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

O’Hare, Eugene; Jeggo, Ross; Kim, Eun-Mee; Barbour, Bridgeen; Walczak, Jean-Sébastien; Palmer, P. E. S.; Lyons, Taylor; Page, Deaglan; Hanna, Donncha; Meara, Jolyon; Spanswick, David; Jian-ping, Guo; McGeer, Edith G.; McGeer, Patrick L.; Hobson, Peter

doi:10.1016/j.neuropharm.2015.04.020

Cited by 30 publications

(19 citation statements)

References 26 publications

(32 reference statements)

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“…2). This effect of 7PA2 CM on memory has been reported extensively (e.g., O'Hare et al, 2016) but not the effect on RRRs. Bilateral IH injection of aggregated Aβ1-42 and bilateral IH injection of aggregated NAC61-95 produced a significant increase in incorrect lever perseverations (Fig.…”

Section: Discussionsupporting

confidence: 52%

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

O’Hare

Page

Curran

et al. 2017

Behavioural Pharmacology

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Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular (ICV) injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aβ1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (DLB; aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was employed for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aβ1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas ICV injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), that also establish detrimental side effects on memory.

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Section: Discussionsupporting

confidence: 52%

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

O’Hare

Page

Curran

et al. 2017

Behavioural Pharmacology

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“…Whereas some studies report a decrease in soluble forms of brain A␤ peptides [17,18,23], other studies failed to observe an effect [20,21,50,51]. Behavioral studies of bexarotene-treated AD animals have either reported no improvement [19,21,50,51] Fig. 5.…”

Section: Discussionmentioning

confidence: 98%

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Kuntz

Candela

Saint-Pol

et al. 2015

JAD

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Abstract.One of the prime features of Alzheimer's disease (AD) is the excessive accumulation of amyloid-␤ (A␤) peptides in the brain. Several recent studies suggest that this phenomenon results from the dysregulation of cholesterol homeostasis in the brain and impaired bidirectional A␤ exchange between blood and brain. These mechanisms appear to be closely related and are controlled by the blood-brain barrier (BBB) at the brain microvessel level. In animal models of AD, the anticancer drug bexarotene (a retinoid X receptor agonist) has been found to restore cognitive functions and decrease the brain amyloid burden by regulating cholesterol homeostasis. However, the drug's therapeutic effect is subject to debate and the exact mechanism of action has not been characterized. Therefore, the objective of this present study was to determine bexarotene's effects on the BBB. Using an in vitro model of the human BBB, we investigated the drug's effects on cholesterol exchange between abluminal and luminal compartments and the apical-to-basolateral transport of A␤ peptides across the BBB. Our results demonstrated that bexarotene induces the expression of ABCA1 but not ApoE. This upregulation correlates with an increase in ApoE2-, ApoE4-, ApoA-I-, and HDL-mediated cholesterol efflux. Regarding the transport of A␤ peptides, bexarotene increases the expression of ABCB1, which in turn decreases A␤ apical-to-basolateral transport. Our results showed that bexarotene not only promotes the cholesterol exchange between the brain and the blood but also decreases the influx of A␤ peptides across BBB, suggesting that bexarotene is a promising drug candidate for the treatment of AD.

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“…In recent years, an oncolytic, Bexarotene , which was previously used to treat certain forms of lymphoma, has attracted a lot of attention. Preclinical studies in animals have shown that it causes abrupt yet reversible reduction of amyloid plaques improving cognitive functions.…”

Section: Current Strategies Of Ad Drug Developmentmentioning

confidence: 99%

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

Бачурин

Bovina

Ustyugov

2017

Medicinal Research Reviews

258

159

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Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.

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

Cited by 30 publications

References 26 publications

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia

Bexarotene Promotes Cholesterol Efflux and Restricts Apical-to-Basolateral Transport of Amyloid-β Peptides in an In Vitro Model of the Human Blood-Brain Barrier

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends

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