Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-α and IL-1β in an Aβ_25–35-induced Rat Model of Alzheimer’s Disease

Article type: Research Article

Authors: Li, Lin^{a; 1} | Xu, Shaofeng^{a; 1} | Liu, Lifei^b | Feng, Rentian^b | Gong, Yongxiang^b | Zhao, Xuyang^{b; *} | Li, Jiang^a | Cai, Jie^a | Feng, Nan^a | Wang, Ling^a | Wang, Xiaoliang^{a; *} | Peng, Ying^{a; *}

Affiliations: [a] 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 | [b] Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou, China

Correspondence: [*] Correspondence to: Ying Peng, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Tel.: +86 10 63165173; Fax: +86 10 63017757; E-mail: [email protected]; Xuyang Zhao, Hisun Institute, Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China. Tel.: +86 10 88827869; Fax: +86 10 88827887; E-mail: [email protected] and Xiaoliang Wang, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Tel.: +86 10 63165330; Fax: +86 10 63165330; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: 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.

Keywords: AD-35, Alzheimer’s disease, amyloid-β, cognitive impairment, metal ions, neuroinflammatory response

DOI: 10.3233/JAD-160587

Journal: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1403-1417, 2017