β-Asarone Inhibits Neuronal Apoptosis via the CaMKII/CREB/Bcl-2 Signaling Pathway in an in vitro Model and AβPP/PS1 Mice

Abstract

β-Asarone, an active component of the Acori graminei rhizome that has been used as traditional Chinese herb, has been reported to be capable of inhibiting neuronal apoptosis. However, the signaling mechanism underlying the inhibitory effect of β-asarone has remained elusive. This study was aimed to investigate whether the CaMKII signaling pathway is involved in the β-asarone mediated neuroprotection. Using PC12 cells and primary cultures of cortical neurons treated with amyloid-β (Aβ)(1-40) or Aβ(1-42) peptide, we demonstrated that β-asarone can protect PC12 cells and cortical neurons and inhibit neuronal apoptosis by activating the CaMKII-α/p-CREB/Bcl-2 pathway. Moreover, CaMKII-α overexpression enhanced the β-asarone-induced p-CREB-Bcl-2 expression and anti-apoptotic effects. Interestingly, suppression of CaMKII-α by siRNA or a specific inhibitor can significantly reduce the β-asarone-induced p-CREB and Bcl-2 expression and Aβ(1-40) induced neuronal apoptosis in PC12 cells. AβPP/PS1 mice at the age of 3 months and age-matched wild-type mice were intragastrically administered β-asarone (7 mg/kg/day, 21 mg/kg/day) or a vehicle daily for 4 months. β-asarone improved cognitive function of the AβPP/PS1 mice and reduced neuronal apoptosis in the cortex of the AβPP/PS1 mice. A significant increase in CaMKII/CREB/Bcl-2 expression was observed in the cortex of the AβPP/PS1 mice treated with β-asarone. In summary, our observations demonstrated that β-asarone can inhibit neuronal apoptosis via the CaMKII/CREB/Bcl-2 signaling pathway in in vitro models and in AβPP/PS1 mice. Therefore, β-asarone can be used as a potential therapeutic agent in the long-term treatment of Alzheimer's disease.

β-Asarone Mitigates Amyloidosis and Downregulates RAGE in a Transgenic Mouse Model of Alzheimer’s Disease

“…Pharmacological studies have proved that aasarone has effect on central nervous inhibitory, and was applied in epilepsy, asthma, and depression treatment (Lee et al 2014;Lu et al 2014;Huang et al 2013;Su et al 2014). However, the neuroprotective effects of b-asarone were highly suggested in recent studies, especially in AD investigation (Zou et al 2011;Liu et al 2010;Geng et al 2010;Wei et al 2013). Our previous studies have also suggested that b-asarone could inhibit neuronal apoptosis and improve memory deficits in Tg AD-model mice.…”

“…b-asarone, the essential component of Acori graminei rhizoma (AGR), can easily pass through BBB (Fang et al 2012) and exert neuroprotective effects in both vivo and vitro AD models (Zou et al 2011;Liu et al 2010;Geng et al 2010). Our previous study has proven that b-asarone could reduce neuronal apoptosis and improve memory deficits in Tg AD-model mice (Wei et al 2013). In the present study, we evaluated the effects of b-asarone on amyloidosis in b-amyloid precursor protein and presenilin-1 (APP/PS1) double Tg AD-model mice, and the results showed that b-asarone could improve the survival of neurons of APP/PS1 mice, and in the meanwhile, decrease Ab deposition and Ab1-42 level in the hippocampus and cortex of APP/PS1 mice brain.…”

Bcl-2 associated with severity of manic symptoms in bipolar patients in a manic phase

“…Bcl-2 might have neuronal anti-apoptotic and neuroprotective effects (Manji et al, 2000;Lei et al, 2012;Wei et al, 2013). Oxidative stress causes brain damage in bipolar patients (Wang et al, 2009); therefore, Bcl-2 levels in bipolar patients in a manic phase might decrease.…”

“…The anti-apoptotic protein Bcl-2 prevents mitochondrial release of cytochrome c, which leads to apoptosis (Scorrano and Korsmeyer, 2003;Ohkubo et al, 2007). In addition, Bcl-2 may inhibit neuronal apoptosis and has a neuroprotective effect (Chen et al, 1997;Manji et al, 2000;Lei et al, 2012;Wei et al, 2013). Anti-apoptotic protein Bcl-2 may play a role in the pathophysiology of bipolar disorder (Benes et al, 2006;Kim et al, 2010).…”

β-Asarone Rescues Pb-Induced Impairments of Spatial Memory and Synaptogenesis in Rats

“…β-asarone can easily pass through the blood brain barrier (BBB) [14] and substantial experimental evidence indicates that β-asarone is the active ingredient for attenuating learning and memory deficits [15–17]. Moreover, β-asarone could alleviate cognitive impairments in Parkinson’s disease [13], Alzheimer’s disease [18, 19], and neuroinflammatory [20], etc. Traditional use and clinical reports showed that β-asarone is effective for the treatment of learning and memory deficits, so we hypothesized that it may manage memory impairments following chronic Pb exposure.…”