scholarly journals A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4197 ◽  
Author(s):  
Katalin Prokai-Tatrai ◽  
Laszlo Prokai
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Estrogen Therapy ◽  
High Concentration ◽  
Beneficial Effects ◽  
Non Invasive ◽  
Site Of Action ◽  
The Central Nervous System ◽  
And Gender ◽  
Preclinical Animal Models

Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.

scholarly journals Self-buffering capacity of a human sulfatase for central nervous system delivery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi Wen ◽  
Nazila Salamat-Miller ◽  
Keethkumar Jain ◽  
Katherine Taylor
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Buffering Capacity ◽  
The Self ◽  
High Concentration ◽  
Formulation Design ◽  
The Central Nervous System ◽  
Therapeutic Enzymes ◽  
Intrathecal Space

AbstractDirect delivery of therapeutic enzymes to the Central Nervous System requires stringent formulation design. Not only should the formulation design consider the delicate balance of existing ions, proteins, and osmolality in the cerebrospinal fluid, it must also provide long term efficacy and stability for the enzyme. One fundamental approach to this predicament is designing formulations with no buffering species. In this study, we report a high concentration, saline-based formulation for a human sulfatase for its delivery into the intrathecal space. A high concentration formulation (≤ 40 mg/mL) was developed through a series of systematic studies that demonstrated the feasibility of a self-buffered formulation for this molecule. The self-buffering capacity phenomenon was found to be a product of both the protein itself and potentially the residual phosphates associated with the protein. To date, the self-buffered formulation for this molecule has been stable for up to 4 years when stored at 5 ± 3 °C, with no changes either in the pH values or other quality attributes of the molecule. The high concentration self-buffered protein formulation was also observed to be stable when exposed to multiple freeze–thaw cycles and was robust during in-use and agitation studies.

Odor Perception

2012 ◽  
pp. 44-59 ◽  
Author(s):  
Mitsuo Tonoike
Keyword(s):  
Signal Transduction ◽  
Central Nervous System ◽  
Nervous System ◽  
Information Processing ◽  
Non Invasive ◽  
Olfactory Acuity ◽  
Central Regions ◽  
Olfactory Systems ◽  
The Central Nervous System ◽  
The Brain

Though olfaction is one of the necessary senses and indispensable for the maintenance of the life of the animal, the mechanism of olfaction had not yet been understood well compared with other sensory systems such as vision and audition. However, recently, the most basic principle of “signal transduction on the reception and transmission for the odor” has been clarified. Therefore, the important next problem is how the information of odors about is processed in the Central Nervous System (CNS) and how odor is perceived in the human brain. In this chapter, the basic olfactory systems in animal and human are described and examples such as “olfactory acuity, threshold, adaptation, and olfactory disorders” are discussed. The mechanism of olfactory information processing is described under the results obtained by using a few new non-invasive measuring methods. In addition, from a few recent studies, it is shown that olfactory neurophysiological information is passing through some deep central regions of the brain before finally being processed in the orbito-frontal areas.

Effects of Certain Indole Amines on Electrical Activity of the Nervous System

1956 ◽  
Vol 185 (3) ◽  
pp. 601-606 ◽  
Author(s):  
Alan G. Slocombe ◽  
Hudson Hoagland ◽  
Lillian S. Tozian
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Electrical Activity ◽  
Lysergic Acid ◽  
Subcortical Structures ◽  
Albino Rat ◽  
Site Of Action ◽  
The Central Nervous System ◽  
Recovery From Anesthesia ◽  
The Brain

Lysergic acid diethylamide (LSD), 5-hydroxytryptamine, and adrenochrome were shown to have properties similar to epinephrine in their effects on the spontaneous electrical activity in the brain of the albino rat. The effects of these drugs were shown to be determined by the type of anesthetic used. In Pentothal-anesthetized animals, profound reduction of the electrical activity in both frequency and amplitude was found in response to these drugs, while in ether-anesthetized animals there was no significant effect. There was a tendency for LSD to increase electrical activity when injected following recovery from anesthesia. The significance of this differential response is discussed with respect to structures in the central nervous system primarily affected by ether and Pentothal, and it is suggested that the site of action of these compounds is in Pentothal-sensitive nonspecific pathways. The site of the depressive action of these drugs with Pentothal is further defined by the fact that both cortical and subcortical structures were equally affected, while respiratory and cardio-regulatory centers were not significantly depressed. This implicates one of the lower nonspecific centers with widespread cortical and subcortical projections.

scholarly journals SITE OF ACTION OF TRANS-π-OXOCAMPHOR IN THE CENTRAL NERVOUS SYSTEM OF THE CAT

1964 ◽  
Vol 14 (2) ◽  
pp. 229-230 ◽  
Author(s):  
HIROSHI KUMAGAI ◽  
FUMINORI SARAI ◽  
TAKEHIKO HUKUHARA ◽  
YOSHIAKI SAJI ◽  
SUEHIRO NAKANISHP ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Site Of Action ◽  
The Central Nervous System

scholarly journals Neuroprotective Aspects of Cannabinoid Compounds

2020 ◽  
Vol 5 (2) ◽  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Reliable Data ◽  
Protective Effects ◽  
Neuroprotective Agents ◽  
Beneficial Effects ◽  
Cannabinoid Compounds ◽  
The Central Nervous System ◽  
Effective Use

The accumulation of reliable data on the effects of cannabinoids is essential for understanding their possible beneficial effects on the central nervous system (CNS). Investigating individual substances along with the action of different combinations may show new possibilities for cannabinoids as neuroprotective agents. The data collected so far reveals the complexity of the mechanism of cannabinoids action on CNS, and even more complex and poorly understood are the effects when combined. Moreover, combining cannabinoids with different drugs and chemicals may lead to a decrease in beneficial effects. These characteristics of their action emphasize the complexity of the molecular mechanisms of neuroprotection and the lack of reliable information that may contribute to the safe and effective use of cannabinoids as medicines with valuable neuroprotective properties. The current brief review summarizes present data related to the protective effects of some cannabinoids on CNS and possible mechanisms involved in cannabinoid-mediated neuroprotection.

scholarly journals Cerebral vasculitis: clinical features and diagnostic principles

2001 ◽  
Vol XXXIII (3-4) ◽  
pp. 71-77
Author(s):  
I. G. Salikhov ◽  
E. I. Bogdanov ◽  
A. T. Zabbarova
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Early Diagnosis ◽  
Clinical Manifestations ◽  
Cerebral Vasculitis ◽  
Malignant Diseases ◽  
Non Invasive ◽  
The Central Nervous System ◽  
Diagnostic Capabilities ◽  
Primary Vasculitis

Cerebral vasculitis (CV) is a severe, potentially disabling disease that usually develops in the presence of rheumatic, infectious, medicinal, or malignant diseases. In rare cases, isolated (primary) vasculitis of the central nervous system (CNS) is observed [17, 33]. The complex pathogenesis, polymorphism of clinical manifestations, and the absence in most cases of reliable non-invasive diagnostic criteria for CV complicate early diagnosis and treatment. In this regard, it seems relevant to analyze the features of clinical manifestations and diagnostic capabilities in cerebrovascular pathology caused by vasculitis.

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