P C Waldmeier

Novartis, Bâle, Basel-City, Switzerland

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Publications (149)441.79 Total impact

  • Peter C. Waldmeier · Klemens Kaupmann · Stephan Urwyler ·

    Journal of Neural Transmission 04/2009; 116(4). DOI:10.1007/s00702-009-0206-0 · 2.40 Impact Factor
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    Peter C. Waldmeier · Klemens Kaupmann · Stephan Urwyler ·
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    ABSTRACT: Γ-Aminobutyric acid B (GABAB) receptors are heterodimers composed of two subunits GABAB(1) and GABAB(2), the former existing in two isoforms GABAB(1a) and GABAB(1b). The contributions of individual receptor subunits and isoforms to GABAB auto- and heteroreceptor functions were investigated, using release experiments in cortical slice preparations from corresponding knockout mice. Presynaptic GABAB autoreceptors are located on GABAergic terminals and inhibit GABA release, whereas presynaptic GABAB heteroreceptors control the release of other neurotransmitters (e.g. glutamate). Neither baclofen nor the selective antagonist CGP55845 at maximally active concentrations affected [3H]GABA release in slices from GABAB(1)−/− mice. The amount of [3H]GABA released per pulse was unaffected by the stimulation frequency in slices from GABAB(1)−/− and GABAB(2)−/− demonstrating a loss of GABAB autoreceptor function in these knockout animals. The GABAB receptor agonist baclofen was ineffective in modulating glutamate release in cortical slices from GABAB(2)−/− mice, showing that heteroreceptor function was abolished as well. Next we investigated knockout mice for the two predominant GABAB(1) isoforms expressed in brain, GABAB(1a) and GABAB(1b). In cortical, hippocampal and striatal slices from both GABAB(1a)−/− and GABAB(1b)−/− mice, the frequency dependence of [3H]GABA released per pulse was maintained, suggesting that both isoforms participate or can substitute for each other in GABAB autoreceptor function. By contrast, the efficacy of baclofen to inhibit glutamate release was substantially reduced in GABAB(1a)−/−, but essentially unaltered in GABAB(1b)−/− mice. Our data suggest that functional GABAB heteroreceptors regulating glutamate release are predominantly, but not exclusively composed of GABAB(1a) and GABAB(2) subunits.
    Journal of Neural Transmission 10/2008; 115(10):1401-1411. DOI:10.1007/s00702-008-0095-7 · 2.40 Impact Factor
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    ABSTRACT: Cerebral ischemia followed by reperfusion activates numerous pathways that lead to cell death. One such pathway involves the release of large quantities of the excitatory amino acid glutamate into the synapse and activation of N-methyl-D-aspartate receptors. This causes an increase in mitochondrial calcium levels ([Ca(2+)](m)) and a production of reactive oxygen species (ROS), both of which may induce the mitochondrial permeability transition (MPT). As a consequence, there is eventual mitochondrial failure culminating in either apoptotic or necrotic cell death. Thus, agents that inhibit MPT might prove useful as therapeutic interventions in cerebral ischemia. In this study, we have investigated the neuroprotective efficacy of the novel compound NIM811. Similar in structure of its parent compound cyclosporin A, NIM811 is a potent inhibitor of the MPT. Unlike cyclosporin A, however, it is essentially void of immunosuppressive actions, allowing the role of MPT to be clarified in ischemia/reperfusion injury. The results of these studies demonstrate that NIM811 provides almost 40% protection in a model of transient focal cerebral ischemia. This was associated with a nearly 10% reduction in mitochondrial reactive species formation and 34% and 38% reduction of cytochrome c release in core and penumbra, respectively. Treatment with NIM811 also increased calcium retention capacity by approximately 20%. Interestingly, NIM811 failed to improve ischemia-induced impairment of bioenergetics. The neuroprotective effects of NIM811 were not due to drug-induced alterations in cerebral perfusion after ischemia. Activation of MPT appears to be an important process in ischemia/reperfusion injury and may be a therapeutic target.
    Journal of Neurotrauma 06/2007; 24(5):895-908. DOI:10.1089/neu.2006.0122 · 3.71 Impact Factor
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    Z Zhong · T P Theruvath · R T Currin · P C Waldmeier · J J Lemasters ·
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    ABSTRACT: ATP decreases markedly in small-for-size liver grafts. This study tested if the mitochondrial permeability transition (MPT) underlies dysfunction of small-for-size livers. Half-size livers were implanted into recipients of about twice the donor weight, resulting in quarter-size liver grafts. NIM811 (5 microM), a nonimmunosuppressive MPT inhibitor was added to the storage solutions. Mitochondrial polarization and cell death were assessed by confocal microscopy of rhodamine 123 (Rh123) and propidium iodide (PI), respectively. After quarter-size transplantation, alanine aminotransferase (ALT), serum bilirubin and necrosis all increased. NIM811 blocked these increases by >70%. After 38 h, BrdU labeling, a marker of cell proliferation and graft weight increase were 3% and 5%, respectively, which NIM811 increased to 30% and 42%. NIM811 also increased survival of quarter-size grafts. In sham-operated livers, hepatocytes exhibited punctate Rh123 fluorescence. By contrast, in quarter-size grafts at 18 h after implantation, mitochondria of most hepatocytes did not take up Rh123, indicating mitochondrial depolarization. Nearly all hepatocytes not taking up Rh123 continued to exclude PI at 18 h, indicating that depolarization preceded cell death. NIM811 and free radical-scavenging polyphenols strongly attenuated mitochondrial depolarization. In conclusion, mitochondria depolarized after quarter-size liver transplantation. NIM811 decreased injury and stimulated regeneration, probably by inhibiting free radical-dependent MPT onset.
    American Journal of Transplantation 05/2007; 7(5):1103-11. DOI:10.1111/j.1600-6143.2007.01770.x · 5.68 Impact Factor
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    ABSTRACT: Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.
    Biochemical Pharmacology 12/2006; 72(10):1197-206. DOI:10.1016/j.bcp.2006.06.031 · 5.01 Impact Factor
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    ABSTRACT: The clinically established positron emission tomography (PET) tracers 6-[(18)F]-fluoro-l-DOPA ([(18)F]FDOPA), 6-[(18)F]-fluoro-l-m-tyrosine ([(18)F]FMT) and 2beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(2-[(18)F]-fluoroethyl)-nortropane ([(18)F]FECNT) serve as markers of presynaptic integrity of dopaminergic nerve terminals in humans. This study describes our efforts to adopt the methodology of human Parkinson's disease (PD) PET studies to mice. The PET imaging characteristics of [(18)F]FDOPA, [(18)F]FMT and [(18)F]FECNT were analyzed in healthy C57BL/6 mice using the dedicated small-animal PET tomograph quad-HIDAC. Furthermore, [(18)F]FECNT was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. [(18)F]FDOPA and [(18)F]FMT failed to clearly visualize the mouse striatum, whereas PET experiments using [(18)F]FECNT proved that the employed methodology is capable of delineating the striatum in mice with exquisite resolution. Moreover, [(18)F]FECNT PET imaging of healthy and MPTP-lesioned mice demonstrated that the detection and quantification of striatal degeneration in lesioned mice can be accomplished. This study shows the feasibility of using [(18)F]FECNT PET to analyze noninvasively the striatal degeneration in the MPTP mouse model of PD. This methodology can be therefore considered as a viable complement to established in vivo microdialysis and postmortem techniques.
    Nuclear Medicine and Biology 08/2006; 33(5):607-14. DOI:10.1016/j.nucmedbio.2006.04.005 · 2.41 Impact Factor
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    ABSTRACT: GABAB1-/- mice, which are devoid of functional GABAB receptors, consistently exhibit marked hyperlocomotion when exposed to a novel environment. Telemetry recordings now revealed that, in a familiar environment, GABAB1-/- mice display an altered pattern of circadian activity but no hyperlocomotion. This indicates that hyperlocomotion is only triggered when GABAB1-/- mice are aroused by novelty. In microdialysis experiments, GABAB1-/- mice exhibited a 2-fold increased extracellular level of dopamine in the striatum. Following D-amphetamine administration, GABAB1-/- mice released less dopamine than wild-type mice, indicative of a reduced cytoplasmic dopamine pool. The hyperdopaminergic state of GABAB1-/- mice is accompanied by molecular changes, including reduced levels of tyrosine hydroxylase mRNA, D1 receptor binding-sites and Ser40 phosphorylation of tyrosine hydroxylase. Tyrosine hydroxylase activity, tissue dopamine content and dopamine metabolism do not appear to be measurably altered. Pharmacological and electrophysiological experiments support that the hyperdopaminergic state of GABAB1-/- mice is not severe enough to inactivate dopamine D2 receptors and to disrupt D2-mediated feedback inhibition of tyrosine hydroxylase activity. The data support that loss of GABAB activity results in a sustained moderate hyperdopaminergic state, which is phenotypically revealed by contextual hyperlocomotor activity. Importantly, the presence of an inhibitory GABA tone on the dopaminergic system mediated by GABAB receptors provides an opportunity for therapeutic intervention.
    Journal of Neurochemistry 06/2006; 97(4):979-91. DOI:10.1111/j.1471-4159.2006.03806.x · 4.28 Impact Factor

  • Journal of Cerebral Blood Flow & Metabolism 08/2005; 25. DOI:10.1038/sj.jcbfm.9591524.0005 · 5.41 Impact Factor
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    P.G. Sullivan · A.G. Rabchevsky · P.C. Waldmeier · J.E. Springer ·
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    ABSTRACT: Experimental traumatic brain injury (TBI) and spinal cord injury (SCI) result in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids (EAA), increased reactive oxygen species (ROS), and the disruption of Ca(2+) homeostasis are major factors contributing to the ensuing neuropathology. Mitochondria serve as the powerhouse of the cell by maintaining ratios of ATP:ADP that thermodynamically favor the hydrolysis of ATP to ADP + P(i), yet a byproduct of this process is the generation of ROS. Proton-pumping by components of the electron transport system (ETS) generates a membrane potential (DeltaPsi) that can then be used to phosphorylate ADP or sequester Ca(2+) out of the cytosol into the mitochondrial matrix. This allows mitochondria to act as cellular Ca(2+) sinks and to be in phase with changes in cytosolic Ca(2+) levels. Under extreme loads of Ca(2+), however, opening of the mitochondrial permeability transition pore (mPTP) results in the extrusion of mitochondrial Ca(2+) and other high- and low-molecular weight components. This catastrophic event discharges DeltaPsi and uncouples the ETS from ATP production. Cyclosporin A (CsA), a potent immunosuppressive drug, inhibits mitochondrial permeability transition (mPT) by binding to matrix cyclophilin D and blocking its binding to the adenine nucleotide translocator. Peripherally administered CsA attenuates mitochondrial dysfunction and neuronal damage in an experimental rodent model of TBI, in a dose-dependent manner. The underlying mechanism of neuroprotection afforded by CsA is most likely via interaction with the mPTP because the immunosuppressant FK506, which has no effect on the mPT, was not neuroprotective. When CsA was administrated after experimental SCI at the same dosage and regimen used TBI paradigms, however, it had no beneficial neuroprotective effects. This review takes a comprehensive and critical look at the evidence supporting the role for mPT in central nervous system (CNS) trauma and highlights the differential responses of CNS mitochondria to mPT induction and the implications this has for therapeutically targeting the mPT in TBI and SCI.
    Journal of Neuroscience Research 01/2005; 79(1-2):231-9. DOI:10.1002/jnr.20292 · 2.59 Impact Factor
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    ABSTRACT: Cyclosporin A (CsA) is highly neuroprotective in several animal models of acute neurological damage and neurodegenerative disease with inhibition of the mitochondrial permeability transition (mPT) having emerged as a possible mechanism for the observed neuroprotection. In the present study, we have evaluated two new nonimmunosuppressive cyclosporin analogs NIM811 (Novartis) and UNIL025 (Debiopharm) for their ability to inhibit mPT in rat brain-derived mitochondria. Both NIM811 and UNIL025 were found to be powerful inhibitors of calcium-induced mitochondrial swelling under energized and deenergized conditions, and the maximal effects were identical to those of native CsA. The potencies of mPT inhibition by NIM811 and UNIL025 were stronger, with almost one order of magnitude higher potency for UNIL025 compared to CsA, correlating to their respective inhibitory action of cyclophilin activity. These compounds will be instrumental in the evaluation of mPT as a central target for neuroprotection in vivo.
    Journal of Bioenergetics 09/2004; 36(4):407-13. DOI:10.1023/B:JOBB.0000041776.31885.45 · 3.21 Impact Factor
  • Peter C Waldmeier · William G Tatton ·
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    ABSTRACT: Current treatment options for neurodegenerative diseases are limited and mainly affect only the symptoms of disease. Because of the unknown and probably multiple causes of these diseases, they cannot be readily targeted. However, it has been established that apoptosis contributes to neuronal loss in most neurodegenerative diseases. A possible treatment option is to interrupt the signaling networks that link neuronal damage to apoptotic degradation in neurodegeneration. The viability of this option depends upon the extent to which apoptosis accounts for neuron loss, whether or not interruption of apoptosis signaling results in recovery of neurological function and whether or not there are significant downsides to targeting apoptosis. Several compounds acting at different sites in known apoptotic signaling networks are currently in development and a few are in clinical trial. If an apoptosis-targeted compound succeeds in slowing or halting neurological dysfunction in one or more neurodegenerative diseases, a new era in the treatment of neurodegenerative diseases will begin.
    Drug Discovery Today 04/2004; 9(5):210-8. DOI:10.1016/S1359-6446(03)03000-9 · 6.69 Impact Factor
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    ABSTRACT: γ-Hydroxybutyrate (GHB), a metabolite of γ-aminobutyric acid (GABA), is proposed to function as a neu neuronsmitter or neuromodulator. γ-Hydroxybutyrate and its prodrug, γ-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [ 3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABA B receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5- hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2- dimethyl-propyl)-phenol GHB induced functional GTPγ[35S] responses in brain membrane preparations from wild-type but not GABA B(1)-/- mice. The GTPγ[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3, 4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPγ[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABA B(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.
    European Journal of Neuroscience 12/2003; 18(10):2722-30. DOI:10.1111/j.1460-9568.2003.03013.x · 3.18 Impact Factor
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    ABSTRACT: The mitochondrial permeability transition (MPT) plays an important role in damage-induced cell death, and agents inhibiting the MPT may have a therapeutic potential for treating human conditions such as ischemia/reperfusion injury, trauma, and neurodegenerative diseases. The mitochondrial matrix protein, cyclophilin D (CYP D), a member of a family of highly homologous peptidylprolyl cis-trans isomerases (PPIases), plays a decisive role in MPT, being an integral constituent of the MPT pore. Other putative MPT pore proteins include the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC). In an alternative model, the MPT pore is formed by clusters of misfolded membrane proteins outlining aqueous channels that are regulated by CYP D and other chaperone-like proteins. Like cyclophilin A (CYP A) and other cyclophilin family members, CYP D is targeted by the immunosuppressant cyclosporin A (CsA). CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A. The relevance of MPT inhibition by CsA for its cytoprotective effects is well documented in many cellular models. Mechanisms of action in vivo are more difficult to define, and accordingly the evidence is as yet less compelling in in vivo animal models of ischemia/reperfusion injury, trauma and neurodegenerative diseases. Notwithstanding, CYP D is a drug target of high interest. Structural considerations suggest feasibility of designing CYP D ligands without immunosuppressant properties. This is highly desirable, since they have the potential of being useful therapeutic agents in a variety of disease states. It might be a tougher challenge to obtain compounds specific for CYP D vs. other cyclophilins, and/or of small molecular weight, allowing brain penetration to make them suitable for treating neurodegenerative diseases.
    Current Medicinal Chemistry 09/2003; 10(16):1485-506. DOI:10.2174/0929867033457160 · 3.85 Impact Factor
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    Peter C Waldmeier ·
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    ABSTRACT: The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 05/2003; 27(2):303-21. DOI:10.1016/S0278-5846(03)00025-3 · 3.69 Impact Factor
  • Peter C Waldmeier · Jean-Jacques Feldtrauer · Ting Qian · John J Lemasters ·
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    ABSTRACT: Cyclosporin A (CsA) shows cytoprotective properties in many cellular and in vivo models that may depend on interference of the interaction of cyclophilin A with calcineurin or of cyclophilin D with the mitochondrial permeability transition (PT) pore. The nonimmunosuppressive cyclosporin derivative N-methyl-4-valine-cyclosporin (PKF220-384) inhibits the mitochondrial permeability transition (MPT) like CsA but without calcineurin inactivation. PKF220-384 has been used to discriminate between PT pore- and calcineurin mediated effects but is no longer available. Here, we evaluated the effects of another nonimmunosuppressive cyclosporin derivative, N-methyl-4-isoleucine-cyclosporin (NIM811) on the MPT. Using two newly developed microtiter plate assays, one measuring mitochondrial swelling from absorbance and the other measuring mitochondrial membrane potential from changes in safranin fluorescence, we show that NIM811 blocks the MPT induced by calcium and inorganic phosphate, alone or in combination with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the complex I inhibitor rotenone, and the prooxidant t-butylhydroperoxide. NIM811 was equipotent to CsA and half as potent as PKF220-384. Additionally, we show that NIM811 blocks cell killing and prevents in situ mitochondrial inner membrane permeabilization and depolarization during tumor necrosis factor-alpha-induced apoptosis to cultured rat hepatocytes. NIM811 inhibition of apoptosis was equipotent with CsA except at higher concentrations: CsA lost efficacy but NIM 811 did not. We conclude that NIM811 is a useful alternative to PKF220-384 to investigate the role of the mitochondrial permeability transition in apoptotic and necrotic cell death.
    Molecular Pharmacology 08/2002; 62(1):22-9. DOI:10.1124/mol.62.1.22 · 4.13 Impact Factor
  • P C Waldmeier · W.P.J.M. Spooren · B Hengerer ·
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    ABSTRACT: The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease. CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) with CGP 3466 (0.1 mg/kg s.c.) or CGP 3466B (0.014 mg/kg and 0.14 mg/kg p.o.) b.i.d. for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (0.0014 mg/kg p.o.) showed a marginal effect, whereas a high dose, i.e. 1.4 mg/kg p.o., was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that received intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 mg/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, skilled paw use was assessed by means of the staircase test. The results indicated a significant improvement of skilled motor performance as measured by means of the number of eaten pellets. Since due to the long wash-out period a symptomatic effect of CGP 3466B can be ruled out, it is likely that this improvement was related to interference with the course of the degeneration of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in in vitro and in vivo models of Parkinson's disease. In addition, treatment with CGP 3466 resulted in improved skilled motor performance in 6-OHDA-lesioned rats.
    Archiv für Experimentelle Pathologie und Pharmakologie 01/2001; 362(6):526-37. DOI:10.1007/s002100000300 · 2.47 Impact Factor
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    ABSTRACT: Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.
    The Journal of Cell Biology 01/2001; 151(7):1537-48. · 9.83 Impact Factor
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    ABSTRACT: Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.
    The Journal of Cell Biology 12/2000; 151(7):1537-1548. DOI:10.1083/jcb.151.7.1537 · 9.83 Impact Factor
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    Y Sagot · N Toni · D Perrelet · S Lurot · B King · H Rixner · L Mattenberger · P C Waldmeier · A C Kato ·
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    ABSTRACT: Apoptosis and mitochondrial dysfunction are thought to be involved in the aetiology of neurodegenerative diseases. We have tested an orally active anti-apoptotic molecule (CGP 3466B) that binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in an animal model with motoneuron degeneration, i.e. a mouse mutant with progressive motor neuronopathy (pmn). In pmn/pmn mice, CGP 3466B was administered orally (10–100 nmol kg−1) at the onset of the clinical symptoms (2 weeks after birth). CGP 3466B slowed disease progression as determined by a 57% increase in life-span, preservation of body weight and motor performance. This improvement was accompanied by a decreased loss of motoneurons and motoneuron fibres as well as an increase in retrograde transport. Electron microscopic analysis showed that CGP 3466B protects mitochondria which appear to be selectively disrupted in the motoneurons of pmn/pmn mice. The data support evaluation of CGP 3466B as a potential treatment for motor neuron disease. British Journal of Pharmacology (2000) 131, 721–728; doi:10.1038/sj.bjp.0703633
    British Journal of Pharmacology 11/2000; 131(4):721-8. DOI:10.1038/sj.bjp.0703633 · 4.84 Impact Factor
  • P C Waldmeier · A A Boulton · A R Cools · A C Kato · W G Tatton ·
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    ABSTRACT: (-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
    Journal of neural transmission. Supplementum 02/2000; 60(60):197-214. DOI:10.1007/978-3-7091-6301-6_13 · 1.07 Impact Factor

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  • 1998-2009
    • Novartis
      Bâle, Basel-City, Switzerland
  • 2003
    • Novartis Institutes for BioMedical Research
      • Global Discovery Chemistry Group
      Cambridge, Massachusetts, United States
  • 2002-2003
    • University of North Carolina at Chapel Hill
      North Carolina, United States
  • 1996
    • Paul Scherrer Institut
      • Center for Radiopharmaceutical Sciences (CRS)
      Aargau, Switzerland
  • 1983
    • Central Institute of Mental Health
      Mannheim, Baden-Württemberg, Germany
  • 1982
    • AVACO AG, Switzerland
      Basel-Landschaft, Switzerland
  • 1973-1976
    • LKC Switzerland Ltd.
      Basel-Landschaft, Switzerland