RECOMBINANT HUMAN CILIARY NEUROTROPHIC FACTOR ALTERS THE THRESHOLD OF HIPPOCAMPAL PYRAMIDAL NEURON SENSITIVITY TO EXCITOTOXIN DAMAGE - SYNERGISTIC EFFECTS OF MONOSIALOGANGLIOSIDES

Ciliary neurotrophic factor (CNTF) is a multifunctional protein which not only promotes neuronal survival in vitro and in vivo but also controls cell division of neuronal precursors, transmitter differentiation, and glial cell differentiation. Recent studies have indicated that neurotrophic factors can alter hippocampal neuronal threshold to excitotoxin sensitivity. To examine such a role for CNTF, cultures of rat embryonic hippocampal neurons were maintained with recombinant human CNTF for different times, prior to exposure to a toxic dose of glutamate at 5 days in vitro for a further 24 hr. The cytotoxic action of 200 muM glutamate (approximately 40% of pyramidal neurons remaining after 24 hr) was reduced in a concentration-dependent manner in cultures receiving a prior exposure to CNTF within the first 3 days of cell plating: 30 ng/ml CNTF permitted about 75% of the initial number of pyramidal neurons to survive. Presentation of CNTF less than 48 hr before glutamate challenge was ineffective at up to 100 ng/ml. When pyramidal neurons were cultured with a subthreshold concentration (2 ng/ml) of CNTF together with 10 muM of the monosialoganglioside GM1 (or its inner ester form) in the same paradigm, the resulting neuronal survival was similar to that seen with 30 ng/ml CNTF in the face of a glutamate challenge. Such low doses of either CNTF or ganglioside alone were ineffective. The ability of trophic factors to influence the threshold of neuronal sensitivity to excitatory amino acid injury suggests that these proteins could play an important role in the reparative capacity of acutely traumatized central neurons and in neurodegenerative diseases linked to an excitotoxic mechanism. Furthermore, monosialogangliosides may represent useful pharmacological agents for facilitating neurotrophic factor-initiated nerve cell recovery processes.