Premium
P4–430: Antisense oligonucleotide‐mediated inhibition of miR‐33 in cultured neurons, astrocytes and microglia: Effects on ABCA1 expression, APOE lipidation, cellular cholesterol and beta‐amyloid neurotoxicity
Author(s) -
Qureshi Asad,
Karasinska Joanna,
Kang Martin,
Kaur Achint,
Ruddle Piers,
Franciosi Sonia,
Hayden Michael
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.08.263
Subject(s) - abca1 , microglia , neurodegeneration , neurotoxicity , biology , microbiology and biotechnology , apolipoprotein e , cholesterol , amyloid beta , pharmacology , chemistry , biochemistry , transporter , immunology , medicine , inflammation , gene , toxicity , disease , organic chemistry , peptide
Background: DSP-8658, a novel selective peroxisome proliferator-activated receptor (PPAR)a/gmodulator, is a Phase I clinical stage drug candidate for the treatment of Alzheimer’s disease (AD). We have previously reported that DSP-8658 enhances the microglial uptake of amyloid b-peptide(Ab), which is a proposed trigger of the onset of AD, and also improves cognitive function in APP/PS1 transgenic mice. The present study describes the acute or subacute symptomatic effects of DSP-8658 on cognitive function and the results in 104-week rat carcinogenicity study.Methods: To investigate procognitive effects of DSP-8658 at 1-30 mg/kg, p.o., we performed a mouse object recognition test, a mouse Y-maze test and a rat passive avoidance test. To clarify the safety profile of DSP-8658 more, the 104-week carcinogenicity study of rats was conducted. Results: DSP8658 (30mg/kg) significantly prevented the object memory loss in aged mice. DSP-8658 (3 mg/kg) also improved the spatial working memory impairment caused by LPS-induced neuroinflammation in mice. In the rat passive avoidance test, DSP-8658 (10mg/kg) significantly ameliorated scopolamine-induced memory impairment. On the other hand, Wy14643 (PPARa agonist) and Rosiglitazone (PPARg agonist) also showed procognitive effects, but those maximum effects were less than that of DSP8658. These results indicate that DSP-8658 has a great potential to restore the memory deficits caused by aging, cholinergic dysfunction and inflammation, which are the important characteristic features of AD pathology. The potent efficacies of DSP-8658 on procognitive function, which is superior to those of the single agonists of PPAR subtypes, may be mediated by its dual agonistic activities on both PPARa and g. In the 104-week rat carcinogenicity study, DSP-8658 induced tumors only at the highest doses producing AUC 10-fold therapeutic exposures with the maximum recommended human dose, and had enough cardiovascular safety margin, indicating that DSP-8658 exhibits good safety profiles as a PPARmodulator.Conclusions: Based on the nonclinical pharmacological and safety data, DSP-8658 has a highly promising therapeutic profile as a drug for both symptomatic and disease-modifying treatment of AD. DSP-8658 is expected to be efficacious for AD in the following clinical trials.