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
Restricted accessResearch articleFirst published online February 20, 2017
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
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.
KoffieRM, Meyer-LuehmannM, HashimotoT, AdamsKW, MielkeML, Garcia-AllozaM, MichevaKD, SmithSJ, KimML, LeeVM, et al. (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A106, 4012–4017.
5.
HudryE, WuHY, Arbel-OrnathM, HashimotoT, MatsouakaR, FanZ, Spires-JonesTL, BetenskyRA, BacskaiBJ, HymanBT (2012) Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer’s disease. J Neurosci32, 3176–3192.
ChenK, IribarrenP, HuJ, ChenJ, GongW, ChoEH, LockettS, DunlopNM, WangJM (2006) Activation of toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem281, 3651–3659.
11.
ShadfarS, HwangCJ, LimMS, ChoiDY, HongJT (2015) Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents. Arch Pharm Res38, 2106–2119.
12.
LiY, ZhouS, LiJ, SunY, HasimuH, LiuR, ZhangT (2015) Quercetin protects human brain microvascular endothelial cells from fibrillar beta-amyloid1-40-induced toxicity. Acta Pharm Sin B5, 47–54.
13.
ChernyRA, AtwoodCS, XilinasME, GrayDN, JonesWD, McLeanCA, BarnhamKJ, VolitakisI, FraserFW, KimY, HuangX, GoldsteinLE, MoirRD, LimJT, BeyreutherK, ZhengH, TanziRE, MastersCL, BushAI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron30, 665–676.
14.
ChoiJ-S, BraymerJJ, NangaRPR, RamamoorthyA, LimMH (2010) Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity. Proc Natl Acad Sci U S A107, 21990–21995.
15.
GodyńJ, JończykJ, PanekD, MalawskaB (2016) Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep68, 127–138.
16.
TanCC, YuJT, WangHF, TanMS, MengXF, WangC, JiangT, ZhuXC, TanL (2014) Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis41, 615–631.
17.
GreigSL (2015) Memantine ER/donepezil: A review in Alzheimer’s disease. CNS Drugs29, 963–970.
18.
BaiH, ZhaoX, ZhongJ, GongY, ZhuQ, LiuX, ZhengX, LiuL (2014) Benzodioxole derivative and preparation method and use thereof. WO 2014005421 A1. 2014-09-01.
19.
GuoLL, GuanZZ, HuangY, WangYL, ShiJS (2013) The neurotoxicity of beta-amyloid peptide toward rat brain is associated with enhanced oxidative stress, inflammation and apoptosi s, all of which can be attenuated by scutellarin. Exp Toxicol Pathol65, 579–584.
20.
EllmanGL, CourtneyKD, AndresV, Feather-StoneRMJr (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol7, 88–95.
21.
HeY, YaoPF, ChenSB, HuangZH, HuangSL, TanJH, LiD, GuLQ, HuangZS (2013) Synthesis and evaluation of 7,8-dehydrorutaecarpine derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem63, 299–312.
22.
BrewerGJ (2015) Divalent copper as a major triggering agent in Alzheimer’s disease. J Alzheimers Dis46, 593–604.
23.
LeVineH3rd (1993) Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: Detection of amyloid aggregation in solution. Protein Sci2, 404–410.
24.
AdlardPA, ChernyRA, FinkelsteinDI, GautierE, RobbE, CortesM, VolitakisI, LiuX, SmithJP, PerezK, LaughtonK, LiQX, CharmanSA, NicolazzoJA, WilkinsS, DelevaK, LynchT, KokG, RitchieCW, TanziRE, CappaiR, MastersCL, BarnhamKJ, BushAI (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron59, 43–55.
25.
PengY, HuY, XuS, RongX, LiJ, LiP, WangL, YangJ, WangX (2014) Potassium 2-(1-hydroxypentyl)-benzoate improves memory deficits and attenuates amyloid and tau pathologies in a mouse model of Alzheimer’s disease. J Pharmacol Exp Ther350, 361–374.
26.
PengY, HuY, XuS, LiP, LiJ, LuL, YangH, FengN, WangL, WangX (2012) L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer’s transgenic mice. J Alzheimers Dis29, 379–391.
27.
GreenoughMA, CamakarisJ, BushAI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int62, 540–555.
LeeS, SuhYH, KimS, KimY (1999) Comparison of the structures of beta amyloid peptide (25–35) and substance P in trifluoroethanol/water solution. J Biomol Struct Dyn17, 381–391.
30.
GraceEA, RabinerCA, BusciglioJ (2002) Characterization of neuronal dystrophy induced by fibrillar amyloid beta: Implications for Alzheimer’s disease. Neuroscience114, 265–273.
PereiraC, AgostinhoP, MoreiraPI, CardosoSM, OliveiraCR (2005) Alzheimer’s disease-associated neurotoxic mechanisms and neuroprotective strategies. Curr Drug Targets CNS Neurol Disord4, 383–403.
33.
LiJ, WenPY, LiWW, ZhouJ (2015) Upregulation effects of Tanshinone IIA on the expressions of NeuN, Nissl body, and IκB and downregulation effects on the expressions of GFAP and NF-κB in the brain tissues of rat models of Alzheimer’s disease. Neuroreport26, 758–766.
34.
MrakRE, GriffinWS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging26, 349–354.
35.
KamphuisW, MiddeldorpJ, KooijmanL, SluijsJA, KooiEJ, MoetonM, FreriksM, MizeeMR, HolEM (2014) Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol Aging35, 492–510.
36.
ShapiroLA, PerezZD, ForestiML, ArisiGM, RibakCE (2009) Morphological and ultrastructural features of Iba1-immunolabeled microglial cells in the hippocampal dentate gyrus. Brain Res1266, 29–36.
37.
ChengP, AlbertsI, LiX (2013) The role of ERK1/2 in the regulation of proliferation and differentiation of astrocytes in developing brain. Int J Dev Neurosci31, 783–789.
38.
BushAI (2013) The metal theory of Alzheimer’s disease. J Alzheimers Dis33(Suppl 1), S277–S281.
39.
AtwoodCS, MoirRD, HuangX, ScarpaRC, BacarraNM, RomanoDM, HartshornMA, TanziRE, BushAI (1998) Dramatic aggregation of Alzheimer Abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem273, 12817–12826.
KimHY, KimHV, JoS, LeeCJ, ChoiSY, KimDJ, KimY (2015) EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques. Nat Commun6, 8997.
42.
Benseny-CasesN, KlementievaO, CladeraJ (2012) In vitro oligomerization and fibrillogenesis of amyloid-beta peptides. Subcell Biochem65, 53–74.
43.
ChenHL, ChangCY, LeeHT, LinHH, LuPJ, YangCN, ShiauCW, ShawAY (2009) Synthesis and pharmacological exploitation of clioquinol-derived copper-binding apoptosis inducers triggering reactive oxygen species generation and MAPK pathway activation. Bioorg Med Chem17, 7239–7247.
44.
QiangW, KelleyK, TyckoR (2013) Polymorph-specific kinetics and thermodynamics of β-amyloid fibril growth. J Am Chem Soc135, 6860–6871.
45.
BrännströmK, ÖhmanA, NilssonL, PihlM, SandbladL, OlofssonA (2014) The N-terminal region of amyloid β controls the aggregation rate and fibril stability at low pH through a gain of function mechanism. J Am Chem Soc136, 10956–10964.
46.
LynchT, ChernyRA, BushAI (2000) Oxidative processes in Alzheimer’s disease: The role of Aβ-metal interactions. Exp Gerontol35, 445–451.
47.
HuangX, AtwoodCS, HartshornMA, MulthaupG, GoldsteinLE, ScarpaLC, CuajungcoMP, GrayDN, LimJ, MoirRD, TanziRE, BushAI (1999) The Aβ peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry38, 7609–7616.
