Papers by Julie Lotharius
Role of mitochondrial dysfunction and dopamine-dependent oxidative stress in amphetamine-induced toxicity
Annals of Neurology, 2001
To define the molecular mechanisms underlying amphetamine (AMPH) neurotoxicity, primary cultures ... more To define the molecular mechanisms underlying amphetamine (AMPH) neurotoxicity, primary cultures of dopaminergic neurons were examined for drug-induced changes in dopamine (DA) distribution, oxidative stress, protein damage, and cell death. As in earlier studies, AMPH rapidly redistributed vesicular DA to the cytoplasm, where it underwent outward transport through the DA transporter. DA was concurrently oxidized to produce a threefold increase in free radicals, as measured by the redox-sensitive dye dihydroethidium. Intracellular DA depletion using the DA synthesis inhibitor alpha-methyl-p-tyrosine or the vesicular monoamine transport blocker reserpine prevented drug-induced free radical formation. Despite these AMPH-induced changes, neither protein oxidation nor cell death was observed until 1 and 4 days, respectively. AMPH also induced an early burst of free radicals in a CNS-derived dopaminergic cell line. However, AMPH-mediated attenuation of ATP production and mitochondrial function was not observed in these cells until 48 to 72 hours. Thus, neither metabolic dysfunction nor loss of viability was a direct consequence of AMPH neurotoxicity. In contrast, when primary cultures of dopaminergic neurons were exposed to AMPH in the presence of subtoxic doses of the mitochondrial complex I inhibitor rotenone, cell death was dramatically increased, mimicking the effects of a known parkinsonism-inducing toxin. Thus, metabolic stress may predispose dopaminergic neurons to injury by free radical-promoting insults such as AMPH.
Toxicology and Applied Pharmacology, Nov 1, 2009
LUHMES cells are conditionally-immortalized non-transformed human fetal cells that can be differe... more LUHMES cells are conditionally-immortalized non-transformed human fetal cells that can be differentiated to acquire a dopaminergic neuron-like phenotype under appropriate growth conditions. After differentiation by GDNF and cyclic adenosine monophosphate, LUHMES were sensitive to 1-methyl-4-phenylpyridinium (MPP + ) toxicity at ≤5 μM, but resistant to the parental compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The high homogeneity and purity of the cultures allowed the detection of metabolic changes during the degeneration. Cellular ATP dropped in two phases after 24 and 48 h; cellular glutathione (GSH) decreased continuously, paralleled by an increase in lipid peroxidation. These events were accompanied by a time-dependent degeneration of neurites. Block of the dopamine transporter by GBR 12909 or mazindol completely abrogated MPP + toxicity. Inhibition of de novo dopamine synthesis by αmethyl-L-tyrosine or 3-iodo-L-tyrosine attenuated toxicity, but did not reduce the initial drop in ATP. Inhibition of mixed lineage kinases by CEP1347 completely prevented the MPP + -induced loss of viability and intracellular GSH, but failed to attenuate the initial drop of ATP. For the quantitative assessment of neurite degeneration, an automated imaging-based high content screening approach was applied and confirmed the findings made by pharmacological interventions in this study. Our data indicate that inhibition of mitochondrial ATP synthesis is not sufficient to trigger cell death in MPP + -treated LUHMES.
Lancet Infectious Diseases, Jun 1, 2017
Background DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, ... more Background DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Methods Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced bloodstage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). Findings In part 1, 73 participants were enrolled between April 12, 2013, and July 14, 2015 (DSM265, n=55; placebo, n=18). In part 2, nine participants were enrolled between Sept 30 and Nov 25, 2013 (150 mg DSM265, n=7; 10 mg/kg mefloquine, n=2). In part 1, 117 adverse events were reported; no drug-related serious or severe events were reported. The most common drug-related adverse event was headache. The mean DSM265 peak plasma concentration (C max) ranged between 1310 ng/mL and 34 800 ng/mL and was reached in a median time (t max) between 1•5 h and 4 h, with a mean elimination half-life between 86 h and 118 h. In part 2, the log 10 parasite reduction ratio at 48 h in the DSM265 (150 mg) group was 1•55 (95% CI 1•42-1•67) and in the mefloquine (10 mg/kg) group was 2•34 (2•17-2•52), corresponding to a parasite clearance half-life of 9•4 h (8•7-10•2) and 6•2 h (5•7-6•7), respectively. The median minimum inhibitory concentration of DSM265 in blood was estimated as 1040 ng/mL (range 552-1500), resulting in a predicted single efficacious dose of 340 mg. Parasite clearance was significantly faster in participants who received mefloquine than in participants who received DSM265 (p<0•0001). Interpretation The good safety profile, long elimination half-life, and antimalarial effect of DSM265 supports its development as a partner drug in a single-dose antimalarial combination treatment.
Neurobiology of Disease, Oct 1, 2003
Neurodegenerative diseases such as Parkinson's disease exhibit complex features of cell death ref... more Neurodegenerative diseases such as Parkinson's disease exhibit complex features of cell death reflecting both the primary lesion as well as surrounding interconnected events. Because Bcl-2 family members are intimately involved in cell death processes, the present study used dopaminergic cultures from control, Bcl-2-overexpressing, or Bax-deficient genetically modified animals to determine the in situ effects of parkinsonism-inducing toxins. MPP ϩ-mediated cell death was attenuated by Bcl-2 but did not require Bax. Accordingly, mutations or deletions within Bax heterodimerization domains, BH1, BH2, or BH3 had no effect on Bcl-2's ability to prevent cell death, whereas the cell-death suppressing BH4 domain did. Although both staurosporine and 6-OHDA induced apoptosis, overexpression of Bcl-2 only rescued cells from programmed cell death induced by staurosporine. Thus, differential cell death pathways are associated with these cytotoxic signals in primary models of Parkinson's disease.
Journal of Biological Chemistry, Dec 1, 2000
Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP ؉), into dopaminergic... more Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP ؉), into dopaminergic terminals is thought to block Complex I activity leading to ATP loss and overproduction of reactive oxygen species (ROS). The present study indicates that MPP ؉-induced ROS formation is not mitochondrial in origin but results from intracellular dopamine (DA) oxidation. Although a mean lethal dose of MPP ؉ led to ROS production in identified dopaminergic neurons, toxic doses of the Complex I inhibitor rotenone did not. Concurrent with ROS formation, MPP ؉ redistributed vesicular DA to the cytoplasm prior to its extrusion from the cell by reverse transport via the DA transporter. MPP ؉-induced DA redistribution was also associated with cell death. Depleting cells of newly synthesized and/or stored DA significantly attenuated both superoxide production and cell death, whereas enhancing intracellular DA content exacerbated dopaminergic sensitivity to MPP ؉. Lastly, depleting cells of DA in the presence of succinate completely abolished MPP ؉-induced cell death. Thus, MPP ؉ neurotoxicity is a multi-component process involving both mitochondrial dysfunction and ROS generated by vesicular DA displacement. These results suggest that in the presence of a Complex I defect, misregulation of DA storage could lead to the loss of nigrostriatal neurons in Parkinson's disease.
Experimental Neurology, Jun 1, 2005
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopa... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.
British Journal of Pharmacology, Nov 1, 2007
Background and purpose: Glycogen synthase kinase-3 (GSK-3) affects neuropathological events assoc... more Background and purpose: Glycogen synthase kinase-3 (GSK-3) affects neuropathological events associated with Alzheimeŕs disease (AD) such as hyperphosphorylation of the protein, tau. GSK-3b expression, enzyme activity and tau phosphorylated at AD-relevant epitopes are elevated in juvenile rodent brains. Here, we assess five GSK-3b inhibitors and lithium in lowering phosphorylated tau (p-tau) and GSK-3b enzyme activity levels in 12-day old postnatal rats. Experimental approach: Brain levels of inhibitors following treatment in vivo were optimized based on pharmacokinetic data. At optimal doses, p-tau (Ser 396) levels in brain tissue was measured by immunoblotting and correlated with GSK-3b enzyme activities in the same tissues. Effects of GSK inhibitors on p-tau, GSK-3b activities and cell death were measured in a human neuronal cell line (LUHMES). Key results: Lithium and CHIR98014 reduced tau phosphorylation (Ser 396) in the cortex and hippocampus of postnatal rats, while Alsterpaullone and SB216763 were effective only in hippocampus. AR-A014418 and Indirubin-3 0-monoxime were ineffective in either brain region. Inhibition of p-tau in brain required several-fold higher levels of GSK inhibitors than the IC 50 values obtained in recombinant or cell-based GSK-3b enzyme activity assays. The inhibitory effect on GSK-3b activity ex vivo correlated with protection against cell death and decrease of p-tau-in LUHMES cells, using low mM inhibitor concentrations. Conclusions and Implications: Selective small-molecule inhibitors of GSK-3 reduce tau phosphorylation in vivo. These findings corroborate earlier suggestions that GSK-3b may be an attractive target for disease-modification in AD and related conditions where tau phosphorylation is believed to contribute to disease pathogenesis.
Journal of Neurochemistry, Aug 19, 2010
Hypoxia-inducible transcription factors (HIFs) are transcription factors, which play a central ro... more Hypoxia-inducible transcription factors (HIFs) are transcription factors, which play a central role in the regulation of cellular and systemic oxygen homeostasis. HIFs are dimeric ab heteromers and three a isoforms are known, HIF-1a, HIF-2a and HIF-3a. While the b subunit is constitutively expressed, HIF activity depends on the level of the a subunit, which is tightly regulated by cellular oxygen concentration. Two distinct processes, which directly depend on oxygen concentration, have been identified so far. In one process a specific proline residue in the HIF-1a subunit is trans-4hydroxylated. This promotes interaction with the von Hippel Lindau ubiquitin ligase complex, which targets the HIF-a subunit for ubiquitin-mediated proteolysis (Epstein et al. 2001). In another oxygen dependent process, b-hydroxylation of an asparagine residue, down-regulates transactivation by preventing association of the HIF-a subunit C-terminal activation domain with the co-activator p300/CREB-binding protein (Lando et al. 2002). Both prolyl and asparaginyl hydroxylation of HIF-a are catalyzed by enzymes belonging to the Fe(II) and 2-oxoglutarate dependent dioxygenase superfamily (Bruick and McKnight 2001; Epstein et al. 2001). These enzymes have an absolute requirement for molecular oxygen as co-substrate and their activity is reduced by hypoxia whereby non-hydroxylated HIF-a subunit remains transcriptionally active (Epstein et al. 2001). So far a single HIF asparaginyl hydroxylase, factor inhibiting HIF has been identified, whereas three different subtypes of HIF prolyl hydroxylases (HPH) have been identified (Lando et al. 2002). Based on this knowledge it has been shown that
Inflammation in parkinson’s disease
Springer eBooks, 2007
ABSTRACT Parkinson’s disease∈dexParkinson’s disease (PD) is a neurodegenerative disorder characte... more ABSTRACT Parkinson’s disease∈dexParkinson’s disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra∈dex substantia nigra (SN). Several pathogenic mechanisms have been implicated in the demise of these cells, including dopamine∈dexdopamine-dependent oxidative stress, mitochondrial dysfunction, excitotoxicity, and proteasomal impairment. In recent years, the involvement of neuroinflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia∈dexmicroglia and increased levels of inflammatory mediators been detected in the striatum of PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. For example, post-mortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine∈dex methyl-4-phenyl-1,2,3,6- tetrahydropyridine, revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link neurodegeneration and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD
Brain Research, Dec 1, 2007
An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-... more An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. Here, we demonstrate that transfection of VMAT2 in the dopaminergic cell line, PC12, increases intracellular dopamine content, augments potassium-induced dopamine release and attenuates cell death induced by the cytosolic dopamine enhancer, methamphetamine, suggesting an enhancement in vesicular dopamine storage. In rat ventral mesencephalic cultures highly enriched for dopaminergic neurons, lentiviral delivery of recombinant VMAT2 using a neuronal-specific promoter also resulted in elevated intracellular dopamine content and neurotransmitter release after depolarization. The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.
American Journal of Tropical Medicine and Hygiene, Dec 6, 2010
* C max = maximum concentration; T max = time after administration of drug when maximum plasma co... more * C max = maximum concentration; T max = time after administration of drug when maximum plasma concentration is reached; AUC = area under curve; t ½ = half-life; Cl/F = bioavailability. † Values are medians and ranges.
The Lancet. Infectious diseases, Jun 28, 2017
DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme e... more DSM265 is a novel antimalarial that inhibits plasmodial dihydroorotate dehydrogenase, an enzyme essential for pyrimidine biosynthesis. We investigated the safety, tolerability, and pharmacokinetics of DSM265, and tested its antimalarial activity. Healthy participants aged 18-55 years were enrolled in a two-part study: part 1, a single ascending dose (25-1200 mg), double-blind, randomised, placebo-controlled study, and part 2, an open-label, randomised, active-comparator controlled study, in which participants were inoculated with Plasmodium falciparum induced blood-stage malaria (IBSM) and treated with DSM265 (150 mg) or mefloquine (10 mg/kg). Primary endpoints were DSM265 safety, tolerability, and pharmacokinetics. Randomisation lists were created using a validated, automated system. Both parts were registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12613000522718 (part 1) and number ACTRN12613000527763 (part 2). In part 1, 73 participants were enrolle...
Impaired dopamine storage resulting from a-synuclein mutations may contribute to the pathogenesis of Parkinson's disease
Science translational medicine, Jan 15, 2015
Malaria is one of the most significant causes of childhood mortality, but disease control efforts... more Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provi...
Nature Reviews Neuroscience, 2002
A neurotransmitter that is characterized by a catechol ring and an alkylamine side chain; example... more A neurotransmitter that is characterized by a catechol ring and an alkylamine side chain; examples are dopamine, adrenaline and noradrenaline. OXIDATIVE STRESS A state of imbalance between the production of reactive oxygen species and their clearance by cellular antioxidant systems.
The Journal of Immunology, 2004
Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and ... more Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-γ. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of ∼100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-κB, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astroc...
Human Molecular Genetics, 2002
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inabili... more Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the inability to initiate, execute and control movement. Neuropathologically, there is a striking loss of dopamine-producing neurons in the substantia nigra pars compacta, accompanied by depletion of dopamine in the striatum. Most forms of PD are sporadic, though in some cases familial inheritance is observed. In the late 1990s, two mutations in the a-synuclein gene were linked to rare, autosomal dominant forms of PD. Previously cloned from cholinergic vesicles of the Torpedo electric ray, a-synuclein is highly enriched in presynaptic nerve terminals and appears to be involved in synapse maintenance and plasticity. It is expressed ubiquitously in the brain, raising the important question of why dopaminergic neurons are primarily targeted in persons carrying mutations in a-synuclein. In this article, we review the current literature on a-synuclein and suggest a possible role for this protein in vesicle recycling via its regulation of phospholipase D2, its fatty acid-binding properties, or both. Exogenous application of dopamine, as well as redistribution of vesicular dopamine to the cytoplasm, can be toxic to dopaminergic neurons. Thus, impaired neurotransmitter storage arising from mutations in a-synuclein could lead to cytoplasmic accumulation of dopamine. The breakdown of this labile neurotransmitter in the cytoplasm could, in turn, promote oxidative stress and metabolic dysfunction, both of which have been observed in nigral tissue from PD patients.
Experimental Neurology, 2005
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopa... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.
The American Journal of Tropical Medicine and Hygiene, 2010
* C max = maximum concentration; T max = time after administration of drug when maximum plasma co... more * C max = maximum concentration; T max = time after administration of drug when maximum plasma concentration is reached; AUC = area under curve; t ½ = half-life; Cl/F = bioavailability. † Values are medians and ranges.
The Journal of Neuroscience the Official Journal of the Society For Neuroscience, Feb 15, 1999
Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD).... more Oxidative stress is thought to contribute to dopaminergic cell death in Parkinson's disease (PD). The neurotoxin 6-hydroxydopamine (6-OHDA), which is easily oxidized to reactive oxygen species (ROS), appears to induce neuronal death by a free radical-mediated mechanism, whereas the involvement of free radicals in N-methyl-4-phenylpyridinium (MPP ϩ ) toxicity is less clear. Using free radical-sensitive fluorophores and vital dyes with post hoc identification of tyrosine hydroxylase-positive neurons, we monitored markers of apoptosis and the production of ROS in dopaminergic neurons treated with either 6-OHDA or MPP ϩ . Annexin-V staining suggested that 6-OHDA but not MPP ϩ -mediated cell death was apoptotic. In accordance with this assignment, the general caspase inhibitor Boc-(Asp)-fluoromethylketone only blocked 6-OHDA neurotoxicity. Both toxins exhibited an early, sustained rise in ROS, although only 6-OHDA induced a collapse in mitochondrial membrane potential temporally related to the increase in ROS. Recently, derivatives of buckminsterfullerene (C 60 ) molecules have been shown to act as potent antioxidants in several models of oxidative stress . Significant, dose-dependent levels of protection were also seen in these in vitro models of PD using the C 3 carboxyfullerene derivative. Specifically, C 3 was fully protective in the 6-OHDA paradigm, whereas it only partially rescued dopaminergic neurons from MPP ϩ -induced cell death. In either model, it was more effective than glialderived neurotrophic factor. These data suggest that cell death in response to 6-OHDA and MPP ϩ may progress through different mechanisms, which can be partially or entirely saved by carboxyfullerenes.
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Papers by Julie Lotharius