Proliferation of microglial cells induced by 1‐methyl‐4‐phenylpyridinium in mesencephalic cultures results from an astrocyte‐dependent mechanism: role of granulocyte macrophage colony‐stimulating factor

Abstract

There is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/ glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD) and is associated with a progressive loss of dopaminergic neurones in the substantia nigra pars compacta (SNpc). The ensuing diminution of the dopamine (DA) concentration in the main projection area of these neurones, the caudate nucleus and the putamen, induces the characteristic motor symptoms of the disease, which include bradykinesia/ akinesia, rest tremor and rigidity (Agid 1991).Whereas the cause of PD remains unknown, the mechanisms of neuronal death are beginning to be understood. Thus, it is becoming increasingly probable that inflammation plays an important role in the pathogenesis of this neurodegenerative disorder (Hirsch et al. 2003). This hypothesis is supported by several lines of evidence. First, an increased number of major histocompatibility complex class II-positive microglial cells has been found in the SNpc of patients who developed PD (McGeer et al. 1988) or suffered from parkinsonism due to accidental administration of the DA toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al. 1999). The same observation was also made in the SNpc of MPTPtreated mice (Liberatore et al. 1999)

Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats

“…Different experiments were carried out using cultures of astrocytes or dopaminergic neurons (cell line MES 23.5) or microglial cells (N9), taking into account that dopaminergic neurotoxins such as MPP þ act directly on dopaminergic neurons and astrocytes but indirectly on microglia (Henze et al, 2005), and that the previous experiments indicated that ER-a is responsible for the lack of neuroprotection of estrogen after LTED.…”

Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity

“…In the brain, TNF␣ is a potent signal for the activation of both microglia and astroglia (76), and like IL-1␤, TNF␣ also robustly activates CN/NFAT signaling in astrocytes (26). GM-CSF appears to play a crucial role in amplifying the local microglial response in areas of neuronal damage and/or protein aggregation (77). Indeed, GM-CSF and other colonystimulating factors are powerful signals for microglial activation and subsequent release of IL-1␤ (78).…”

Up-regulation of heme oxygenase-1 as a resistance mechanism against MPP+ induced cytotoxicity in Raw 264.7 macrophages

“…MPP + could stimulate the production of free radicals or ROS in neuronal cells; thus, this agent is commonly employed in neurological studies to induce oxidative and/or inflammatory injury [15][16][17] . Recently, several studies have demonstrated that MPP + stimulates the production of the superoxide radical in vitro and induces cell death in glial cells 18,19 . Here, we employed Raw 264.…”