Resveratrol Attenuates Aβ-Induced Early Hippocampal Neuron Excitability Impairment via Recovery of Function of Potassium Channels

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease. Amyloid-β (Aβ) is not only the morphological hallmark but also the initiator of the pathology process of AD. As a natural compound found in grapes, resveratrol shows a protective effect on the pathophysiology of AD, but the underlying mechanism is not very clear. This study was to investigate whether resveratrol could attenuate Aβ-induced early impairment in hippocampal neuron excitability and the underlying mechanism. The excitability and voltage-gated potassium currents were examined in rat hippocampal CA1 pyramidal neurons by using whole-cell patch-clamp technique. It was found that Aβ increased the excitability of neurons. Resveratrol could reverse the Aβ-induced increase in the frequency of repetitive firing and the spike half-width of action potential (AP). Moreover, resveratrol can attenuate Aβ-induced decreases in transient potassium channel (I ) and delay rectifier potassium channel (I) of neurons. It was also found that resveratrol could decline the increase of protein kinase A (PKA) and inhibit the activation of PI3K/Akt signaling pathway induced by Aβ. The results suggest that resveratrol alleviates Aβ-induced dysfunction in hippocampal CA1 pyramidal neurons via recovery of the function of I and I by inhibiting the increase of PKA and the activation of PI3K/Akt signaling pathway.

Neuroprotective Effect of Resveratrol via Activation of Sirt1 Signaling in a Rat Model of Combined Diabetes and Alzheimer’s Disease

“…Studies have suggested that resveratrol is a Sirt1 activator (Pallas et al, 2009;Wu et al, 2011) and that Sirt1 is integral to the main neuroprotective mechanism of resveratrol. Moreover, the AMPK (Chiang et al, 2018;Guo and Zhang, 2018;Pineda-Ramirez et al, 2019), PI3K-AKT (Yin et al, 2017;Hui et al, 2018), and cAMP (Zhang et al, 2013) signaling pathways are also involved in resveratrol's protective action in some disease models. In this study, we found that Sirt1 expression was significantly increased in the brains of rats from the resveratrol control group and resveratrol treatment group versus healthy controls and model rats, respectively, and that these changes were reversed by the Sirt1 inhibitor EX527.…”

Neuroprotective Mechanisms of Resveratrol in Alzheimer’s Disease: Role of SIRT1

“…Therefore, it is also important to emphasize that these neuroprotective effects can also be mediated by other action mechanisms of resveratrol. Another neuroprotective mechanisms of resveratrol include the following: (i) inhibits the tauopathy by interfering with the MID1-PP2A (midline 1-protein phosphatase 2A) complex or by altering or partially inhibiting of the glycogen synthase kinase 3 beta (GSK3 β ) and p53 interaction [ 6 , 110 ]; (ii) improves learning and long-term memory formation through the microRNA (microribonucleic acid)-CREB (cAMP response element-binding protein)-BDNF pathway [ 20 ]; (iii) protects against A β -mediated neuronal impairment (inflammation and oxidative stress) by activation of AMP-activated protein kinase- (AMPK-) dependent signaling and inhibition of NF- κ B expression and iNOS levels [ 160 ]; (iv) antioxidative activity by reduction in levels of ROS enhances the expression of various antioxidant defensive enzymes (heme oxygenase 1, catalase, glutathione peroxidase, and superoxide dismutase), downregulation of prooxidative stress proteins (i.e., plaque-induced glycogen synthase kinase-3 β (GSK-3 β ), and AMPK [ 8 , 10 ]; (v) improves cognitive impairment due to inhibition of cholinesterase activity [ 161 ]; (vi) inhibits the A β plaque synthesis by restoration of normal cellular autophagy via the TyrRS-PARP1 (auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1)-SIRT1 signaling pathway and enhancement of transthyretin (transporter protein) binding to A β oligomers [ 162 ]; (vii) inhibits mammalian target of rapamycin (mTOR) signaling and induces AMPK, thereby stimulating the clearance of A β aggregates [ 110 ]; (viii) prevents the neuronal cell death by attenuating apoptosis via Akt/p38 MAPK signaling and inhibits caspase-3 and B cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein signaling [ 163 , 164 ]; (ix) increases intracellular calcium levels, promoting the activation of calcium/calmodulin-dependent protein kinase kinase β -CamKK β -AMPK pathway, which alters mitochondrial function and leads to a decrease in ROS generation [ 165 ]; (x) attenuated injury and promoted proliferation of the neural stem cells, at least in part, by upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), HO-1, and NAD(P)H:quinone oxidoreductase 1 (NQO1) [ 166 ]; and (xi) inhibits the neuronal electrical activity by mechanisms associated with large conductance of Ca 2+ potassium channels and attenuates A β -induced early hippocampal neuron excitability impairment [ 167 ]. Therefore, resveratrol may be an important tool to protect neuronal cells from oxidative damage and a promising strategy in the treatment of AD.…”

Resveratrol targeting tau proteins, amyloid‐beta aggregations, and their adverse effects: An updated review

“…So, restoring potassium channel function is a potential strategy in AD therapy. In order to prevent the mentioned adverse impacts of Aβ deposits on potassium channels, Res downregulates and suppresses the induction of protein kinase A (PKA) and PI3K/Akt signaling pathway (Yin et al, 2017). As it was discussed ear- ing with electron transfer chain (Amakiri, Kubosumi, Tran, & Reddy, 2019;J.…”