Noradrenaline and Parkinson's Disease

Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease

Circadian Clock Protein Content and Daily Rhythm of Locomotor Activity Are Altered after Chronic Exposure to Lead in Rat

Lead exposure has been reported to produce many clinical features, including parkinsonism. However, its consequences on the circadian rhythms are still unknown. Here we aimed to examine the circadian rhythms of locomotor activity following lead intoxication and investigate the mechanisms by which lead may induce alterations of circadian rhythms in rats. Male Wistar rats were injected with lead or sodium acetate (10 mg/kg/day, i.p.) during 4 weeks. Both groups were tested in the “open field” to quantify the exploratory activity and in the rotarod to evaluate motor coordination. Then, animals were submitted to continuous 24 h recordings of locomotor activity under 14/10 Light/dark (14/10 LD) cycle and in complete darkness (DD). At the end of experiments, the clock proteins BMAL1, PER1-2, and CRY1-2 were assayed in the suprachiasmatic nucleus (SCN) using immunohistochemistry. We showed that lead significantly reduced the number of crossing in the open field, impaired motor coordination and altered the daily locomotor activity rhythm. When the LD cycle was advanced by 6 h, both groups adjusted their daily locomotor activity to the new LD cycle with high onset variability in lead-intoxicated rats compared to controls. Lead also led to a decrease in the number of immunoreactive cells (ir-) of BMAL1, PER1, and PER2 without affecting the number of ir-CRY1 and ir-CRY2 cells in the SCN. Our data provide strong evidence that lead intoxication disturbs the rhythm of locomotor activity and alters clock proteins expression in the SCN. They contribute to the understanding of the mechanism by which lead induce circadian rhythms disturbances

Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA) and the serotonergic (5-HT) system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA) and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD) patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected

Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA) and the serotonergic (5-HT) system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA) and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson's disease (PD) patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.The project was funded by grants from the Government of the Basque Country (IT 747-13), the Spanish Government [SAF2016-77758-R (AEI/FEDER, UE)] and by the Fondation de France. PDD acknowledges the support given by the cooperation for science and technology (COST) action CM15120. PDD and AB acknowledge the support of the Centre National de la Recherche Scientifique

Involvement of Basal Ganglia Network in Motor Disabilities Induced by Typical Antipsychotics

BACKGROUND:Clinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor side-effects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, alpha-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat. METHODS AND FINDINGS:The motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats. We show that alpha-flupentixol induced EPS paralleled by a decrease in the firing rate and a disorganization of the firing pattern in both substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). Furthermore, alpha-flupentixol induced an increase in the firing rate of globus pallidus (GP) neurons. In the striatum, we recorded two populations of medium spiny neurons (MSNs) after their antidromic identification. At basal level, both striato-pallidal and striato-nigral MSNs were found to be unaffected by alpha-flupentixol. However, during electrical cortico-striatal activation only striato-pallidal, but not striato-nigral, MSNs were found to be inhibited by alpha-flupentixol. Together, our results suggest that the changes in STN and SNr neuronal activity are a consequence of increased neuronal activity of globus pallidus (GP). Indeed, after selective GP lesion, alpha-flupentixol failed to induce EPS and to alter STN neuronal activity. CONCLUSION:Our study reports strong evidence to show that hypokinesia and catalepsy induced by alpha-flupentixol are triggered by dramatic changes occurring in basal ganglia network. We provide new insight into the key role of GP in the pathophysiology of APD-induced EPS suggesting that the GP can be considered as a potential target for the treatment of EPS

Deep Brain Stimulation in Moroccan Patients With Parkinson's Disease: The Experience of Neurology Department of Rabat

Introduction: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known as a therapy of choice of advanced Parkinson's disease. The present study aimed to assess the beneficial and side effects of STN DBS in Moroccan Parkinsonian patients.Material and Methods: Thirty five patients underwent bilateral STN DBS from 2008 to 2016 in the Rabat University Hospital. Patients were assessed preoperatively and followed up for 6 to 12 months using the Unified Parkinson's Disease Rating Scale in four conditions (stimulation OFF and ON and medication OFF and ON), the levodopa-equivalent daily dose (LEDD), dyskinesia and fluctuation scores and PDQ39 scale for quality of life (QOL). Postoperative side effects were also recorded.Results: The mean age at disease onset was 42.31 ± 7.29 years [28–58] and the mean age at surgery was 54.66 ± 8.51 years [34–70]. The median disease duration was 11.95 ± 4.28 years [5–22]. Sixty-three percentage of patients were male. 11.4% of patients were tremor dominant while 45.71 showed akinetic-rigid form and 42.90 were classified as mixed phenotype. The LEDD before surgery was 1200 mg/day [800-1500]. All patients had motor fluctuations whereas non-motor fluctuations were present in 61.80% of cases. STN DBS decreased the LEDD by 51.72%, as the mean LEDD post-surgery was 450 [188-800]. The UPDRS-III was improved by 52.27%, dyskinesia score by 66.70% and motor fluctuations by 50%, whereas QOL improved by 27.12%. Post-operative side effects were hypophonia (2 cases), infection (3 cases), and pneumocephalus (2 cases).Conclusion: Our results showed that STN DBS is an effective treatment in Moroccan Parkinsonian patients leading to a major improvement of the most disabling symptoms (dyskinesia, motor fluctuation) and a better QOL

Les Anticancéreux: nouvelles approches thérapeutiques.

Une meilleure compréhension des mécanismes de l’oncogenèse a permis l’émergence de nouvelles stratégies thérapeutiques ces dernières années. De nombreuses molécules dont certaines actuellement encore en cours de développement font figure de propositions thérapeutiques innovantes et porteuses d’espoirs, c’est notamment le cas de : - La thérapie génique: puisque la conversion génétique même d’un simple gène peut reverser la tumorogènicité d’un cancer et ce malgré sa composante polygénique ou bien induire l’apoptose de certaines cellules cancéreuses. - Des thérapies ciblées: nous nous sommes intéressés à celles ciblant les récepteurs des facteurs de croissance de type insuline (lGF) et les cyclines soit par inhibition de la prolifération induite par IGFI ou IGFII, soit par arrêt du cycle cellulaire et stimulation de l'apoptose de diverses lignées cancéreuses. - Des thérapies ciblant le CTLA-4 et les Toll-like récepteurs: par modulation immune des signaux de costimulation en immunothérapie menant a une induction de réponses immunitaires efficaces. - De la thérapie par sénescence par le biais de molécules pro-apoptotiques visant a palier au potentiel prolifératif illimité des cellules cancéreuses en induisant leur apoptose. Notre travail a pour but de mettre en évidence l’intérêt de ces nouvelles thérapeutiques ainsi que leur mécanismes, qui nous l’espérons, serons en mesure d’enrichir l’arsenal thérapeutique de l’oncologue dans un futur très proche

ETUDE DE L'EVOLUTION DES CHANGEMENTS PATHOLOGIQUES DE L'ACTIVITE DES NEURONES DU NOYAU SUBTHALAMIQUE ET RECHERCHE DES STRUCTURES A L'ORIGINE DE CES CHANGEMENTS DANS UN MODELE DE LA MALADIE DE PARKINSON CHEZ LE RAT (DOCTORAT (NEUROSCIENCES))

GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF