Update in Critical Care Medicine - Nervous system: Metabolic syndrome in

astrocyte injury -

cellular and molecular implications Kar-Lok Wong MD, PhD, FICS黃家樂 醫生 博士 教授

Director & Professor Department of Anesthesiology Institute of Clinical Medical ScienceChina Medical University & Hospital, Taichung, TaiwanHonorary Professor LKS Faculty of Medicine, University of Hong Kong, Hong KongVisiting Professor Shandong Medical University, Shandong, ChinaTaishan Medical University, Taian, Shandong, ChinaDirectorLaboratory Animal Center China Medical University & Hospital Taichung, Taiwan

Introduction• Metabolic syndrome (MS) is quite common. Approximately 20%-30% of

the population in industrialized countries have MS

• By the year 2010, the MS is expected to affect 50-75 million people in the US alone (Ford 2002). In Taiwan, MS is present in more than 30% of the Taiwan adult population aged 40 years and over in a metropolitan area

• Pan et al has been reported that; for most BMI values, the prevalence of hypertension, diabetes, and hyperuricemia were higher for Taiwanese than for US whites.

• BMI-comorbidity relations were stronger in Taiwanese than in US blacks for all comorbidities studied (Pan 2004).

• It has become a significant health problem in Taiwan, but the resource injected by the government seems insufficient to deal with this difficult issue in the future.

• Men with the MS as defined by the NCEP criteria (National Cholesterol Education Program Adult Treatment Program III) had a 2.05-fold risk for all strokes and 2.41-fold risk for ischemic stroke.

• The etiologic fraction estimates suggest that elimination of the MS would result in a 19% reduction in overall stroke. ( Kurl 2006, Boden-Albala 2008).

• Prevention of the MS presents a great challenge for clinicians with respect to coronary heart disease and stroke.

• Metabolic syndrome (MS) encompasses a group of problems which will put a person at a high risk of developing cardiovascular diseases, including heart attack and stroke (Circulation. 2004; 109: 433)

• Effective prevention or treatment of MS significantly reduces the risk for developing serious complications. (Circulation. 2004; 109: 433)

• Palmitic acid (PA) is a saturated fatty acid, when being excessive, is a significant risk factor for development of MS or stroke. However, damage by MS to astrocytes is relatively unexplored.

• Catechin is an effective antioxidant which would be beneficial to neurons subjected to reactive oxygen species (ROS) damage as well as on cardiovascular diseases. (Circulation Research, 2010;107:1167)

• This study was to identify the mechanism(s) of PA-induced cytotoxicity in rat astrocytes and also to assess the protective effects of catechin.

Functional Roles of Astrocytes

• Blood-Brain Barrier

• Glucose metabolism– store glucose as glycogen/ ATP

• Maintenance of the extracellular environment– Clearance excessive glutamate

• Regulate neurogenesis, gliogenesis, neuroprotective

(Alfonso et al., 2006; Pellerin, 2005; Walz, 2000Prat et al., 2001)

Functional Roles of Astrocyte

(Allen & Barres, 2009)

Polyphenolic Catechins• Polyphenols Family

• Anti- oxidative effect : ROS ↓, and NADPH scavenger

• Anti-inflammation

• Aging, Parkinson disease (PD), Alzheimer’s disease (AD),

Stroke, Cardiovascular disease, obesity, diabetes, cancers…

(Zaveri, 2005)

Green Tea

Aims

1. To investigate the lipotoxic mechanism of PA in astrocyte.

2. To examine whether catechin can protect astrocyte from PA- induced lipotoxicity.

1. PA- induced concentration- dependent astrocytes death protected by catechin

3. PA-induced cell death was abrogated by ascorbic acid but not by salubrinal

0

40

80

120

Cel

l V

iab

ilit

y (%

Con

trol

)

*

#

*

Palmitic Acid

Cell Death

ER stress: JNK, Chop, p-eIF2, Ca2+

MMP: Cyt C, Bax, p-38 MAPK,

Glucose uptake

NADPH or Lipoxygenase:

Apocynin, AA- 861

ROS

• Reactive Oxygen Species:

– Superoxide (O2-)

– Peroxynitrite (ONOO-)

– Hydrogen Peroxide (H2O2)

– Hydroxyl Radical ( OH)∙

(Hoot, 2005; Minicis & Brenner, 2007; Schramm et al., 2012; Trachootham et al., 2009)

Control

50 µm

Control

50 µm

A CH x 30 min

50 µm

B

PA + CH 30 min

50 µm

D PA x30 min

50 µm

C

4. PA-elicited ROS formation was prevented by catechin and rotenone.

Cell Death( Mann, 2006; Verfaillie et al., 2012)

Cell Death

ER stress: JNK, Chop, p-eIF2, Ca2+

MMP: Cyt C, Bax, p-38 MAPK,

Glucose uptake

NADPH or Lipoxygenase:

Apocynin, AA- 861

Palmitic Acid

(Cited from: http:// www.med.monash.edu.au)

ConclusionsPA-induced apoptotic death of astrocytes :

• appeard to be unrelated to Ca2+ elevation, Ca2+ store depletion and ER stress

• resulted from ROS formation and mitochondrial potential collapse

• could be prevented by catechin, through inhibition on ROS generation and protection on mitochondrial functional integrity

Conclusion

• Our results demonstrated that PA-induced cytotoxicity in astrocyte could be prevented by catechin through inhibition of ROS generation and protection on mitochondrial functional integrity

• This study delivers important new insight in the molecular pathways that may contribute to the protective effects of catechin on astrocyte in metabolic syndrome