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RS-0406 arrests amyloid-beta oligomer-induced behavioural deterioration in vivo.
- Source :
-
Behavioural brain research [Behav Brain Res] 2010 Jun 26; Vol. 210 (1), pp. 32-7. Date of Electronic Publication: 2010 Feb 05. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Behavior, Animal drug effects
Behavior, Animal physiology
Cell Line
Cognition Disorders chemically induced
Diamines administration & dosage
Diamines chemistry
Dose-Response Relationship, Drug
Humans
Male
Motor Activity drug effects
Motor Activity physiology
Neuroprotective Agents administration & dosage
Neuroprotective Agents chemistry
Neuropsychological Tests
Pyridazines administration & dosage
Pyridazines chemistry
Random Allocation
Rats
Rats, Sprague-Dawley
Reinforcement Schedule
Amyloid beta-Peptides metabolism
Cognition Disorders drug therapy
Cognition Disorders metabolism
Diamines pharmacology
Neuroprotective Agents pharmacology
Pyridazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7549
- Volume :
- 210
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Behavioural brain research
- Publication Type :
- Academic Journal
- Accession number :
- 20138088
- Full Text :
- https://doi.org/10.1016/j.bbr.2010.01.044