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P4–255: Effects of tetrahydroxystilbene– glucoside on rat model of β–amyloid increased induced by hypercholesterolemia
Author(s) -
Zhao Ling,
Li Lin
Publication year - 2006
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.2006.05.1994
Subject(s) - cholesterol , medicine , endocrinology , morris water navigation task , very low density lipoprotein , hippocampus , hemorheology , lipoprotein , high density lipoprotein , chemistry
production and related neurotoxicity, to characterize small molecules as potential drugs for the treatment of AD. Methods: ExonHit Therapeutics has used its proprietary technology DATASTM. Results: (1) Alternative splicing of the small GTP-binding protein Rac1 led to the expression of a constitutively active, ROS producing, variant in AD brain. ExonHit Therapeutics has developed several series of compounds acting as specific Rac1 inhibitors. EHT1864 series prevent ROS generation and A production in vitro, acting at the level of the -secretase without affecting Notch processing. In vivo, EHT1864, the prototypic member of these series, efficiently crosses the BBB and exhibits a good bioavailability and tolerability in rodents, and significantly reduces A levels in guinea pigs. Therefore, A generation by -secretase is under the control of Rac1 in vivo (J Biol Chem. 2005 280(45):37516). EHT1864 series represent good candidates for inhibiting A formation and ROS production in the AD brain. (2) The epsilon subunit of the GABAA receptor and several actors of the cAMP cascade were identified as specifically altered at the level of alternative splicing in AD. EHT0202, a specific regulator of epsilon subunit-containing GABAA receptors and a PDE-4 inhibitor, was selected as a potential drug for AD. EHT0202 has shown in vitro and in vivo (oral administration) neuroprotective properties against excitotoxic and oxidative stresses. EHT0202 reduces A toxicity and redirects APP processing towards the non amyloidogenic pathway, potentially reducing A production and plaques formation. In cognition models using old rats, EHT0202 improves attention, learning capabilities and cognitive behavior. In phase I trials (single / repeated dose), EHT0202 is well tolerated with no sedative or adverse memory effects. EHT0202 is a promising drug for A -related neurodegenerative disorders with cognitive impairment. Conclusions: These data confirm the power of ExonHit Therapeutics’ DATASTM technology to rapidly identify pharmacologically relevant targets in complex diseases such as AD.