O'Hare, Eugene, Scopes, David I. C., Treherne, J. Mark, Norwood, Kelly, Spanswick, David and Kim, Eun-Mee. (2010) RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo. Behavioural Brain Research, Vol.210 (No.1). pp. 32-37. ISSN 0166-4328

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Abstract

Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (A beta) on progressively developing behavioural symptomatology and neuropathology in Alzheimer's disease (AD) have yet to become available. However, a viable strategy may be to target and neutralise soluble A beta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of A beta is therapeutically attractive, as A beta aggregation is a pathological event and pharmacological interventions targeting this are likely to have a non-toxic profile. A behavioural assay, the alternating-lever cyclic-ratio schedule, was used to assess the effect of A beta oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit A beta(1-42) fibrillogenesis and protect against A beta(1-42)-induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human A beta on behaviour and dose dependently reduced the behavioural effects of A beta oligomers, with the highest dose, 10 mu M, maintaining behaviour approximately at control levels. This effect appeared to be central; peripheral confounds having been extensively investigated. This is the first published report on the effects of RS-0406 in vivo and indicates that RS-0406 has potential as a pharmacotherapeutic intervention for behavioural deficits seen in the early stages of AD, and possibly as an intervention in the development of AD neuropathology. Indeed, an analogue of RS-0406 that could be administered peripherally might be a realistic candidate for the clinical treatment of AD. (C) 2010 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Subjects:	B Philosophy. Psychology. Religion > BF Psychology R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Behavioural Brain Research
Publisher:	Elsevier BV
ISSN:	0166-4328
Date:	26 June 2010
Volume:	Vol.210
Number:	No.1
Number of Pages:	6
Page Range:	pp. 32-37
Identification Number:	10.1016/j.bbr.2010.01.044
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/5873

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