Frontiers in CNS Drug Discovery

Volume: 1

Therapeutic Treatment of Alzheimer's Disease Using Metal Complexing Agents

Author(s): Katherine A. Price, Peter J. Crouch, Anthony R. White

Pp: 106-122 (17)

DOI: 10.2174/978160805159511001010106

* (Excluding Mailing and Handling)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of extracellular amyloid plaques, formation of intracellular neurofibrillary tangles and neuronal dysfunction in the brain. A growing body of evidence indicates a central role for biometals such as copper in many critical aspects of AD. The amyloid beta (Aβ) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate Cu and Zn metabolism in the brain. Therefore, aberrant changes to APP or Aβ metabolism could potentially alter biometal homoestasis in AD, leading to increased free radical production and neuronal oxidative stress. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid permeable metal complexing agent, clioquinol (CQ), has shown promising results in animal models of AD and in small clinical trials involving AD patients. Moreover, a new generation of metal-ligand based therapeutics is currently under development. Patents now cover the generation of novel metal ligand structures designed to modulate metal binding to Aβ and quench metal-mediated free radical generation. However, the mechanism by which CQ and other metal complexing agents slow cognitive decline in AD animal models and patients is unknown. Increasing evidence suggests that ligandmediated redistribution of metals at a cellular level in the brain may be important. Further research will be necessary to fully understand the complex pathways associated with efficacious metal-based pharmaceuticals for treatment of AD.


Keywords: Amyloid, copper, ligand, metal, Alzheimer's disease, chelation, metal ionophore, phosphoinositol-3-kinase, 8-hydroxyquinoline, clioquinol

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 873346344 and j.to_ip >=873346344 )) and ((j.from_date <= 1740516084 and j.to_date >= 1740516084 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 1870) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 873346344 and j.to_ip >=873346344 )) and ((j.from_date <= 1740516084 and j.to_date >= 1740516084 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 1870) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 873346344 and j.to_ip >=873346344 )) and ((j.from_date <= 1740516084 and j.to_date >= 1740516084 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 1870)
      790μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 923 and `b`.`banner_from_date` <= 1740516084 and `b`.`banner_to_date` >= 1740516084 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.09msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 923
      • 3: 1740516084
      • 4: 1740516084
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='aad36f504638136717e198d0cbb616c7'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    10Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        CKGrsWWay0ADj9jIcXEDwnl6WfMtYMsE34bzLDy2
        uc_cart_id
        aad36f504638136717e198d0cbb616c7
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/1870" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/1870
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
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        session_attributes
        0 of 0
        array:5 [ "_token" => "CKGrsWWay0ADj9jIcXEDwnl6WfMtYMsE34bzLDy2" "uc_cart_id" => "aad36f504638136717e198d0cbb616c7" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/1870" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:41:24GET/chapter/18701121912