TUMOR NECROSIS FACTORS PROTECT NEURONS AGAINST METABOLIC EXCITOTOXIC INSULTS AND PROMOTE MAINTENANCE OF CALCIUM HOMEOSTASIS

Emerging data indicate that neurotrophic factors and cytokines utilize similar signal transduction mechanisms. Although neurotrophic factors can protect CNS neurons against a variety of insults, the role of cytokines in the injury response is unclear. We now report that TNFbeta and TNFalpha (1 - 100 ng/ml) can protect cultured embryonic rat hippocampal, septal, and cortical neurons against glucose deprivation-induced injury and excitatory amino acid toxicity. The elevation of intracellular calcium concentration ([Ca2+]i) induced by glucose deprivation, glutamate, NMDA, or AMPA was attenuated in neurons pretreated with TNFbeta. The mechanism whereby TNFs stabilize [Ca2+]i may involve regulation of the expression of proteins involved in maintaining [Ca2+]i homeostasis, since both TNFbeta and TNfalpha caused a 4- to 8-fold increase in the number of neurons expressing the calcium-binding protein calbindin-D28k. These data suggest a neuroprotective role for TNFs in the brain's response to injury.