An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons

Abstract

Memantine, a clinically used NMDA receptor antagonist possesses neuroprotective properties, but the exact mechanisms of its beneficial action on neuronal survival are poorly recognized. In the present study, some intracellular mechanisms of memantine effects on staurosporine-evoked cell death were investigated in primary cortical neurons. Memantine (0.1-2 muM) suppressed neuronal apoptosis evoked by staurosporine in 7 DIV cortical neurons, whereas other antagonists of NMDA receptor, MK-801 (1 muM) and AP-5 (100 muM) were ineffective. The anti-apoptotic effects of memantine were not connected with any changes in cytoplasmic calcium concentration or reactive oxygen species level. The immunoblot analysis showed that the staurosporine induced a decrease in p-Akt protein kinase level and that this effect was reversed by memantine treatment. Moreover, the PI3-K inhibitors, wortmannin and LY 294002 attenuated the anti-apoptotic action of memantine on staurosporine-induced cell damage. Furthermore, the ELISA studies showed increased cellular and released BDNF protein level after combined treatment with memantine and staurosporine. There was no effect of memantine on the activation and expression of other protein kinases involved in the mechanism of cellular survival, i.e. ERK1/2, JNK and GSK3-beta. The obtained data suggest an NMDAR-independent action of memantine in attenuation of neuronal apoptosis and point to the engagement of BDNF and PI3-K/Akt pathway in these processes.

Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

“…54 Several NMDA receptor antagonists, including ketamine, memantine and MK-801, increased BDNF, which is necessary for their antidepressant responses. 55,56 Based on these findings and our observation that 7-CTKA enhanced mTOR function and increased postsynaptic protein levels, we hypothesize that 7-CTKA produces antidepressant response through multiple pathways just like other NMDA receptor antagonists.…”

Beclin 1-independent autophagy contributes to apoptosis in cortical neurons

“…Staurosporine (STS), a classical apoptotic stimulus that has been previously widely characterized to induce apoptosis in several different cell types including primary neuronal cultures, [25][26][27] was used to promote apoptosis in primary cultures of cortical neurons. In the present experiments, 1 μM STS induced neuronal death as demonstrated by a progressive increase in the number of pyknotic nuclei from 6 h of STS treatment (Fig.…”

Upregulation of anti-apoptotic factors in upper motor neurons after spinal cord injury in adult zebrafish

“…Furthermore, the anti-apoptotic factors Bcl-2 and p-Akt are upregulated in the fish retina 2-5 days after axotomy, whereas these anti-apoptotic proteins are rapidly downregulated in the rat retina after nerve crush. The upregulation of Bcl-2 and p-Akt in the fish retina is mediated by the activation of the phosphatidylinositol-3-kinase/Akt signaling pathway through insulin-like growth factor-1 (IGF-1) Jantas et al, 2009). In this study, we found that the levels of Bcl-2 and p-Akt increased rapidly in the brainstem approximately 2-fold between 1-6 days after SCI in adult zebrafish (Figs.…”