BACKGROUND

Oxidative stress has been implicated in Alzheimer's disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process.

OBJECTIVE

Reduction and remodeling of γ-aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD.

METHODS

To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures.

RESULTS

We found that GABAB receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABAB receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway.

CONCLUSION

Taken together, our results suggest that GABAB receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD.