CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease

Abstract

BackgroundParkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 is constitutively expressed. It is not known if addition of exogenous CX3CL1 beyond otherwise physiologically normal levels could decrease microglia activation and thereby minimize the secondary neurodegeration following a neurotoxic insult.MethodsThe intrastriatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson disease, was used to test the hypothesis that exogenous CX3CL1 could be neuroprotective. Treatment with recombinant CX3CL1 was delivered to the striatum by an osmotic minipump for 28 days beginning 7 days after the initial insult. Unbiased stereological methods were used to quantify the lesion size in the striatum, the amount of neuronal loss in the substantia nigra, and the amount of microglia activation.ResultsAs hypothesized, CX3CL1 was able to suppress this microglia activation. The reduced microglia activation was found to be neuroprotective as the CX3CL1 treated rats had a smaller lesion volume in the striatum and importantly significantly fewer neurons were lost in the CX3CL1 treated rats.ConclusionThese findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic target for many neurodegenerative diseases, including Parkinson disease and Alzheimer disease, where inflammation plays an important role.

Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

“…9 The neuroprotective role of the CX3CL1-CX3CR1 pathway has also been observed in other neurodegenerative and neuroinflammatory diseases. 11,12 In addition, in vitro studies have shown that both soluble and membrane-bound fractalkines attenuate lipopolysaccharideinduced microglial activation, and fractalkine suppresses microglial activation through the PI3K pathway. 13 In contrast to these observations, in the models of CNS ischemia/ reperfusion, lesion development was protected in both CX3CR1-deficient mice 14 and CX3CL1-deficient mice, 15 and the protection was related to reduced IL-1b and TNF-a expression and decreased leukocyte infiltration in those mice.…”

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…The role of CX3CR1 in the control of neuroinflammation has been extensively studied in the CX3CR1-EGFP mouse line. Although the consequences of CX3CR1 deletion in microglia largely depend on the mouse model used, the overall idea is that a lack of CX3CR1 leads to a hyperactivity of microglia in the diseased brain, thereby unleashing potential neurotoxic properties [113,189,190].…”

Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

“…Interestingly, CXCR1-KO mice show evidence of prolonged activation of microglia after LPS administration, with associated prolonged microglial expression of IL-1b and prolonged expression of depressive-like behavior compared with wild-type mice (Corona et al, 2010). Of note, chronic administration of CX3CL1 into the striatum of rats administered 6-hydroxydopamine to induce a Parkinson'slike syndrome led to suppressed microglial activation and a fewer loss of neurons, suggesting a neuroprotective role for CX3CL1 (Pabon et al, 2011).…”