Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Neuroprotective effects of 1`δ-1`-acetoxyeugenol acetate on Aβ (25-35) induced cognitive dysfunction in mice Hanish Singh Jayasingh Chellammal a , Veerachamy Alagarsamy b , Dhani Ramachandran c , Sridhar Babu Gummadi d , Mohamed Mansor Manan a , Narsimha Reddy Yellu e, ⁎ a Unit of Pharmacology, School of Pharmacy, KPJ Healthcare University College, Kota Seriemas, Nilai, Negeri Sembilan, 71800, Malaysia b Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, Telangana, 502294, India c Unit of Pathology, International Medical School, Management & Science University, University Drive, Section 13, Shah Alam, Selangor, 40100, Malaysia d Department of Pharmaceutical Analysis, Sri Shivani College of Pharmacy, Warangal, Telangana, 506007, India e Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana, 506009, India ARTICLE INFO Keywords: Alzheimer's Disease 1`δ-1`-acetoxyeugenol acetate Aβ (25-35) Oxidative stress Acetylcholinesterase enzyme Corticosterone TNF-α ABSTRACT The progressive accumulation of amyloid beta (Aβ) peptide is neurotoxic and leads to Alzheimer’s type de- mentia. Accumulation of Aβ has been associated with dysfunction of hypothalamic-pituitary-adrenal (HPA) axis and elevated pro-inflammatory cytokines. In this study, we investigated the effect of 1`δ-1`-acetoxyeugenol acetate (DAEA), isolated from Alpinia galanga (L.), on Aβ (25–35) induced neurodegeneration in mice. Mice were treated with three different doses of DAEA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) for 28 days. Aβ (25–35) was injected by intracerebroventricular (i.c.v.) injection on the 15th day of 28 days. Open field, water maze and step- down inhibitory tests were performed on the 27th day to determine the habituation memory, spatial learning, and short- and long-term memory, respectively. Acetylcholinesterase (AChE), Corticosterone, biogenic amines (serotonin and dopamine), tumour necrosis factor-α (TNF-α), and antioxidant parameters such as superoxide dismutase, catalase, glutathione peroxidase and vitamin C were evaluated in brain homogenates after beha- vioural tests to ascertain the cognitive improvement through neuro-immune-endocrine modulation. The DAEA treatment with 25 mg/kg and 50 mg/kg resulted in significant (p< 0.001) improvement of habituation memory and step-down inhibitory avoidance task. In spatial learning, the cognitive improvement was significantly im- proved (p< 0.001) by reduction in escape latency. In the biochemical study, the significant (p< 0.001) re- duction of AChE indicates the preeminent neuroprotection. Corticosterone and TNF-α were significantly (p< 0.01) reduced and biogenic amines were increased with antioxidant markers, which signify the potential in- fluence of DAEA on neuroprotection. Our investigation revealed that the drug DAEA attenuates stress mediated through the HPA axis and regulates the neuroendocrine and neuroimmune function to improve the cognition. DAEA could be a potential lead candidate for the treatment of neurodegeneration. 1. Introduction Amyloid beta (Aβ) peptide aggregation develops during Alzheimer’s dementia, which is characterized by cognitive deterioration with a decline in physical and mental functions [1,2]. Alzheimer’s type dementia is associated with neuropathological lesions including diffuse and neuritic extracellular neurofibrillary tangles [3,4]. Aβ has been implicated to increase acetylcholinesterase enzyme and reactive oxygen species, impairing the neurotransmitter and neurohormonal regulation [5–7]. Moreover, in AD patients, the level of cortisol is elevated and https://doi.org/10.1016/j.biopha.2018.10.189 Received 1 May 2018; Received in revised form 30 October 2018; Accepted 31 October 2018 Abbreviations: 5-HT, serotonin; A.G, Alpinia galanga; AChE, acetylcholinesterase; AD, Alzheimer’s disease; ANOVA, analysis of variance; Aβ, amyloid beta; C, carbon; CAT, catalase; CPCSEA, committee for the purpose of control and supervision of experimental animals; CSF, cerebrospinal fluid; DA, dopamine; DAEA, 1`δ-1`- acetoxyeugenol acetate; DTC, 24-dinitrophenyl hydrazine-thiourea-copper sulfate; EDTA, ethylene diamine tetra acetic acid; ELISA, sandwich enzyme-linked im- munosorbent assay; GCs, glucocorticoids; GPx, glutathione peroxidase; H, hydrogen; hAPP, human amyloid precursor protein; HPA, hypothalamic-pituitary-adrenal axis; HPLC-UV, high performance liquid chromatography- ultra violet; i.c.v, intracerebroventricular; IL, interleukin; LTM, long term memory; NMR, nuclear magnetic resonance; NO, nitric oxide; OPT, ortho-phthaldialdehyde; SOD, superoxide dismutase; STM, short term memory; TGF-β, transforming growth factors; TNF-α, tumour necrosis factor alpha; VIT C, vitamin C ⁎ Corresponding author. E-mail address: ynrku@kakatiya.ac.in (N.R. Yellu). Biomedicine & Pharmacotherapy 109 (2019) 1454–1461 0753-3322/ © 2018 Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). T