Neuronal death and survival : Targeting glutamate-induced cell death mechanisms

Glutamate is the major excitatory neurotransmitter in the mammalian CNS. Excitotoxicity refers to the ability of glutamate to destroy neurons, and this pathological condition may occur e.g. during stroke. In this thesis, cultured cerebellar granule neurons from rat, chicken and mouse were used as model system. The focus was on molecular mechanisms downstream of glutamate stimulation, with emphasis on cell death and protection. It was shown that glutamate induced the generation of toxic ROS associated with peripheral mitochondria due to calcium activated secretory PLA2-IIA. Toxic ROS were scavenged by antioxidants; however, it was also shown that the efficiency as neuroprotectors was lower for some antioxidants in preconditioned cells. NGFI-B (member of the nuclear receptor superfamily) has been shown to play a key role in apoptosis by translocation to the mitochondria. It was shown that new synthesis of NGFI-B was critical for maintenance of glutamate-induced. Treatment targeting the localization of NGFI-B allowed late protection.