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https://www.hindawi.com/journals/omcl/2017/3037876/
Research Article | Open Access
Volume 2017 | Article ID 3037876 | https://doi.org/10.1155/2017/3037876
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Curcumin Reverses the Diazepam-Induced Cognitive Impairment by Modulation of Oxidative Stress and ERK 1/2/NF-κB Pathway in Brain
Alexandra C. Sevastre-Berghian,1Vlad Făgărăsan,1Vlad A. Toma,2,3,4Ioana Bâldea,1Diana Olteanu,1Remus Moldovan,1Nicoleta Decea,1Gabriela A. Filip,1and Simona V. Clichici1
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Academic Editor: Francisco J. Romero
Received20 Apr 2017
Accepted06 Jul 2017
Published02 Oct 2017
Abstract
Oxidative stress and inflammation can be involved in cognitive dysfunction associated with neurodegenerative disorders. Diazepam (DZP) administration has been chosen to simulate the memory impairment. The aim of this study was to evaluate the effects of curcumin (CUR) on spatial cognition, ambulatory activity, and blood and brain oxidative stress levels. The ERK/NF-κB signaling pathway and the histopathological changes in the hippocampus and frontal lobe, in diazepam-treated rats, were also analyzed. The animals were divided into 4 groups: control, carboxymethylcellulose (CMC) + CUR, CMC + DZP, and CUR + CMC + DZP. CUR (150 mg/kg b.w.) was orally administered for 28 days. DZP (2 mg/kg b.w.) was intraperitoneally administered 20 minutes before the behavioral tests (open field test, Y-maze, and elevated plus maze). CUR improved the spontaneous alternation behavior, decreased the oxidative stress levels, both in the blood and in the hippocampus, and downregulated the extracellular signal-regulated kinase (ERK 1/2)/nuclear transcription factor- (NF-) κB/pNF-κB pathway in the hippocampus and the iNOS expression in the hippocampus and frontal lobe of the DZP-treated rats. Histopathologically, no microscopic changes were found. The immunohistochemical signal of iNOS decreased in the DZP and CUR-treated group. Thus, our findings suggest that curcumin administration may improve the cognitive performance and may also have an antioxidant effect.
산화 스트레스와 염증은 신경 퇴행성 장애와 관련된 인지 기능 장애에 관여할 수 있습니다. 기억력 장애를 시뮬레이션하기 위해 디아제팜(DZP) 투여가 선택되었습니다. 이 연구의 목적은 공간 인지력, 보행 활동, 혈액 및 뇌 산화 스트레스 수준에 대한 커큐민(CUR)의 효과를 평가하는 것이었습니다. 또한 디아제팜을 투여한 쥐의 해마와 전두엽의 ERK/NF-κB 신호 전달 경로와 조직 병리학적인 변화도 분석했습니다. 쥐를 대조군, 카르복시메틸셀룰로오스(CMC) + CUR, CMC + DZP, CUR + CMC + DZP의 4개 그룹으로 나누었습니다. CUR(150 mg/kg b.w.)을 28일간 경구 투여했습니다. 행동 테스트(개방형 필드 테스트, Y-미로, 상승 플러스 미로)를 실시하기 20분 전에 DZP(2mg/kg bw)를 복강 내로 투여했습니다. CUR은 자발적 교대 행동을 개선하고, 혈액과 해마에서 산화 스트레스 수준을 감소시켰으며, 세포 외 신호 조절 키나아제(ERK 1/2)/핵 전사인자(NF-) κB/pNF-κB 경로와 해마 및 전두엽의 iNOS 발현을 하향 조절했습니다(DZP 처리 쥐의 해마 및 전두엽). 조직 병리학적으로는 미세한 변화가 발견되지 않았습니다. iNOS의 면역 조직 화학적 신호는 DZP 및 CUR 처리 그룹에서 감소했습니다. 따라서 우리의 연구 결과는 커큐민 투여가 인지 능력을 개선하고 항산화 효과도 가질 수 있음을 시사합니다.
1. Introduction
Memory, one of the most complex brain functions, involving multiple neuronal pathways and neurotransmitters, is considered the ability of an individual to record, retain, and recall the information when needed [1, 2].
Aging, stressful conditions, reduced brain metabolism, high oxidative stress levels, inflammation, or reduced plasticity has been hypothesized to be involved in cognitive dysfunction associated with neurodegenerative disorders, such as Alzheimer’s (AD) or Parkinson’s disease (PD) [3–5]. The high incidence of the abovementioned disorders over the past decades determined the scientists’ focus on different therapies in order to improve the quality of life of these individuals suffering from neurodegenerative diseases. Although, in the past years, the stem cell therapies have been tried to attenuate the progression of these disorders, none of them has fully proved its efficiency [6].
Considering the multiple hypotheses regarding the mechanisms that lead to neuronal dysfunction, for example, inflammation [7], oxidative stress [8], mitochondrial dysfunction [9], and axonal transport deficits [10], the need of an alternative therapy that may provide some symptomatic relief is highly needed [3–5, 11]. However, neuroprotection does not seem to fully inhibit the disease progression, at least a delay can be achieved.
Curcumin (CUR), a natural compound (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene- 3,5-dione), found as a major component in turmeric, extracted from the rhizome of Curcuma longa L., has been used in traditional medicine for thousands of years. Nowadays, it is widely used in South and Southeast Asia as a spice and as a coloring agent in food. In the past years, several scientific reports have mentioned its potential benefits, some of which are anticarcinogenic, neuroprotective, anti-inflammatory, and antioxidant effects [12–14]. At molecular level, curcumin downregulates various proinflammatory intracellular systems such as NF-κB, inducible nitric oxide synthase (iNOS), hypoxia-inducible factor-1, and proinflammatory cytokine such as: interleukin- (IL-) 6, IL-1β, and tumor necrosis factor- (TNF-) α. It also exerts antiapoptotic function by overexpression of Bcl-2 and decrease of the bax/Bcl-2 ratio. As an antioxidant, curcumin increases Cu-Zn superoxide dismutase (SOD), restores depletion of the glutathione (GSH) levels, inhibits ROS and mitochondrial cell death pathway, and activates the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway [6, 12].
As curcumin has been suggested to prove valuable properties, the present study was designed to investigate the effects of curcumin administration on ambulatory activity and spatial working memory (a form of short-term memory) and on blood and brain oxidative stress levels in diazepam-treated rats. Based on the literature, 2 mg/kg body weight (kg b.w.) of diazepam would impair memory in rodents [15]. The administration of diazepam (DZP, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one), a benzodiazepine compound, serves as an interoceptive behavioral model (the stimulus lies within the body) to evaluate memory in rodents [1, 3, 16, 17].
Benzodiazepines (BZDs) are widely used as anxiolytics, sedative hypnotics, anticonvulsants, and muscle relaxants or for anesthesia induction. Although BZDs are well tolerated, they are still known for their clinical issues such as cognitive and psychomotor impairment, sedation, dependence, rebound anxiety, and discontinuation syndrome [18–21]. Memory seems to be particularly sensitive to BZD action, known as “acquisition impairing” molecules [22]. Thus, BZDs impair long-term memory, more specifically anterograde memory (amnesia for events occurring after drug absorption, for instance) [18, 23].
The target of BZDs is the γ-aminobutyric acid- (GABA-) A receptor, which is a ligand-gated chloride channel, activated by GABA. GABA is an amino acid that exerts an inhibitory neurotransmission in the central nervous system, thus reducing the excitability of neurons. [18].
The GABA-A receptor complex is composed of 5 glycoprotein subunits, containing 2 α, 2 β, and 1 γ subunits. Side effects of the BZDs, such as sedation and anterograde amnesia, are α1 mediated [22, 24]. Based on these data, our study intended to evaluate the effect of a high dose of DZP on spatial cognition in conjunction with oxidative stress, ERK 1/2/NF-κB signaling pathway, and histopathological changes in the hippocampus, frontal lobe, and whole brain and the impact of curcumin pretreatment on these parameters in rats.
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