricted populations of cells of the cochlear epithelium and in the pineal gland is unclear and requires further investigations including a search for IGF-I receptors in possible target cells. In the sensory ganglia, the presence of high levels of IGF-I mRNA eventually corresponds to the production, by post-translational processing, of the amino-terminal tripeptide of IGF-I, which might represent a neurotransmitter for these sensory neurons.

Characterization of Oscillatory Olfactory Interneurones in the Protocerebrum of the Crayfish

1992 ◽  
Vol 167 (1) ◽  
pp. 15-38
Author(s):  
DEFOREST MELLON ◽  
DAVID C. SANDEMAN ◽  
RENATE E. SANDEMAN
Keyword(s):  
Procambarus Clarkii ◽  
Lucifer Yellow ◽  
Freshwater Crayfish ◽  
University Of Virginia ◽  
Olfactory Pathway ◽  
Electrophysiological Recordings ◽  
Burst Period ◽  
Electron Microscopical ◽  
The Brain

1. We obtained intracellular electrophysiological recordings from local interneurones within the hemi-ellipsoid neuropile of the brain in the freshwater crayfish Cherax destructor and Procambarus clarkii. The recordings were made from perfused, isolated head preparations that provided several indications of a healthy physiological condition. 2. The hemi-ellipsoid interneurones are spontaneously active, generating bursts of action potentials at regular intervals. The inter-burst period differs among neurones, varying from about 1.0 s at the shortest periods to around 30 s for the longest periods. 3. Evidence from both electrophysiological recordings and from injection of Lucifer Yellow and Neurobiotin dyes into hemi-ellipsoid interneurones suggests that some of the cells in the populations are electrically coupled to one another. 4. Hemi-ellipsoid interneurones are driven postsynaptically by axons within the lateral protocerebral tract. Experiments with focal electrical stimulation strongly suggest that the pathways responsible include axons of the olfactory-globular tract. These findings support our previous electron microscopical data showing that olfactory-globular tract axons are presynaptic to the hemi-ellipsoid interneurones. 5. These findings support the conclusion that hemi-ellipsoid interneurones are an integral link in the central olfactory pathway of the crayfish. Note: Present address and address for reprint requests: Department of Biology, Gilmer Hall, University of Virginia, Charlottesville, VA 22901, USA.

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