S-Space College of Agriculture and Life Sciences (농업생명과학대학) Dept. of Agricultural Biotechnology (농생명공학부) Theses (Ph.D. / Sc.D._농생명공학부)
Coffee phenolic phytochemicals and kaempferol protect against oxidative damage of neuronal cells and memory impairments
커피 페놀성 파이토케미컬과 캠페롤의 신경세포의 산화적 손상과 기억장애에 대한 보호 효능
- 농업생명과학대학 농생명공학부
- Issue Date
- 서울대학교 대학원
- coffee; decaffeinated coffee; chlorogenic acid; oxidative stress; neurodegeneration; scopolamine; memory; TNF-α; kaempferol; 4-hydroxynonenal; NADPH oxidase
- 학위논문 (박사)-- 서울대학교 대학원 : 농생명공학부 식품생명공학전공, 2013. 2. 이형주.
- Oxidative stress and inflammation are strongly associated with neurodegenerative disorder such as Alzheimers disease (AD), Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). Oxidative damage is induced by reactive oxygen species (ROS) including hydrogen peroxide (H2O2) and amyloid beta plays a critical role in the development and progression of AD via the generation of ROS such as H2O2. Cytokines such as TNF-α also play a key role in inflammatory processes in AD. High levels of pro-inflammatory cytokines are shown in the brains of dementia. Oxidative stress and inflammation mediate cellular apoptosis in damaged neurons, which might impair brain function. Therefore, natural compounds to target oxidative stress and neuroinflammation are attractive for prevention of neurodegenerative disease.
Recent studies suggest that moderate coffee consumption may reduce the risk of neurodegenerative diseases such as AD or PD. Caffeine is considered to be primarily responsible for the neuropharmacological effects of coffee, and its neuroprotective effects are demonstrated by several studies. However, coffee is a major dietary source of phenolic compounds. Chlorogenic acid (5-O-caffeoylquinic acid) is a major phenolic compound in coffee. However, neuroprotective effect of decaffeinated coffee or coffee phytochemical such as chlorogenic acid and its molecular mechanisms remain to be clarified.
In this study, I confirmed that coffee, decaffeinated coffee and chlorogenic acid attenuated H2O2-induced PC12 and cortical neuronal cell death and apoptosis. These are characterized by nuclear condensation and DNA fragmentation, through inhibition of caspase-3 activation, poly(ADP-ribose)polymerase cleavage and the downregulation of anti-apoptotic proteins including Bcl-2 or Bcl-XL. The accumulation of intracellular ROS and activation of c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in H2O2-treated PC12 cells were diminished by decaffeinated coffee and chlorogenic acid. Coffee, both normal and decaffeinated, protect neurons against H2O2-induced apoptosis with similar effect, suggesting that chlorogenic acid might contribute to neuroprotective effects of coffee.
In this study, I used animal model of scopolamine-induced memory impairment to prove the effect of decaffeinated coffee on memory. Oral gavage administration of decaffeinated coffee inhibited scopolamine-induced memory impairment, which was measured by Morris water maze test and passive avoidance test. Decaffeinated coffee suppressed scopolamine-mediated elevation of tumor necrosis factor-α (TNF-α) and stimulation of nuclear factor-κB (NF-κB) pathway (i.e., phosphorylation of IκBα and p65) in the rat hippocampus. These findings suggest that decaffeinated coffee may prevent memory impairment in human through the inhibition of NF-κB activation and subsequent TNF-α production.
Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a natural flavonoid isolated from tea, mushrooms, kale, broccoli, and other plant sources. Kaempferol inhibited 4-HNE-mediated apoptosis, characterized by nuclear condensation, down-regulation of antiapoptotic protein Bcl-2, and activation of proapoptotic caspase-3. Kaempferol inhibited 4-HNE-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). More importantly, kaempferol directly bound p47phox, a cytosolic subunit of NADPH oxidase (NOX), and significantly inhibited 4-HNE-induced activation of NOX. The antiapoptotic effects of kaempferol were replicated by the NOX inhibitor apocynin, suggesting that NOX is an important enzyme in its effects. My results suggest that kaempferol attenuates 4-HNE-induced activation of JNK and apoptosis by binding p47phox of NOX and potently inhibiting activation of the NOX-JNK signaling pathway in neuron-like cells. Altogether, these results suggest that kaempferol may be a potent prophylactic against NOX-mediated neurodegeneration.
Taken together, these results indicate that coffee and decaffeinated coffee prevent apoptotic neuronal death by oxidative stress and that chlorogenic acid might be largely responsible for these effects. Decaffeinated coffee might protect brain against memory impairment by attenuating NF-κB-TNF-α-mediated tissue injury in the hippocampus. Kaempferol may act through direct binding to p47phox and inhibit 4-HNE-induced NOX activation and JNK-mediated apoptosis in neuron-like cells. These results suggest that regular consumption of coffee, decaffeinated coffee, chlorogenic acid and kaempferol might be beneficial on brain health.