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

Topics: Animals; Carbazoles; Clinical Trials as Topic; Humans; MAP Kinase Signaling System; Neuroprotective Agents; Parkinson Disease; Societies, Scientific

Current therapies for Parkinson's disease significantly improve the quality of life for patients suffering from this neurodegenerative disease, yet none of the current therapies has been convincingly shown to slow or prevent the progression of disease. Much has been learned about the pathophysiology of Parkinson's disease in recent years, and these discoveries offer a variety of potential targets for protective therapy. Mechanisms implicated in the disease process include oxidative stress, mitochondrial dysfunction, protein aggregation and misfolding, inflammation, excitotoxicity, and apoptosis. At the same time, the involvement of these diverse processes makes modeling the disease and evaluation of potential treatments difficult. In addition, available clinical tools are limited in their ability to monitor the progression of the disease. In this review, we summarize the different pathogenic mechanisms implicated in Parkinson's disease and neuroprotective strategies targeting these mechanisms currently under clinical study or under preclinical development, with a view towards strategies that seem most promising.

Topics: Animals; Antioxidants; Antiparkinson Agents; Carbazoles; Clinical Trials as Topic; Dopamine Agonists; Humans; Levodopa; Nerve Growth Factors; Neuroprotective Agents; Oxepins; Parkinson Disease

The prognosis of Parkinson's disease (PD) has been improved with developing anti-parkinsonian agents. Recently the re-evaluation of L-dopa and dopamine agonists is the topic in the world based on focusing non motor side effects of dopamine agonists such as sudden uncontrollable somnolence and valvulopathy in place of motor complication. The development of anti-parkinsonian drugs based on the new mechanism has been progressed such as CEP-1347, AAV-neuturin, AAV-GAD, and AAV-DDC. The most reliable new drug is zonisamide which is originally synthesized in Japan for epilepsy. A nation-wide randomized double blind study showed that Zonisamide improves motor function of advanced PD patients. Long-term efficacy was also shown. The mechanism of zonisamide for PD is the increase of dopamine synthesis and moderate inhibition of monoamine oxydase B activity. Inhibitatory effects of sodium channel and T-type calcium channel may also affects. Zonisamide has neuroprotective effects though inhibition of quinoprotein and increasing the levels of GSH and Mn SOD. Up to now we have no agents with clinically evidenced neuroprotective effects for PD. Base on the results of ELLDOPA study and "delayed start" clinical trials the most important concept for neuroprotection may be the early dopaminergic support for the degenerating dopaminergic system.

Topics: Anticonvulsants; Antiparkinson Agents; Carbazoles; Dopamine Agents; Dopamine Agonists; Drug Design; Genetic Therapy; Humans; Isoxazoles; Levodopa; Neuroprotective Agents; Parkinson Disease; Randomized Controlled Trials as Topic; Substantia Nigra; Zonisamide

There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway.

Topics: Animals; Brain; Carbazoles; Cell Death; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; Models, Biological; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease; Proto-Oncogene Proteins c-jun; 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

Little is known about the impact of providing individual research results to clinical trial participants or the impact of sharing such data.. The objective of this follow-up study was to evaluate the desire of participants for learning their imaging results and the impact of this information on their perception of their PD diagnosis and care.. The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) evaluated the experimental treatment CEP-1347 obtaining dopamine transporter imaging at baseline and 22 months as a secondary outcome. Dopamine transporter imaging and results were categorized as 'dopamine transporter deficit', 'no dopamine transporter deficit' or 'indeterminate.' Self-administered surveys were provided on three occasions to subjects who chose to learn their dopamine transporter imaging results: prior to receiving imaging data, immediately following receipt of imaging information, and three months following image disclosure.. 656/777 subjects (84.4%) consented to receive their individual imaging data, comprising overall result categories of 86.3% 'dopamine transporter deficit', 10.4% 'no dopamine transporter deficit', and 3.4% 'indeterminate.' 99.6% of subjects believed their decision to receive data was correct. Following disclosure of imaging results, 97% of the 'dopamine transporter deficit' and 'indeterminate' subjects believed they had Parkinson disease compared with 34% of 'no dopamine transporter deficit' subjects. About 45% of participants reported that learning individual imaging data resulted in improved understanding of their diagnosis.. The majority of research participants chose to learn their individual dopamine transporter imaging results and were satisfied with their decision. Disclosure of imaging information resulted in improved understanding of parkinsonian symptoms in nearly half of subjects, and less belief among 'no dopamine transporter deficit' subjects that they had a diagnosis of Parkinson disease.

Topics: Antipsychotic Agents; Carbazoles; Cocaine; Dopamine Plasma Membrane Transport Proteins; Female; Health Surveys; Humans; Longitudinal Studies; Male; Parkinson Disease; Radiopharmaceuticals; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

We performed a placebo-controlled trial of CEP-1347, an inhibitor of neuronal apoptotic cell death, in patients with early Parkinson's disease (PD) to determine whether long-term therapy would slow disability progression. This also provided an opportunity to monitor cancer incidence in a large cohort of PD patients followed prospectively including periods before and after patients developed disability requiring dopaminergic therapy. This was a multicenter study of 806 patients with early PD, without disability requiring dopaminergic therapy, assigned randomly to placebo or one of three doses of CEP-1347. Patients were monitored for an average of 1.8 years (1,467 patient-years) with routine cancer screening evaluations and annual skin examinations by a dermatologist. There was no significant excess of cancers among patients taking CEP-1347 compared with placebo for any cancer type (all P > 0.1). Nonmelanoma skin cancers were the most common cancer type observed. The incidence of melanomas was 20.9 times that predicted in the general population. Most melanomas occurred in patients who had never taken dopaminergic therapy. We found no evidence that CEP-1347 affected cancer incidence within 2 years of follow-up. Melanoma occurrence in our PD patients was greater than predicted compared with the general population and was unrelated to dopaminergic therapy. Clinical surveillance of PD patients for melanoma may be warranted.

Topics: Aged; Carbazoles; Chi-Square Distribution; Comorbidity; Disease Progression; Double-Blind Method; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Middle Aged; Neoplasms; Parkinson Disease

CEP-1347 inhibits mixed lineage kinases that activate apoptotic pathways implicated in the pathogenesis of Parkinson disease (PD). CEP-1347 enhances neuronal survival in a variety of nonclinical models and was found to be safe and well tolerated during 4 weeks in PD patients. We conducted the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) to assess its disease-modifying potential in early PD.. Consenting PD patients not yet requiring dopaminergic therapy (n = 806) were randomized equally to CEP-1347 in dosages of 10 mg BID, 25 mg BID, or 50 mg BID, or matching placebo, and were evaluated blindly and prospectively. The primary clinical end point was time to the development of disability requiring dopaminergic therapy. Secondary end points included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) and beta-CIT SPECT imaging of striatal dopamine transporters.. The study was concluded early, after an average of 21.4 months of follow-up, when a planned interim analysis demonstrated that it would be futile to continue experimental treatment. At that time, 108 of 191 subjects randomized to placebo (57%) had reached the primary end point of disability requiring dopaminergic therapy compared with active CEP-1347: 133 of 205 (65%) on 10 mg BID, 126 of 212 (59%) on 25 mg BID, and 127 of 198 (64%) on 50 mg BID. Changes in UPDRS scores and beta-CIT imaging showed similar patterns.. In contrast to research in animal models that predicted favorable disease-modifying outcomes, we found CEP-1347 to be an ineffective treatment in early Parkinson disease.

Topics: Aged; Apoptosis; Apoptosis Regulatory Proteins; Carbazoles; Corpus Striatum; Disease Progression; Dopamine Plasma Membrane Transport Proteins; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Middle Aged; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease; Prospective Studies; Tomography, Emission-Computed, Single-Photon; Treatment Failure

CEP-1347 is an inhibitor of members of the mixed lineage kinase family, key signals triggering apoptotic neuronal death. The authors performed a randomized, blinded, placebo-controlled study assessing the safety, tolerability, pharmacokinetics, and acute symptomatic effects of CEP-1347 in 30 patients with Parkinson's disease (PD). In this short-term study, CEP-1347 was safe and well tolerated. It had no acute effect on parkinsonian symptoms or levodopa pharmacokinetics, making it well suited for larger and longer studies of its potential to modify the course of PD.

Topics: Aged; Antiparkinson Agents; Area Under Curve; Carbazoles; Diarrhea; Double-Blind Method; Female; Humans; Indoles; Levodopa; Male; Middle Aged; Parkinson Disease; Protein Kinase Inhibitors; Treatment Outcome

Topics: Carbazoles; Cell Survival; Disease Progression; Humans; JNK Mitogen-Activated Protein Kinases; Neurons; Neuroprotective Agents; Parkinson Disease; Treatment Failure

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Carbazoles; Clinical Trials as Topic; Cytoprotection; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Indoles; JNK Mitogen-Activated Protein Kinases; Neuroprotective Agents; Parkinson Disease; Treatment Failure

Models of Parkinson's disease (PD) based on selective neuronal death have been used to study pathogenic mechanisms underlying nigral cell death and in some instances to develop symptomatic therapies. For validation of putative neuroprotectants, a model is desirable in which the events leading to neurodegeneration replicate those occurring in the disease. We developed a human in vitro model of PD based on the assumption that dysregulated cytoplasmic dopamine levels trigger cell loss in this disorder. Differentiated human mesencephalic neuron-derived cells were exposed to methamphetamine (METH) to promote cytoplasmic dopamine accumulation. In the presence of elevated iron concentrations, as observed in PD, increased cytosolic dopamine led to oxidative stress, c-Jun N-terminal kinase (JNK) pathway activation, neurite degeneration, and eventually apoptosis. We examined the role of the mixed-lineage kinases (MLKs) in this complex degenerative cascade by using the potent inhibitor 3,9-bis[(ethylthio)methyl]-K-252a (CEP1347). Inhibition of MLKs not only prevented FeCl2+/METH-induced JNK activation and apoptosis but also early events such as neurite degeneration and oxidative stress. This broad neuroprotective action of CEP1347 was associated with increased expression of an oxidative stress-response modulator, activating transcription factor 4. As a functional consequence, transcription of the cystine/glutamate and glycine transporters, cellular cystine uptake and intracellular levels of the redox buffer glutathione were augmented. In conclusion, this new human model of parkinsonian neurodegeneration has the potential to yield new insights into neurorestorative therapeutics and suggests that enhancement of cytoprotective mechanisms, in addition to blockade of apoptosis, may be essential for disease modulation.

Topics: Animals; Apoptosis; Carbazoles; Cell Line; Cells, Cultured; Cystine; Cytosol; Dopamine; Enzyme Activation; Ferrous Compounds; Glutathione; Humans; Hydrogen Peroxide; Indoles; JNK Mitogen-Activated Protein Kinases; Lipid Peroxidation; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mesencephalon; Methamphetamine; Nerve Degeneration; Neurites; Neurons; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Superoxides