Naringin Enhances CaMKII Activity and Improves Long-Term Memory in a Mouse Model of Alzheimer’s Disease

Abstract

The Amyloid-β (Aβ)-induced impairment of hippocampal synaptic plasticity is an underlying mechanism of memory loss in the early stages of Alzheimer’s disease (AD) in human and mouse models. The inhibition of the calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation plays an important role in long-term memory. In this study, we isolated naringin from Pomelo peel (a Citrus species) and studied its effect on long-term memory in the APPswe/PS1dE9 transgenic mouse model of AD. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two naringin (either 50 or 100 mg/kg body weight/day) groups, or an Aricept (2 mg/kg body weight/day) group. After 16 weeks of treatment, we observed that treatment with naringin (100 mg/kg body weight/day) enhanced the autophosphorylation of CaMKII, increased the phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor at a CaMKII-dependent site and improved long-term learning and memory ability. These findings suggest that the increase in CaMKII activity may be one of the mechanisms by which naringin improves long-term cognitive function in the APPswe/PS1dE9 transgenic mouse model of AD.

The Inactivation of JAK2/STAT3 Signaling and Desensitization of M1 mAChR in Minimal Hepatic Encephalopathy (MHE) and the Protection of Naringin Against MHE

“…Considering that naringin improves cognitive deficits in AD [14], we treated MHE rats with naringin (80 mg/kg). Naringin induced a significant increase in SA% in the YM compared with the MHE group (Fig.…”

“…Some studies have reported that the memory-improving effect of naringin on AD models is likely mediated either by enhancing the autophosphorylation of CaMKII, increasing the phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor at a CaMKII -dependent site [14], or by directly increasing GSK-3 β phosphorylation [25]. Additionally, our study observed that the JAK2/STAT3 axis is necessary for the pharmacological effect of naringin on MHE.…”

“…Naringin, a well-known flavanone glycoside of citrus fruits, has been reported to attenuate behavioral alterations and cognitive impairment in kainic acid-induced epilepsy models [12] and 3-nitropropionic acid-induced Huntington models [13]. Moreover, naringin administration improves cognitive deficits in a mouse model of AD [14], as well as colchicine- [15], D-galactose- [16] and aluminium [17]-induced learning and memory impairment models. It has also been shown that naringin enhances memory activity in unstressed and stressed rats, probably by decreasing brain AChE activity [18].…”

Naringin Reverses Neurobehavioral and Biochemical Alterations in Intracerebroventricular Collagenase-Induced Intracerebral Hemorrhage in Rats

“…NGN has well reported neuroprotective and memory enhancing effects [65,70,71]. NGN has proved to enhance long-term memory by enhancing activity of CAMII kinase [72], inhibiting NF-κB induced apoptosis [73] and decreasing cytokine release in vitro [74]. In the present study, MWM test was done to evaluate learning and memory deficits associated with COL-induced stroke.…”

Neurogranin restores amyloid β-mediated synaptic transmission and long-term potentiation deficits

“…Interestingly, Aβ-induced synaptic deficits observed in CA1 hippocampal neurons are also dependent on the activation of NMDARs, but, in contrast, lead to the removal of AMPARs from the synapse (Mattson et al, 1992;Kim et al, 2001;Kamenetz et al, 2003b;Snyder et al, 2005;Tyszkiewicz and Yan, 2005;Hsieh et al, 2006b;Shankar et al, 2007;Parameshwaran et al, 2008;Li et al, 2009;Yamin, 2009;Cerpa et al, 2010;Decker et al, 2010;Kessels et al, 2010a;Ondrejcak et al, 2010;Klyubin et al, 2011;Rammes et al, 2011;Dinamarca et al, 2012;Ferreira et al, 2012;Kessels et al, 2013;Sivanesan et al, 2013;Tamburri et al, 2013). Additionally, the effects of Aβ involve decreased Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity (Gu et al, 2009;Zeng et al, 2010;Wang et al, 2013). Intriguingly, AD is accompanied with decreased levels of neurogranin in pyramidal neurons (Davidsson and Blennow, 1998).…”