In our previous study, we proposed that there may be an unknown pathway in the upper stream of the known signal transduction pathway of Ciliary neurotrophic factor (CNTF) that mediates the neuro-protective function of CNTF. In the present experiment, we observed that the neuro-protective function of the non-classic signal transduction pathway in a L-NMDA (a glutamic acid ion type receptor atagonist) induced hippocampal neuron injury model, using primary culture rat hippocampal neurons, continuous photography and gp130 immunohistochemical assay. The results showed that L-NMDA induced injurious reaction of hippocampal neurons, and CNTF was able to inhibit the toxic action of L-NMDA on hippocampal neurons. Additionally, when JAK/STATs in the known classic signal transduction pathway of CNTF were blocked by PTPi-2, the protective effect of CNTF against L-NMDA injury still existed. L-NMDA caused a rapid increase in the concentration of hippocampal intracellular free [Ca2+]i. CNTF was able to attenuate L-NMDA-induced elevation of [Ca2+]i, and blocking JAK/STATs in the known classic signal trans- duction pathway of CNTF did not affect L-NMDA- induced elevation of [Ca2+]i, indicating that, apart from the known classic signal transduction pathway, there may be some other transduction pathways for CNTF to exert the protective effect on hippocampal neurons, and this pathway is related to [Ca2+].