1,721,033 research outputs found
The role of microglia–lymphocyte interaction in PD neuropathology
No full textNeuroinflammation is a major pathological component of Parkinson’s disease. Chronic microglial
response dominates the histopathology of parkinsonian substantia nigra. In addition infiltrated T lymphocytes
in the brain parenchyma and abnormally activated T lymphocytes in the blood of patients with
Parkinson’s disease have been described. In less than a decade the concept of Parkinson’s disease neuropathology
has been profoundly revised. It is now evident that neurotoxic microgliosis is only part of a
more complex dysregulation of the immune response, that involves both the central and peripheral
immune systems
Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease
No full textIntroduction: Current treatment of Parkinson’s disease (PD) is limited to
symptomatic dopaminergic therapy, while no interventions have been shown
to slow down disease progression.
Areas covered: The following article highlights a group of PPAR-g agonists
called thiazolidinediones (TZDs), which are currently being tested for a putative
disease-modifying benefit in PD, using pioglitazone as a prototypic
compound. PPAR-g is highly expressed in neurons of the substantia nigra
and CNS immune cells. Preclinical data in rodent and primate support an
effect of TZDs in preventing and/or arresting neurodegeneration and development
of motor symptoms. Although no data on the neuroprotective effect
of TZDs is currently available, a clinical trial is ongoing where the primary
objective is to assess pioglitazone’s impact on the progression of PD. The trial
is also evaluating the drug’s safety concerns.
Expert opinion: The efficacy data from clinical trials must be carefully
weighed against the safety concerns. However, given the solid preclinical
data, and since the safety data are not yet fully conclusive and limited to
the diabetic population, PPAR-g research in PD can continue with caution.
Ideally, drug discovery and development efforts will lead to the identification
of new compounds with reduced risk of peripheral side effect
Lack of a role for the D3 receptor in clozapine induction of c-fos demonstrated in D3 dopamine receptor-deficient mice
No full textModulating microglia activity with PPAR-gamma agonists: a promising therapy for Parkinson's disease?
No full textA dysregulated response of the neuroimmune system is a main contributor to the progression of neurodegeneration in Parkinson's disease (PD). Recent findings suggest that protracted activating stimuli including α-synuclein, drive microglia to acquire maladaptive functions and to assume a harmful phenotype that prevail over a restorative one. Based on this concept, disease-modifying drugs should be aimed at targeting suppression of harmful-activated microglia and the associated production of neurotoxic molecules as pro-inflammatory cytokines, while sparing or inducing beneficial-activated microglia. In this study, we review current evidence in support of the beneficial effect of targeting peroxisome-proliferator-activated receptor (PPAR)-γ to achieve neuroprotection in PD. PPAR-γ agonists as rosiglitazone and pioglitazone are currently gaining increasing attention as promising disease-modifying drugs in this disorder. Early in vitro studies, followed by studies in in vivo models of PD, have provided convincing evidence that these drugs inhibit neuronal degeneration likely by selectively targeting the expression of neurotoxic factors in reactive microglia. Potential therapeutic application has been corroborated by recent report of pioglitazone neuroprotective activity in a non-human primate model of PD. All together, preclinical evidence have prompted the translation of pioglitazone to a phase II clinical trial in early P
The interrelationship between dopamine and noradrenaline in the prefrontal cortex: From physiology to therapy
No full textDopamine release and noradrenaline release in the prefrontal cortex are required for the control of neurobiological functions, whose alteration is considered to be critical in the aetiology of widespread diseases such as schizophrenia, depression and attention deficit hyperactivity disorder (ADHD). The therapeutic agents used in treating these diseases may either increase or reduce dopamine and noradrenaline transmission by acting at receptor or at reuptake site level. The capacity of noradrenaline terminals to capture dopamine by means of the noradrenaline transporter (NET) has opened up new perspectives on the mechanism of action of norepinephine reuptake blockers such as long-established antidepressants or the new therapeutic agent for ADHD, atomoxetine. On the other hand, the hypothesis that dopamine and noradrenaline may be co-released from noradrenaline terminals in the prefrontal cortex suggests an additional interpretation of experimental evidence on the regulation of both dopamine and noradrenaline release through the pre-synaptic 2 receptor. Moreover, the high affinity of noradrenaline for the dopamine D4 receptor and its role in the prefrontal cortex, as well as the capacity of atypical antipsychotics to increase both noradrenaline and dopamine release in this area of the brain, support the hypothesis that dopamine-noradrenaline interaction may have a crucial role in the aetiology and in the therapy of schizophrenia. This chapter will illustrate and discuss the evidence for and against the hypothesis that there is an interdependence between dopamine and noradrenaline transmission in the prefrontal cortex, taking into consideration some recent evidence from our laboratory on the effect of chronic treatment with methylphenidate and atomoxetine on dopamine and noradrenaline release in the prefrontal cortex
How reliable is the behavioural evaluation of dyskinesia in animal models of Parkinson's disease?
No full textIn spite of the current availability of several pharmacological therapies for the treatment of Parkinson's disease, side effects are invariably manifested during long-term treatment Dyskinesia, wearing-off and on-off are among the most disabling side effects produced by the dopamine precursor L-dihydroxyphenylalanine and, to a lesser degree, by other pharmacological treatments based on dopamine receptor agonism. Evaluation of the side effects, in particular dyskinesia, produced by antiparkinsonian drug treatments, therefore represents a critical issue in drug validation prior to a clinical trial. Moreover, a reliable model of dyskinesia is a fundamental requirement for the study of the as yet unknown mechanisms at the basis of this severely disabling side effect. The present review aims to provide a critical evaluation of the validity, reliability and utility of animal models of dyskinesia. In the first part of this review, we present a brief overview of the different models of Parkinson's disease focusing on those utilized for the evaluation of dyskinetic movements, then proceed to critically examine the turning behaviour model in an attempt to assess the way in which it has influenced the evaluation of drugs utilized in the treatment of Parkinson's disease. Subsequently, the various models of dyskinesia are reviewed and conclusions are drawn as to how the environment in which experiments are performed can influence the behaviour observed
Alterazioni nei livelli striatali di RNAm della GAD67, dinorfina e enkefalina, in seguito a priming con agonisti dopaminergici nel modello di morbo di parkinson della 6-ohda
No full text
Intranigral injections of glutamate antagonists modulate dopamine D1-mediated turning behavior and striatal c-fos expression
No full textThe contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists was studied in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigro-striatal pathway. Local infusion into the SN of the 6-OHDA lesioned side of NMDA glutamate antagonists MK 801 and CPP or the AMPA antagonist NBQX at doses inducing none or minimal behavioral effects, significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. High doses of MK 801 or CPP infused into the SN produced intense contralateral turning per-se but induced only sparse c-fos expression in the lesioned CPu. The results show that a depression of SN pars reticulata efferent neurons, potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists
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