Received for publication October 22, 2004.
Revised February 9, 2005.
Accepted for publication February 16, 2005.

A Synthetic Derivative of the Natural Product Rocaglaol is a Potent Inhibitor of Cytokine-Mediated Signaling and Shows Neuroprotective Activity In Vitro and in Animal Models of Parkinson's Disease and Traumatic Brain Injury

Abstract

Many acute and chronic neurodegenerative diseases are characterized by a localized inflammatory response and constitutive activation of the transcription factors nuclear factor-kappa B (NF-B) and activator protein-1 (AP-1) as well as their upstream activating signaling cascades. Ample evidence indicates the implication of these processes in the pathogenesis of several CNS diseases. Here we show that a synthetic derivative of the natural product rocaglaol (compound A) displays potent anti-inflammatory properties in human endothelial and murine glial cells in vitro. Compound A inhibited cytokine- and LPS-induced release of various cytokines/chemokines and of nitric oxide as well as expression of the adhesion molecule endothelial leukocyte adhesion molecule-1 and the inducible enzymes nitric oxide synthase and cyclooxygenase-2. As shown by immunocytochemistry and immunoblot compound A inhibited NF-B and AP-1 activity in mixed glial cultures. Compound A exhibited neuroprotective activity in vitro and in vivo. 1-Methyl-4-phenylpyridinium-induced damage of mesencephalic dopaminergic neurons was significantly decreased and chronic treatment of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-injected mice with Compound A significantly and dose-dependently reduced dopaminergic neuronal cell death. In addition, acute application of compound A to rats suffering from traumatic brain injury induced by subdural haematoma resulted in a significant reduction of the cerebral infarct volume. These results suggest that by inhibiting NF-B and AP-1 signaling compound A is able to reduce tissue inflammation and neuronal cell death resulting in significant neuropotection in animal models of acute and chronic neurodegeneration.

Key words: Interleukins, Tumor necrosis factor, AP-1, NFkappaB, Ischemia/Reperfusion