The role of microglia–lymphocyte interaction in PD neuropathology

Neuroinflammation 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

THE INTERRELATIONSHIP OF DOPAMINE AND NORADRENALINE IN THE PREFRONTAL CORTEX : FROM PHYSIOOLGY TO THERAPY

Dopamine 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. Available Options: Version: Download: Windows - Englis

Modulating microglia activity with PPAR-gamma agonists: a promising therapy for Parkinson's disease?

A 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 MPTP/probenecid model of progressive Parkinson's disease

Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and a chronic loss of motor functions. The investigation of progressive degenerative mechanisms and possible neuroprotective approaches for PD depends upon the development of an experimental animal model that reproduces the neuropathology observed in humans. This chapter describes the generation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. This model displays key features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase-positive neurons and DA levels in the brain. The MPTPp mouse model provides an important tool for the study of mechanisms contributing to the pathological dysfunction of PD at the cellular and whole animal level

Adenosine A2A receptors and Parkinson's disease

The drug treatment of Parkinson’s disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A2A receptors (A2AARs) provide a viable target. A2AARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A2AAR antagonists can modulate γ-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A2AAR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A2AAR antagonist istradefylline reduces “off” time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A2AAR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A2AAR antagonists in central nervous system disorders, and their full utility is still to be uncovered

The 6-hydroxydopamine model of Parkinson's disease

The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable topical tool used chiefly in modeling Parkinson's disease in the rat. The classical method of intracerebral infusion of 6-OHDA, involving a massive destruction of nigrostriatal dopaminergic neurons, is largely used to investigate motor and biochemical dysfunctions in Parkinson's disease. Subsequently, more subtle models of partial dopaminergic degeneration have been developed with the aim of revealing finer motor deficits. The present review will examine the main features of 6-OHDA models, namely the mechanisms of neurotoxin-induced neurodegeneration as well as several behavioural deficits and motor dysfunctions, including the priming model, modeled by this means. An overview o the most recent morphological and biochemical findings obtained with the 6-OHDA model will also be provided, particular attention being focused on the newly investigated intracellular mechanisms at the striatal level (e.g., A(2A) and NMDA receptors, PKA, CaMKII, ERK kinases, as well as immediate early genes, GAD67 and peptides). Thanks to studies performed in the 6-OHDA model, all these mechanisms have now been hypothesised to represent the site of pathological dysfunction at cellular level in Parkinson's disease

Intranigral injections of glutamate antagonists modulate dopamine D1-mediated turning behavior and striatal c-fos expression

The 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

Alterations in GAD67, dynorphin and enkephalin mRNA in striatal output neurons following priming in the 6-OHDA model of Parkinson’s disease

In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, administration of a dopaminergic agonist sensitizes rats to a subsequent administration of dopaminergic drugs given days apart (priming). In situ hybridization was used to evaluate changes on striatal gene expression of rats primed three days previously with either L-dopa, SKF38393 or quinpirole. Double labeling was used to identify the neuronal population in which such alterations occurred. GAD67 and enkephalin mRNA were increased by the lesion whereas dynorphin mRNA was decreased as compared to the intact striatum. Priming with L-dopa and SKF38393 significantly increased GAD67 mRNA in the lesioned striatum and reversed dynorphin mRNA reduction, as compared to drug-naive rats, whereas quinpirole failed to produce any effect. Enkephalin mRNA was not affected by priming. Results suggest that 6-OHDA lesion-induced adaptive changes on striatal gene expression are modified by priming. Priming brings striatal output neurons to a higher level of activity, which may explain the sensitized behavioral response observed following a dopaminergic agonist challenge. These changes are in relation to the different types of dopamine agonists utilized and suggest that modifications in gene expression induced by priming might be predictive of the dyskinetic potential of a dru

Do PPAR-Gamma Agonists Have a Future in Parkinson's Disease Therapy?

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR)-γ agonists commonly used as insulin-sensitizing drugs for the treatment of type 2 diabetes. In the last decade, PPAR-γ agonists have received increasing attention for their neuroprotective properties displayed in a variety of neurodegenerative diseases, including Parkinson's disease (PD), likely related to the anti-infammatory activity of these compounds. Recent studies indicate that neuroinflammation, specifically reactive microglia, plays important roles in PD pathogenesis. Moreover, after the discovery of infiltrating activated Limphocytes in the substantia nigra (SN) of PD patients, most recent research supports a role of immune-mediated mechanisms in the pathological process leading to chronic neuroinflammation and dopaminergic degeneration. PPAR-γ are highly expressed in cells of both central and peripheral immune systems, playing a pivotal role in microglial activation as well as in monocytes and T cells differentiation, in which they act as key regulators of immune responses. Here, we review preclinical evidences of PPAR-γ-induced neuroprotection in experimental PD models and highlight relative anti-inflammatory mechanisms involving either central or peripheral immunomodulatory activity. Specific targeting of immune functions contributing to neuroinflammation either directly (central) or indirectly (peripheral) may represent a novel therapeutic approach for disease modifying therapies in PD