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

c-Jun N-terminal kinase (JNK) plays an integral role in neuronal death in multiple cell lines following a wide variety of stimuli and in a number of physiological functions that may be involved in human disease, including CNS diseases. In the past decades, many researchers in this field have found and reinforced the concept that prolonged activation of JNK signalling can induce neuronal cell death by both a transcriptional induction of death-promoting genes and modulation of the mitochondrial apoptosis pathways. Data are emerging to extend the understanding of the JNK signalling and confirm the possibility that targeting JNK signalling may offer an effective therapy for pathological conditions in the near future. This review will focus on the pro-apoptotic role of JNK signalling and updated pharmacological inhibitors of this pathway.

Topics: Acetonitriles; Animals; Anthracenes; Apoptosis; Benzothiazoles; Carbazoles; Humans; Indole Alkaloids; Indoles; JNK Mitogen-Activated Protein Kinases; Neuroprotective Agents; Protein Kinase Inhibitors; Signal Transduction; Thiazoles

The c-Jun N-terminal protein kinases (JNKs) form one subfamily of the mitogen-activated protein kinase (MAPK) group of serine/threonine protein kinases. The JNKs were first identified by their activation in response to a variety of extracellular stresses and their ability to phosphorylate the N-terminal transactivation domain of the transcription factor c-Jun. One approach to study the function of the JNKs has included in vivo gene knockouts of each of the three JNK genes. Whilst loss of either JNK1 or JNK2 alone appears to have no serious consequences, their combined knockout is embryonic lethal. In contrast, the loss of JNK3 is not embryonic lethal, but rather protects the adult brain from glutamate-induced excitotoxicity. This latter example has generated considerable enthusiasm with JNK3, considered an appropriate target for the treatment of diseases in which neuronal death should be prevented (e.g. stroke, Alzheimer's and Parkinson's diseases). More recently, these gene knockout animals have been used to demonstrate that JNK could provide a suitable target for the protection against obesity and diabetes and that JNKs may act as tumour suppressors. Considerable effort is being directed to the development of chemical inhibitors of the activators of JNKs (e.g. CEP-1347, an inhibitor of the MLK family of JNK pathway activators) or of the JNKs themselves (e.g. SP600125, a direct inhibitor of JNK activity). These most commonly used inhibitors have demonstrated efficacy for use in vivo, with the successful intervention to decrease brain damage in animal models (CEP-1347) or to ameliorate some of the symptoms of arthritis in other animal models (SP600125). Alternative peptide-based inhibitors of JNKs are now also in development. The possible identification of allosteric modifiers rather than direct ATP competitors could lead to inhibitors of unprecedented specificity and efficacy.

Topics: Amino Acid Sequence; Animals; Anthracenes; Carbazoles; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Models, Molecular; Molecular Sequence Data; Peptides

Activation of the JNK pathway and induction of the AP-1 transcription factor c-Jun are critical for neuronal apoptosis caused by a variety of insults. Ara-C-induced DNA damage caused rapid sympathetic neuronal death that was associated with an increase of c-jun expression. In addition, c-Jun was phosphorylated in its N-terminal transactivation domain, which is important for c-Jun-mediated gene transcription. Blocking c-Jun activation by JNK pathway inhibition prevented neuronal death after stress. In contrast, neither the JNK inhibitor SP600125 nor the mixed lineage kinase inhibitor CEP-1347 prevented cytosine arabinoside-induced neuronal death, demonstrating that the JNK pathway was not necessary for DNA damage-induced neuronal apoptosis. Surprisingly, SP600125 or CEP-1347 could not block c-Jun induction or phosphorylation after DNA damage. Pharmacological inhibitors of cyclin-dependent kinase (CDK) activity completely prevented c-Jun phosphorylation after DNA damage. These results demonstrate that c-Jun activation during DNA damage-induced neuronal apoptosis was independent of the classical JNK pathway and was mediated by a novel c-Jun kinase. Based on pharmacological criteria, DNA damage-induced neuronal c-Jun kinase may be a member of the CDK family or be activated by a CDK-like kinase. Activation of this novel kinase and subsequent phosphorylation of c-Jun may be important in neuronal death after DNA damage.

Topics: Animals; Animals, Newborn; Anthracenes; Apoptosis; Carbazoles; Cell Culture Techniques; Cell Survival; Cytarabine; DNA; DNA Damage; Enzyme Inhibitors; Etoposide; Indoles; JNK Mitogen-Activated Protein Kinases; Kinetics; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Nerve Growth Factor; Neurons; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Superior Cervical Ganglion; Transcription Factor AP-1