Charlotte Laloux

Vigilance states in a parkinsonian model, the MPTP mouse

Sleep disturbances and vigilance disorders are frequently observed in Parkinsons disease. Despite the fact that the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse is one of the best‐known animal models of Parkinsons disease, sleep analysis has never previously been performed in this system. In the present study, we explored sleep–wakefulness cycles in MPTP‐treated mice and compared the results to data from untreated mice. MPTP (25 mg/kg) was injected daily for 5 days. After recovery, polysomnography was recorded over 48 h. Dopaminergic lesions of the substantia nigra and striata were evaluated using immunohistochemical markers. Immunohistochemical analysis showed a loss of dopaminergic neurons in MPTP mice. Compared with controls, MPTP‐treated mice presented changes in sleep architecture throughout the nycthemeral period, with longer wakefulness and paradoxical sleep episodes and an increase in the amount of paradoxical sleep. We observed changes in sleep architecture in MPTP‐treated mice, compared with saline‐treated mice. MPTP mice show more consolidated vigilance states with higher amount of paradoxical sleep than controls. Although the MPTP‐treated mouse is not a good model of sleep disturbances in PD, our results suggest that it could be a good pharmacological model for studying the effects of dopaminergic treatments on animal sleep–wakefulness cycles.

Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC.

Parkinsons disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.

Differential susceptibility to the PPAR-γ agonist pioglitazone in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine rodent models of Parkinson's disease

A growing body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists are valuable candidates as disease modifiers in Parkinsons disease (PD) and may thus enable neuroprotection and preserve motor function. The present study sought to evaluate the effect of the PPAR-gamma agonist pioglitazone in two different animal models of PD. The study was based on nigral dopaminergic neuron labelling and the assessment of motor behaviour in (i) the frequently investigated MPTP mouse model and (ii) the less well-known bilateral 6-OHDA rat model. In MPTP-injected mice, pioglitazone reversed body weight loss and the reduction in rearing frequency and induced significant neuroprotection of the nigrostriatal dopaminergic pathway (by 24%, compared with vehicle). In contrast, pioglitazone did not have any effect on the 73.5% loss of dopaminergic neurons or motor impairments (a reduced rearing frequency and a loss of strength in the forepaws) in bilateral 6-OHDA rats. The PPAR-gamma agonist pioglitazone had a significant neuroprotective effect in MPTP mice but not in bilateral 6-OHDA rats. The various effects of PPAR agonists in both models can be accounted by the different action mechanism of the 2 toxins or by the fact that 3μg 6-OHDA injection was too harmful to be alleviated by the compound. This work supports PPAR-agonists to be relevant in the therapeutic strategy research in Parkinsons disease and highlights the importance in evaluating neuroprotective agent in different models.

Effect of dopaminergic substances on sleep/wakefulness in saline- and MPTP-treated mice.

Sleep/wakefulness (S/W) disorders are frequent in Parkinson’s disease (PD). The underlying causes have yet to be elucidated but dopaminergic neurodegenerative lesions seem to contribute to appearance of the disorders and anti‐Parkinsonian medication is known to accentuate S/W problems. Hence, we reasoned that studying the acute effect of dopaminergic compounds on S/W in an animal model of PD might improve our knowledge of S/W regulation in the context of partial dopaminergic depletion. To this end, we tested the effect of levodopa (l‐dopa), pergolide (a mixed D2/D1 agonist) and lisuride (a D2 agonist) on S/W recordings in MPTP‐treated mice, in comparison with controls. Our results showed that dopaminergic compounds modify S/W amounts in both control and MPTP mice. Wakefulness amounts are greater in MPTP mice after l‐dopa (50 mg kg−1) and lisuride (1 mg kg−1) injections compared with control mice. Moreover, the paradoxical sleep latency was significantly longer in MPTP mice after high‐dose l‐dopa administration. Our observations suggest that the actions of both l‐dopa and lisuride on S/W differ slightly in MPTP mice relative to controls. Hence, MPTP‐induced partial DA depletion may modulate the effect of dopaminergic compounds on S/W regulation.

The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory

Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions.

The effects of serotoninergic, noradrenergic, cholinergic and dopaminergic drugs on vigilance states in MPTP-treated mice

Sleep/wakefulness disorders are frequent in Parkinsons disease. Although the causes have yet to be established, it is known that dopaminergic neuronal lesions modulate paradoxical sleep (PS) regulation structures containing serotonin, noradrenaline and acetylcholine. Our previous vigilance state studies have revealed an increase in the amount of PS over the nyctohemeral period in the MPTP-treated mouse model of Parkinsons disease. The aim of the present work was to compare the effect of drugs modulating serotonin (citalopram), noradrenaline (desipramine), acetylcholine (arecoline) and dopamine (GBR 12909) neurotransmission on sleep/wakefulness patterns in MPTP mice and control mice. Citalopram reduced the amount of PS in MPTP and control mice to the same extent. Desipramine also induced a PS reduction, which was less pronounced in MPTP mice than in control mice. Arecoline increased the amount of PS in MPTP mice but not in controls. GBR 12909 induced a PS reduction (for the highest dose) more pronounced in MPTP mice than in control animals. Given that the responsiveness of MPTP mice differs markedly from that of controls, our study suggests that MPTP can alter sleep/wakefulness neurotransmission systems. Dysfunction of the latter may be responsible for PS disorders in MPTP mice.

Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson’s Disease Stages?

Introduction Magnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson’s disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD. Methods Twenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients. Results The R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages. Conclusion Each pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease.

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

In Parkinsons disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.

AMP-activated protein kinase is essential for the maintenance of energy levels during synaptic activation

Summary Although the brain accounts for only 2% of the total body mass, it consumes the most energy. Neuronal metabolism is tightly controlled, but it remains poorly understood how neurons meet their energy demands to sustain synaptic transmission. Here we provide evidence that AMP-activated protein kinase (AMPK) is pivotal to sustain neuronal energy levels upon synaptic activation by adapting the rate of glycolysis and mitochondrial respiration. Furthermore, this metabolic plasticity is required for the expression of immediate-early genes, synaptic plasticity, and memory formation. Important in this context, in neurodegenerative disorders such as Alzheimer disease, dysregulation of AMPK impairs the metabolic response to synaptic activation and processes that are central to neuronal plasticity. Altogether, our data provide proof of concept that AMPK is an essential player in the regulation of neuroenergetic metabolic plasticity induced in response to synaptic activation and that its deregulation might lead to cognitive impairments.