RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo.
Clinically accessible compounds that arrest or reverse the effects of amyloid-beta (Abeta) 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 Abeta oligomers, which have been shown to mediate synaptic dysfunction and to produce cognitive deficits in the intact organism. Inhibiting the aggregation of Abeta is therapeutically attractive, as Abeta 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 Abeta oligomers and the non-peptide small molecule RS-0406 in male Sprague-Dawley rats. RS-0406 has been shown to inhibit Abeta(1-42) fibrillogenesis and protect against Abeta(1-42)-induced cytotoxicity in primary hippocampal neurons. In the current study, RS-0406 ameliorated the adverse effects of secreted oligomers of human Abeta on behaviour and dose dependently reduced the behavioural effects of Abeta oligomers, with the highest dose, 10microM, 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.
School of Psychology, Queens University, Belfast, Northern Ireland, UK. e.ohare@qub.qc.uk <e.ohare@qub.qc.uk>
Eugene
E
O'Hare
David I C
DI
Scopes
J Mark
JM
Treherne
Kelly
K
Norwood
David
D
Spanswick
Eun-Mee
EM
Kim
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D003959:Diamines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009483:Neuropsychological Tests; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule
D016229:Amyloid beta-Peptides; D003959:Diamines; C472970:N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine; D018696:Neuroprotective Agents; D011724:Pyridazines