Memory-enhancing effect of aspirin is mediated through opioid system modulation in an AlCl3-induced neurotoxicity mouse model

Abstract

Abstract. Neurodegenerative disorders such as Alzheimer's disease (AD) are multifaceted and there are currently a limited number of therapeutic strategies available to treat them. Aspirin is known to act on multiple therapeutic targets and is a successful anti-inflammatory agent in various tissues. The present study aimed to ascertain the performance of aspirin when employed as a therapeutic agent to treat neurodegeneration on novel targets, including opioid system genes, in an AlCl 3 -induced neurotoxicity mouse model. The effects of two doses of aspirin (5 and 20 mg/kg aspirin for 12 days) were investigated in an AlCl 3 -induced neurotoxicity mouse model (150 mg/kg AlCl 3 for 12 days). Neurological improvements were assessed through different behavioral tests and the effects of aspirin on opioid system gene expression levels were assessed by reverse transcription-polymerase chain reaction. Both doses resulted in improvements in cognitive behavior. A 5 mg/kg dose of aspirin was revealed to be effective for spatial memory improvement (7.14±0.84 sec), whilst a 20 mg/kg dose was superior for improving extinction learning (7.63±4.04%). Aspirin (5 mg/kg) also significantly improved contextual memory (48.05±10.6%) when compared with the AlCl 3 -treated group (1.49±0.62%; P<0.001). Aspirin was also observed to significantly decrease δ-opioid receptor expression in the cortex (1.09±0.08 and 1.27±0.08, respectively) at both doses (5 and 20 mg/kg) when compared with the AlCl 3 -treated group (3.69±1.43; P<0.05). Furthermore, aspirin at 5 mg/kg significantly reduced expression of prodynorphin in the cortex (0.57±0.20) when compared with the AlCl 3 -treated group (1.95±0.84; P<0.05). Notably, the effect of aspirin was significant in the cortex but not in the hippocampus. In summary, aspirin was effective in ameliorating the AD-like symptoms via the modulation of opioid systems. However, additional studies are required to determine the long term effects of aspirin on such conditions.

Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer's Disease via PPARα

“…Therefore, enhanced expression of the V0a1 subunit might result in escape from ER quality control mechanisms and lead to a greater abundance of this protein in the lysosomes and thereby rectify the lysosomal acidification defect. Importantly, v-ATPase can be regulated by TFEB (Palmieri et al, 2011;Peña-Llopis et al, 2011;Settembre et al, 2011). Therefore, TFEB-mediated transcriptional upregulation of v-ATPase and thereby restoration of the acidic environment of the neuronal lysosomes, leading to improved lysosomal proteolysis, could be one of the plausible mechanisms underlying aspirin-mediated reduction in intraneuronal A␤.…”

“…Therefore, TFEB-mediated transcriptional upregulation of v-ATPase and thereby restoration of the acidic environment of the neuronal lysosomes, leading to improved lysosomal proteolysis, could be one of the plausible mechanisms underlying aspirin-mediated reduction in intraneuronal A␤. Interestingly, aspirin has been reported to inhibit the activity of glycogen synthase kinase-3␤ (GSK-3␤) (Ou et al, 2010), a serine/threonine kinase that has been widely regarded to be involved in numerous aspects of AD development and progression, including senile plaque pathology (Balaraman et al, 2006;Llorens-Martín et al, 2014). A GSK-3␤ inhibitor has been shown to restore acidification under PS1/2deficient conditions (Avrahami et al, 2013).…”

“…cognitive impairment in the 5XFAD mouse (Avrahami and Eldar-Finkelman, 2013; Avrahami et al, 2013). Mounting evidence has highlighted the role of GSK-3␤ inhibition in improving several AD-related phenotypes in different models of AD (Koh et al, 2008;Serenó et al, 2009;Parr et al, 2012;Ly et al, 2013). Although we did not explore the effect of aspirin on GSK-3␤ inhibition in our study, it could be a relevant mechanism through which aspirin restores the neuronal acidification.…”

High-Dose Aspirin Reverses Tartrazine-Induced Cell Growth Dysregulation Independent of p53 Signaling and Antioxidant Mechanisms in Rat Brain

“…Artificial colors added to food can have harmful and toxic effects [1]. Tartrazine is reportedly toxic, whereas aspirin is thought to have prophylactic effects at low doses [8, 10, 19]. In this study, we investigated the effects of the color additive tartrazine on the expression of cell cycle regulatory genes, oxidative stress, and histopathological alterations in the brain and examined whether high-dose aspirin would protect against these effects.…”

“…Besides its analgesic, antipyretic, antiplatelet, and anti-inflammatory properties, aspirin is thought to be an antitumorigenic and neuroprotective agent [9]. Aspirin reduced neuroinflammation and oxidative stress in a rat model of neurocognitive disorder [8] and improved learning, memory, social behavior, and noncognitive behavior in mice; as such, it is recommended as a multitarget drug for Alzheimer's disease [10]. The antitumor activities of aspirin involve inhibition of cell proliferation by inducing cell cycle arrest through downregulation of cyclins and cyclin-dependent kinases (CDKs) and upregulation of CDK inhibitors [11].…”