Auraptene has neuroprotective and memory enhancing effects in a rat model of Alzheimer’s disease

Background: Auraptene is a simple coumarin that exhibits multiple protective activities in the brain. Alzheimer’s disease is a complex, multifactorial, and progressive neurodegenerative disease. Microinjection of the β-amyloid peptide (Aβ) into the hippocampus of rat has been recognized as a reliable and stable animal model of Alzheimer’s disease, which mimics the memory deficits. In the present study, the memory enhancing effects of auraptene were studied in rats that Aβ was injected into their hippocampus to create a model of Alzheimer’s disease. Methods: Different doses of auraptene (5, 10 and 25 mg/kg) were administered intraperitoneally to male Wistar rats. The spatial memory performance was tested by Morris water maze after Alzheimer`s induction. The hippocampal expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins were calculated for evaluating the neuroprotective and anti-apoptotic effects of Auraptene in the brain tissue. Results: In comparison with the control group, auraptene significantly decreased the escape latency time in the treated rats. In addition, auraptene increased the percentage of time spent and traveled pathway in the target quadrant. Molecular data showed that auraptene attenuated the Bax/Bcl-2 ratio in the hippocampus of rats. Conclusion: This study demonstrated the memory enhancing effect of Aur after Aβ injection, which could be through inhibiting the apoptotic pathways in the hippocampus of rats. Keyword: Spatial memory, auraptene, rat/Wistar, bax protein Neurology Asia 2020; 25(3) : 353 – 360 Address Correspondence to: Omid Gholami, Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran. Tel: +985144018481, Email: omidghphd@gmail.com Date of Submission: 17 February 2020, Date of Acceptance 5 June 2020 and loss of neurons, the most important accepted mechanism in Alzheimer’s pathophysiology is the amyloid cascade hypothesis.1 In pathologic conditions, the amyloid precursor protein (APP) is not properly broken down by βand γ-secretase. The incorrect processing of the APP gene results in the production of modified β-amyloid peptides, which results in the formation of extracellular β-amyloid deposits.4 With regards to the multiple roles of beta amyloid in the neuronal degeneration mechanisms, a compound that would be able to prevent β amyloid toxicity in various ways could have a better effect on controlling the progression of Alzheimer’s disease.5 Apoptosis has two major pathways; the extrinsic and intrinsic pathways. The Bcl-2 family members have a role in the intrinsic (mitochondrial) pathway. The Bcl-2 family proteins include antiapoptotic (such as Bcl-2) INTRODUCTION Dementia is a progressive neurodegenerative disorder that affects about 1 to 2 percent of the population over the age of 65.1 Different types of dementia include Alzheimer’s disease, cerebrovascular dementia, lewy body dementia, frontotemporal dementia and Parkinson`s disease.2 The most common type is Alzheimer’s disease, which usually occurs with gradual progression of learning and memory loss.1 There are several hypotheses in the pathogenesis of Alzheimer’s disease, including beta-amyloid peptide hypothesis, inflammation, Tau protein, cholinergic hypothesis, oxidative stress, hypoxia, calcium imbalance, abnormal accumulation of metals and accumulation of β amyloid in mitochondria and bone marrow.3 Although the pathological changes commonly found in Alzheimer’s disease include amyloid plaques, neurofibrillary tangles, Neurology Asia September 2020 354 and proapoptotic proteins (such as Bax). 6 It has been shown that the ratio of Bcl-2 to Bax plays a pivotal role in cell survival and death.7 Neuronal apoptosis is induced beyond the pathological changes in Alzheimer`s disease.7 This apoptosis can be caused by β-amyloid protein in transgenic mice and neuronal cell culture. β-amyloid could induce the translocation of Bax protein to the mitochondria, which can increase the Bax/Bcl-2 ratio and initiate the activation of the intrinsic apoptotic pathway.8,9 Auraptene (Aur, C19H22O3) (Figure 1) is a terpenyloxy coumarin in the citrus family, which is found mainly in their skin.10 This compound, which forms the bulk of coumarin in citrus,11 is found in the orange and grapefruit essential oil.10 Several studies have shown that Aur has valuable effects, including anti-inflammatory12,13, anticarcinogenic14,15, anti-Helicobacteria16, as well as some regulatory activities in the metabolism of liver fats.17,18 Based on previous studies that showed the neuroprotective and memory enhancing effects of Aur11,19-23, in the present work, we investigated the neuroprotective and memory enhancement effects of Aur in a rat model of Alzheimer’s disease induced by β-amyloid injections.