Raf Inhibitors as Therapeutic Agents Against Neurodegenerative Diseases

Title: Raf Inhibitors as Therapeutic Agents Against Neurodegenerative Diseases

Volume: 9 Issue: 1

Author(s): Sarah Burgess and Valentina Echeverria

Affiliation:

Keywords: GW5074, sorafenib, Cox-2, iNOS, NFκB, neurodegeneration

Abstract: The active form of the serine/threonine kinase cRaf-1 is upregulated postmortem in the brains of Alzheimers disease (AD) patients and in transgenic mouse models of AD pathology. The persistent activation of cRaf-1 can activate the proinflammatory factor NFκB and consequently, upregulate the expression of several of its downstream factors such as the amyloid precursor protein (APP), Cox-2 and iNOS. These factors have been found upregulated in numerous neurodegenerative conditions including AD, epilepsy, brain trauma, and psychological stress. The Raf kinase inhibitors, GW5074 and ZM336372, are neuroprotective against many different neurotoxic insults in vitro, including the A.. peptide, glutamate and glutathione depletion. Recently, we have reported that the multikinase and potent Raf inhibitor sorafenib reversed memory impairment and reduced the expression of APP, Cox-2, and iNOS in the brain of the transgenic mouse model of AD, APPswe. Similar improvement of behavioral outcome was attained after acute treatment with GW5074 in a mouse model of Huntingtons disease. Several Raf inhibitors have been developed to treat aggressive forms of cancer showing an upregulation of Raf kinases. These Raf inhibitors offer a great promise as therapeutic tools against neurological disorders. The negative and positive aspects of these inhibitors as anti-neurodegenerative agents are discussed.

Cite this article as:

Burgess Sarah and Echeverria Valentina, Raf Inhibitors as Therapeutic Agents Against Neurodegenerative Diseases, CNS & Neurological Disorders - Drug Targets 2010; 9 (1) . https://dx.doi.org/10.2174/187152710790966632