Lack of support for bexarotene as a treatment for Alzheimer's disease

NEUROPHARMACOLOGY

卷:100

Article

O'Hare, Eugene¹  Jeggo, Ross²  Kim, Eun-Mee³  Barbour, Bridgeen¹  Walczak, Jean-Sebastien⁴  Palmer, Philip¹  Lyons, Taylor¹  Page, Deaglan¹  Hanna, Donncha¹  Meara, Jolyon R.⁵  Spanswick, David^2,4,6  Guo, Jian-Ping⁷  McGeer, Edith G.⁷  McGeer, Patrick L.⁷  Hobson, Peter⁵ 

[1] Queens Univ Belfast, Sch Psychol, Belfast BT7 1NN, Antrim, North Ireland

[2] Neurosolut Ltd, Coventry CV4 7ZS, W Midlands, England

[3] Univ Ulster, Sch Psychol, Coleraine BT52 1SA, Londonderry, North Ireland

[4] Cerebrasol Ltd, Montreal, PQ H3W1JO, Canada

[5] Cardiff Univ, Inst Primary Care & Publ Hlth, Cardiff CF10 3XQ, S Glam, Wales

[6] Monash Univ, Dept Physiol, Clayton, Vic 3800, Australia

[7] Univ British Columbia, Kinsmen Lab Neurol Res, Vancouver, BC V6T 1Z3, Canada

关键词: Bexarotene;    Alzheimer's disease;    Beta-amyloid;    Oligomers;    Synaptic transmission;    Behavior;   

DOI  :  10.1016/j.neuropharm.2015.04.020

来源: Elsevier

【 摘 要 】

Bexarotene has been reported to reduce brain amyloid-beta (A beta) levels and to improve cognitive function in transgenic mouse models of Alzheimer's disease (AD). Four groups failed to fully replicate the primary results but the original authors claimed overall support for the general conclusions. Because of its potential clinical importance, the current work studied the effects of bexarotene using two animal species and highly relevant paradigms. Rats were tested for the ability of bexarotene to prevent changes induced by an A beta challenge in the form intracerebroventricular (i.c.v) administration of 7PA2 conditioned medium (7PA2 CM) which contains high levels of A beta species. Bexarotene had no effect on the long-term potentiation of evoked extracellular field excitatory postsynaptic potentials induced by i.c.v. 7PA2 CM. It also had no effect following subcutaneous administration of 2, 5, 10 and 15 mg/kg on behavioral/cognitive impairment using an alternating-lever cyclic-ratio schedule of operant responding in the rat. The effects of bexarotene were further tested using the APPSwFILon, PSEN1*M146L*L286V transgenic mouse model of AD, starting at the time A beta deposits first begin to develop. Mice were sacrificed after 48 days of exposure to 100 mg bexarotene per day. No significant difference between test and control mice was found using a water-maze test, and no significant difference in the number of A beta deposits in cerebral cortex, using two different antibodies, was apparent. These results question the potential efficacy of bexarotene for AD treatment, even if instigated in the preclinical period prior to the onset of cognitive deficits reported for human AD. This article is part of the Special Issue entitled 'Synaptopathy - from Biology to Therapy'. (C) 2015 Elsevier Ltd. All rights reserved.

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