Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ25-35-induced Rat Model of Alzheimer's Disease.
The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Lin
L
Li
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Shaofeng
S
Xu
Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China.
Lifei
L
Liu
Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China.
Rentian
R
Feng
Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China.
Yongxiang
Y
Gong
Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China.
Xuyang
X
Zhao
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Jiang
J
Li
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Jie
J
Cai
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Nan
N
Feng
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Ling
L
Wang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Xiaoliang
X
Wang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Ying
Y
Peng
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018697:Nootropic Agents / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments; D010880:Piperidines / Q000494:pharmacology; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C000594089:IL1B protein, rat; D007189:Indans; D053583:Interleukin-1beta; D018697:Nootropic Agents; D010446:Peptide Fragments; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D000077265:Donepezil
AD-35; Alzheimer’s disease; amyloid-β; cognitive impairment; metal ions; neuroinflammatory response