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Intranasal Dantroline Administration For The Treatment Of Alzheimer Disease

An Alzheimer's, intranasal technology for neurological diseases, medical preparations containing active ingredients, pharmaceutical formulations, etc., which can solve the limitations of new effective drug development, insufficient cell or animal models, lack of SAD mechanism, etc.

Pending Publication Date: 2022-07-29
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lack of understanding of the mechanisms of SAD and its inadequate cellular or animal models limit the development of new and effective drugs for the treatment of AD

Method used

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  • Intranasal Dantroline Administration For The Treatment Of Alzheimer Disease
  • Intranasal Dantroline Administration For The Treatment Of Alzheimer Disease
  • Intranasal Dantroline Administration For The Treatment Of Alzheimer Disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0067] Dantrolene inhibits impaired neurogenesis and synaptogenesis in induced pluripotent stem cells from Alzheimer's disease patients

[0068] While not wishing to be bound by any particular theory, it is believed that dantrolene inhibits impaired neurogenesis by correcting calcium dysregulation due to ryanodine receptor overactivation and associated impaired lysosomal and autophagic function. synapses occur. In this study, and by using iPSCs and their derived neural progenitor cells (NPCs) and basal forebrain cholinergic neurons (BFCNs) from both SAD patients and FAD patients, the effect of dantrolene on neurogenesis was investigated and the effects and mechanisms of synaptogenesis. Dantrolene significantly ameliorated neurogenesis and synaptogenesis impairment, which was related to correcting RyR hyperactivation, intracellular Ca 2+ Dysregulation is associated with disruption of autophagy.

[0069] Materials and Methods

[0070] cell culture

[0071] Human control (AG...

example 2

[0112] Intranasal administration of dantrolene increases its concentration and duration in the brain

[0113] Intranasal administration of dantrolene is proposed as a novel therapeutic approach to maximize the potential neuroprotective effects of dantrolene in various neurodegenerative diseases, especially AD, while minimizing its toxicity and side effects. As described herein, this study shows that intranasal administration of dantrolene in mice significantly increases the concentration and duration of dantrolene in the brain compared to the usual oral administration.

[0114] Materials and Methods

[0115] animal

[0116]All procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania. Male and female C57BL / 6 mice, 2-4 months old, weighing 25-35 g, were used in all experiments. Mice were maintained at 21-22°C on a 12-hour light-dark cycle with food and water ad libitum. All efforts ...

example 3

[0145] Intranasal dantrolene as a disease-modifying drug in Alzheimer's disease 5XFAD mice

[0146] This study investigated plasma and brain concentrations in 5XFAD mice and the therapeutic efficacy and associated side effects of intranasal dantrolene, not only as a symptom-relieving drug but also as a disease-modifying drug, and compared with that in different FAD animals. The subcutaneous approach performed in the model was compared as described by Peng J et al., Neuroscience Letters Letters 2012;516:274, which is incorporated by reference in its entirety.

[0147] Materials and Methods

[0148] animal

[0149] All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Pennsylvania. Two pairs of 5XFAD mice (B6SJL-Tg(APPSwFIL on, PSEN1*M146L*LV286V)6799Vas / Mmjax) and wild-type mice (B6SJLF1 / J) mice were purchased from Jackson Laboratories (Bar Harbor, Maine) and housed. These 5XFAD transgenic mice overexpress mutant human A...

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Abstract

Methods for inhibiting impaired neurogenesis and / or synaptic occurrence in neurons of a subject suffering from or suspected of having Alzheimer's disease (AD), methods for ameliorating and / or slowing down a decline in cognitive function following the onset of neuropathology and cognitive dysfunction caused by AD, and methods for improving and / or slowing down a decline in cognitive function following the onset of neuropathology and cognitive dysfunction caused by AD. Methods for ameliorating and / or slowing memory decline prior to the onset of symptoms of AD, methods for increasing the concentration and duration of dantroline in the brain, and methods for ameliorating and / or slowing memory decline after the onset of symptoms of AD, comprising intranasally administering to a subject in need thereof an amount of a pharmaceutical composition, the pharmaceutical composition comprises dantrolin which is effective in inhibiting the excessive activation of the N-methyl-D-aspartic acid (NMDA) receptor and / or the raney receptor (RyR). The method further comprises administering to the subject a therapeutically effective amount of a glutamate receptor antagonist.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to US Provisional Application No. 62 / 868,820, filed June 28, 2019, which is hereby incorporated by reference in its entirety. [0003] Government Interest Statement [0004] This invention was made with government support under Grant Nos. GM084979 and AG061447 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. technical field [0005] The present invention relates to methods for treating Alzheimer's disease by intranasal dantrolene administration. The present invention also relates to methods of inhibiting impaired neurogenesis and / or synaptogenesis in neurons of a subject having or suspected of having Alzheimer's disease (AD); ameliorating and / or slowing down neuropathology and methods of cognitive decline after onset of cognitive dysfunction, said neuropathology and said cognitive dysfunction caused by AD; methods of imp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4166A61K9/00A61P43/00
CPCA61P43/00A61K31/4178A61K9/0043A61K45/06A61P25/28A61K2300/00
Inventor 魏华锋孟庆成梁戈M·法桑·依肯海尔
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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