TNFα siRNA reduces brain TNF and EEG delta wave activity in rats

Tumor necrosis factor alpha (TNF alpha) is a pleiotropic cytokine with several CNS physiological and pathophysiological actions including sleep, memory, thermal and appetite regulation. Short interfering RNAs (siRNA) targeting TNFa were incubated with cortical cell cultures and microinjected into the primary somatosensory cortex (SSctx) of rats. The TNFa siRNA treatment specifically reduced TNF alpha mRNA by 45 % in vitro without affecting interleukin-6 or gluR1-4 mRNA levels. In vivo the TNF alpha siRNA alpha reduced TNF alpha mRNA, interleukin-6 mRNA and gluR1 mRNA levels compared to treatment with a scrambled control siRNA. After in vivo microinjection, the density of TNF alpha-immunoreactive cells in layer V of the SSctx was also reduced. Electroencephalogram (EEG) delta wave power was decreased on days 2 and 3 on the side of the brain that received the TNF alpha siRNA microinjection relative to the side receiving the control siRNA. These findings support the hypothesis that TNF alpha siRNA attenuates TNF alpha mRNA and TNF alpha protein in the rat cortex and that those reductions reduce cortical EEG delta power. Results also are consistent with the notion that TNF alpha is involved in CNS physiology including sleep regulation. (c) 2007 Elsevier B.V. All rights reserved.