Kukoamine (KuA) is a
spermine alkaloid present in
traditional Chinese medicine Cortex Lycii radices, which possesses various pharmacological properties. Our previous studies have demonstrated that KuA exerts
neuroprotective effects against H2O2-induced oxidative stress, radiation-induced
neuroinflammation, oxidative stress and neuronal apoptosis, as well as
neurotoxin-induced
Parkinson's disease through apoptosis inhibition and autophagy enhancement. The present study aimed to investigate the
neuroprotective effects of KuA against
NMDA-induced neuronal injury in cultured primary cortical neurons and explore the underlying mechanism. Incubation with 200 μM
NMDA for 30 min induced excitotoxicity in primary cultured cortical neurons. The results demonstrated that pretreatment with KuA attenuated
NMDA induced cell injury, LDH leakage and neuronal apoptosis. KuA also regulated apoptosis-related
proteins. Thus, incubation with the
alkaloid decreased the ratio of Bax/Bcl-2, and inhibited the release of
cytochrome C, the expression of p53 and the cleavage of
caspase-3. Moreover, KuA prevented the upregulation of GluN2B-containing
NMDA receptors (NMDAR). Additionally, pretreatment with KuA reversed
NMDA-induced dephosphorylation of Akt and GSK-3β and the protective effect of KuA on
NMDA-induced cytotoxicity was abolished by
wortmannin, a PI3K inhibitor. Taken together, these results indicated that KuA exerted
neuroprotective effects against
NMDA-induced neurotoxicity in cultural primary cortical neurons and caused the down-regulation of GluN2B-containing NMDARs as well as the phosphorylation of
proteins belonging to the PI3K/Akt/GSK-3β signaling pathway.