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.
Keywords: GW5074, sorafenib, Cox-2, iNOS, NFκB, neurodegeneration
CNS & Neurological Disorders - Drug Targets
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.
Export Options
About this article
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
DOI https://dx.doi.org/10.2174/187152710790966632 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Tactile Angle Discrimination Decreases due to Subjective Cognitive Decline in Alzheimer’s Disease
Current Alzheimer Research GABAA Receptor Channel Pharmacology
Current Pharmaceutical Design Use of Intravenous Immunoglobulin in the Treatment of Immune-Mediated Demyelinating Diseases of the Nervous System
Current Pharmaceutical Design Synthesis, Antifungal Activity and Carbonic Anhydrase Inhibitory Properties of Cu (II) Bis (3, 4 Dimethoxybenzoate) Bis (Nicotinamide) Dihydrate
Current Enzyme Inhibition Herbal Medicine for Anxiety, Depression and Insomnia
Current Neuropharmacology Chemistry, Biological Properties and SAR Analysis of Quinoxalinones
Mini-Reviews in Medicinal Chemistry Pharmacological Management of Huntingtons Disease: An Evidence- Based Review
Current Pharmaceutical Design Severe Preeclampsia
Current Women`s Health Reviews Anticonvulsant and Antinociceptive Actions of Novel Adenosine Kinase Inhibitors
Current Topics in Medicinal Chemistry Therapeutic Benefits of <i>Piper nigrum</i>: A Review
Current Bioactive Compounds Subject Index to Volume 9
Current Pharmaceutical Design An Agathokakological Tale of Δ<sup>9</sup>-THC: Exploration of Possible Biological Targets
Current Drug Targets Protein-Protein Interactions and Subunit Composition of Ion Channels
CNS & Neurological Disorders - Drug Targets The Endocannabinoid System May Modulate Sleep Disorders in Aging
Current Neuropharmacology Protective Effects of Curcumin against Iron-induced Toxicity
Current Pharmaceutical Biotechnology Recent Advancement in Computer-Aided Drug Design
Current Pharmaceutical Design Serpin Regulation of Fibrinolytic System: Implications for Therapeutic Applications in Cardiovascular Diseases
Cardiovascular & Hematological Agents in Medicinal Chemistry Nutrition and Bone Health: Its Relationship to Osteoporosis
Current Nutrition & Food Science Drug-Resistance in Central Nervous System Tumors: From the Traditional Cell-Resistance Model to the Genetically Driven Approaches on Therapy
Current Pharmaceutical Biotechnology Design, Synthesis and Anticonvulsant Activity Evaluation of 7-Substituted –[1,2,4]-Triazolo[4,3-f]Pyrimidine Derivatives
Medicinal Chemistry