Nutrition 30 (2014) 337–342
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Basic nutritional investigation
Green tea polyphenols protect against okadaic acid-induced acute learning and memory impairments in rats Hongyu Li Ph.D. a, Xiukui Wu M.Sc. a, Qiong Wu Ph.D. a, Dezheng Gong M.Sc. a, Meijun Shi M.Sc. a, Lili Guan Ph.D. a, Jun Zhang M.D. a, Jing Liu Ph.D. a, Bo Yuan M.Sc. a, Guozhu Han M.Sc. b, Yuan Zou Ph.D. a, * a b
Department of Physiology, Dalian Medical University, Dalian, China Faculty of Pharmacology, Dalian Medical University, Dalian, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 April 2013 Accepted 26 August 2013
Objective: Green tea polyphenols (GTPs) are now being considered possible protective agents in neurodegenerative diseases such as Alzheimer’s disease (AD). Previous studies suggested that GTPs could inhibit amyloid fibril formation and protect neurons from toxicity induced by b-amyloid. However, whether GTPs can ameliorate learning and memory impairments and also reduce tau hyperphosphorylation induced by okadaic acid (OA) in rats remains unclear. The aim of this study was to determine if GTPs have neuroprotection against OA-induced neurotoxicity. Methods: In this work, rats were pretreated with GTPs by intragastric administration for 4 wk. Then OA was microinjected into the right dorsal hippocampus. Morris water maze tests were used to test the ethologic changes in all groups, and tau protein hyperphosphorylation was detected both in vivo and in vitro. Results: The ethologic test indicated that the staying time and swimming distance in the target quadrant were significantly decreased after OA treatment, whereas rats pretreated with GTPs stayed longer in the target quadrant. Methyl thiazolyl tetrazolium assay and lactate dehydrogenase leakage showed that GTPs greatly ameliorated primary hippocampal neurons damage induced by OA. Furthermore, reduced hyperphosphorylated tau protein was detected with GTPs pretreatment. Conclusion: Taken together, our results suggest that GTPs have neuroprotection against OA-induced neurotoxicity. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Green tea polyphenols Tau protein Hyperphosphorylation Okadaic acid Neuroprotection
Introduction Neurofibrillary tangles (NFTs) are thought to be a major hallmark of Alzheimer’s disease (AD) and are composed of bundles of paired helical filaments (PHF) [1]. Tau proteins in neurons are a group of microtubule-associated proteins and play a key role in axonal transportation and neurite outgrowth [2]. A balance is being kept between tau phosphorylation and dephosphorylation under physiological conditions [3]. Yet the hyperphosphorylated HL and XW contributed equally to this work. All authors listed in the manuscript contributed substantially to the work. HL, JZ, and JL were responsible for the ethologic tests; XW, QW, MS, and LG were responsible for the investigations in vitro; DG was responsible for the animal care and model preparation; BY was responsible for the primary cell culture; GH guided the pharmacologic effect of GTPs; YZ was responsible for the design and implementation of the research. * Corresponding author: Tel.: þ86 411 86110280; fax: þ86 411 86110378. E-mail address: [email protected] (Y. Zou). 0899-9007/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2013.08.021
tau, the main component in PHF, is found in many neurodegenerative diseases such as AD [2,3]. The hyperphosphorylation of tau makes tau protein lose its biological activity and its resistance to proteolytic degradation and probably initiates the AD cascade [4–6]. The severity of dementia in individuals with AD is positively correlated with the number of NFTs, which are decreased by inhibiting the hyperphosphorylation of tau [7]. Green tea polyphenols (GTPs), the natural flavonoids in green tea, are composed of ()-epigallocatechin-3-gallate (EGCG), ()-epigallocatechin (EGC), ()-epicatechin (EC), ()-epicatechin gallate (ECG), and catechin. Many studies have reported that either GTPs or EGCG have antioxidative [8], antiinflammatory [9], and anti-neurodegeneration [10,11] effects. GTPs have been shown able to reduce cerebral amyloidosis (the other hallmark in individuals with AD) and attenuate amyloid b (Ab)-induced neurotoxicity both in AD mice models [12,13] and primary cultured hippocampal neurons [14].
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H. Li et al. / Nutrition 30 (2014) 337–342
Okadaic acid (OA), one of the marine toxins, is a selective and potent inhibitor of two of the serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A), which mainly catalyze the dephosphorylation of tau protein. Selective inhibition of PP1 and PP2A by OA can induce an Alzheimer-like hyperphosphorylation of tau both in vivo and in vitro [3]. However, whether GTPs attenuate the hyperphosphorylation of tau induced by OA remains unknown. Our study aims to investigate whether GTPs have the protective effects on cognitive impairments induced by OA toxicity. Materials and methods Animals and chemicals Adult Sprague-Dawley (SD) rats (weighing 250–300 g) and newly born SD rats (
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Basic nutritional investigation
Green tea polyphenols protect against okadaic acid-induced acute learning and memory impairments in rats Hongyu Li Ph.D. a, Xiukui Wu M.Sc. a, Qiong Wu Ph.D. a, Dezheng Gong M.Sc. a, Meijun Shi M.Sc. a, Lili Guan Ph.D. a, Jun Zhang M.D. a, Jing Liu Ph.D. a, Bo Yuan M.Sc. a, Guozhu Han M.Sc. b, Yuan Zou Ph.D. a, * a b
Department of Physiology, Dalian Medical University, Dalian, China Faculty of Pharmacology, Dalian Medical University, Dalian, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 April 2013 Accepted 26 August 2013
Objective: Green tea polyphenols (GTPs) are now being considered possible protective agents in neurodegenerative diseases such as Alzheimer’s disease (AD). Previous studies suggested that GTPs could inhibit amyloid fibril formation and protect neurons from toxicity induced by b-amyloid. However, whether GTPs can ameliorate learning and memory impairments and also reduce tau hyperphosphorylation induced by okadaic acid (OA) in rats remains unclear. The aim of this study was to determine if GTPs have neuroprotection against OA-induced neurotoxicity. Methods: In this work, rats were pretreated with GTPs by intragastric administration for 4 wk. Then OA was microinjected into the right dorsal hippocampus. Morris water maze tests were used to test the ethologic changes in all groups, and tau protein hyperphosphorylation was detected both in vivo and in vitro. Results: The ethologic test indicated that the staying time and swimming distance in the target quadrant were significantly decreased after OA treatment, whereas rats pretreated with GTPs stayed longer in the target quadrant. Methyl thiazolyl tetrazolium assay and lactate dehydrogenase leakage showed that GTPs greatly ameliorated primary hippocampal neurons damage induced by OA. Furthermore, reduced hyperphosphorylated tau protein was detected with GTPs pretreatment. Conclusion: Taken together, our results suggest that GTPs have neuroprotection against OA-induced neurotoxicity. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Green tea polyphenols Tau protein Hyperphosphorylation Okadaic acid Neuroprotection
Introduction Neurofibrillary tangles (NFTs) are thought to be a major hallmark of Alzheimer’s disease (AD) and are composed of bundles of paired helical filaments (PHF) [1]. Tau proteins in neurons are a group of microtubule-associated proteins and play a key role in axonal transportation and neurite outgrowth [2]. A balance is being kept between tau phosphorylation and dephosphorylation under physiological conditions [3]. Yet the hyperphosphorylated HL and XW contributed equally to this work. All authors listed in the manuscript contributed substantially to the work. HL, JZ, and JL were responsible for the ethologic tests; XW, QW, MS, and LG were responsible for the investigations in vitro; DG was responsible for the animal care and model preparation; BY was responsible for the primary cell culture; GH guided the pharmacologic effect of GTPs; YZ was responsible for the design and implementation of the research. * Corresponding author: Tel.: þ86 411 86110280; fax: þ86 411 86110378. E-mail address: [email protected] (Y. Zou). 0899-9007/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2013.08.021
tau, the main component in PHF, is found in many neurodegenerative diseases such as AD [2,3]. The hyperphosphorylation of tau makes tau protein lose its biological activity and its resistance to proteolytic degradation and probably initiates the AD cascade [4–6]. The severity of dementia in individuals with AD is positively correlated with the number of NFTs, which are decreased by inhibiting the hyperphosphorylation of tau [7]. Green tea polyphenols (GTPs), the natural flavonoids in green tea, are composed of ()-epigallocatechin-3-gallate (EGCG), ()-epigallocatechin (EGC), ()-epicatechin (EC), ()-epicatechin gallate (ECG), and catechin. Many studies have reported that either GTPs or EGCG have antioxidative [8], antiinflammatory [9], and anti-neurodegeneration [10,11] effects. GTPs have been shown able to reduce cerebral amyloidosis (the other hallmark in individuals with AD) and attenuate amyloid b (Ab)-induced neurotoxicity both in AD mice models [12,13] and primary cultured hippocampal neurons [14].
338
H. Li et al. / Nutrition 30 (2014) 337–342
Okadaic acid (OA), one of the marine toxins, is a selective and potent inhibitor of two of the serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A), which mainly catalyze the dephosphorylation of tau protein. Selective inhibition of PP1 and PP2A by OA can induce an Alzheimer-like hyperphosphorylation of tau both in vivo and in vitro [3]. However, whether GTPs attenuate the hyperphosphorylation of tau induced by OA remains unknown. Our study aims to investigate whether GTPs have the protective effects on cognitive impairments induced by OA toxicity. Materials and methods Animals and chemicals Adult Sprague-Dawley (SD) rats (weighing 250–300 g) and newly born SD rats (
