3-9-bis((ethylthio)methyl)-k-252a and Neurodegenerative-Diseases

Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models of acute neuronal injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS. In this review, we provide an overview of DLK signaling mechanisms and describe selected small molecules that have been utilized to inhibit DLK kinase activity in vivo. These compounds represent valuable tools for understanding the role of DLK signaling and evaluating the potential for DLK inhibition as a therapeutic strategy to prevent neuronal degeneration.

Topics: Animals; Calcium-Binding Proteins; Humans; Intercellular Signaling Peptides and Proteins; MAP Kinase Kinase Kinases; Membrane Proteins; Neurodegenerative Diseases; Protein Kinase Inhibitors

Increasing evidence implicates aberrant apoptosis as a fundamental cause of neurodegenerative diseases. Thus elucidating the underlying causes of neuronal programmed cell death may foster the development of therapeutic interventions. Research in the last 15 years provided a solid foundation for understanding molecular mechanisms of neuronal apoptosis. This review discusses the major molecules and signaling pathways leading to neuronal survival or apoptosis with emphasis on several small molecule inhibitors that target neuronal survival with the hope of impeding the detrimental effects of neurodegenerative diseases.

Topics: Animals; Apoptosis; Brain Neoplasms; Carbazoles; Enzyme Inhibitors; Humans; Indoles; MAP Kinase Kinase 4; Models, Biological; Neurodegenerative Diseases; Neurons; p38 Mitogen-Activated Protein Kinases; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

The activation of the c-Jun N-terminal kinase (JNK) pathway is critical for naturally occurring neuronal cell death during development and may be important for the pathological neuronal cell death of neurodegenerative diseases. The small molecule inhibitor of the mixed-lineage kinase (MLK) family of kinases, CEP-1347, inhibits the activation of the JNK pathway and, consequently, the cell death in many cell culture and animal models of neuronal death. CEP-1347 has the ability not only to inhibit cell death but also to maintain the trophic status of neurons in culture. The possible importance of the JNK pathway in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases provides a rationale for the use of CEP-1347 for the treatment of these diseases. CEP-1347 has the potential of not only retarding disease progression but also reversing the severity of symptoms by improving the function of surviving neurons.

Topics: Alzheimer Disease; Animals; Carbazoles; Hearing Loss; Humans; Indole Alkaloids; Indoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; Mitogen-Activated Protein Kinases; Models, Biological; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease

Apoptosis has been proposed as a mechanism of cell death in Alzheimer's, Huntington's and Parkinson's diseases and the occurrence of apoptosis in these disorders suggests a common mechanism. Events such as oxidative stress, calcium toxicity, mitochondria defects, excitatory toxicity, and deficiency of survival factors are all postulated to play varying roles in the pathogenesis of the diseases. However, the transcription factor c-jun may play a role in the pathology and cell death processes that occur in Alzheimer's disease. Parkinson's disease (PD) is also a progressive disorder involving the specific degeneration and death of dopamine neurons in the nigrostriatal pathway. In Parkinson's disease, dopaminergic neurons in the substantia nigra are hypothesized to undergo cell death by apoptotic processes. The commonality of biochemical events and pathways leading to cell death in these diseases continues to be an area under intense investigation. The current therapy for PD and AD remains targeting replacement of lost transmitter, but the ultimate objective in neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss. This chapter will describe a novel approach for the treatment of neurodegenerative diseases through the development of kinase inhibitors that block the active cell death process at an early transcriptional independent step in the stress activated kinase cascade. In particular, preclinical data will be presented on the c-Jun Amino Kinase pathway inhibitor, CEP-1347/KT-7515, with respect to it's properties that make it a desirable clinical candidate for treatment of various neurodegenerative diseases.

Topics: Animals; Apoptosis; Carbazoles; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Neurodegenerative Diseases; Nootropic Agents; Parkinson Disease