CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson\u27s disease

BACKGROUND: Parkinson\u27s 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\u27s 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 neurodegeneration following a neurotoxic insult. METHODS: The 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. RESULTS: As 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. CONCLUSION: These 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

CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson\u27s disease

BACKGROUND: Parkinson\u27s 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\u27s 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 neurodegeneration following a neurotoxic insult. METHODS: The 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. RESULTS: As 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. CONCLUSION: These 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

Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

<p>Abstract</p> <p>Background</p> <p>Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.</p> <p>Results</p> <p>We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.</p> <p>Conclusion</p> <p>The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.</p

A spirulina-enhanced diet provides neuroprotection in an α-synuclein model of Parkinson's disease.

Inflammation in the brain plays a major role in neurodegenerative diseases. In particular, microglial cell activation is believed to be associated with the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). An increase in microglia activation has been shown in the substantia nigra pars compacta (SNpc) of PD models when there has been a decrease in tyrosine hydroxylase (TH) positive cells. This may be a sign of neurotoxicity due to prolonged activation of microglia in both early and late stages of disease progression. Natural products, such as spirulina, derived from blue green algae, are believed to help reverse this effect due to its anti-inflammatory/anti-oxidant properties. An adeno-associated virus vector (AAV9) for α-synuclein was injected in the substantia nigra of rats to model Parkinson's disease and to study the effects of spirulina on the inflammatory response. One month prior to surgeries, rats were fed either a diet enhanced with spirulina or a control diet. Immunohistochemistry was analyzed with unbiased stereological methods to quantify lesion size and microglial activation. As hypothesized, spirulina was neuroprotective in this α-synuclein model of PD as more TH+ and NeuN+ cells were observed; spirulina concomitantly decreased the numbers of activated microglial cells as determined by MHCII expression. This decrease in microglia activation may have been due, in part, to the effect of spirulina to increase expression of the fractalkine receptor (CX3CR1) on microglia. With this study we hypothesize that α-synuclein neurotoxicity is mediated, at least in part, via an interaction with microglia. We observed a decrease in activated microglia in the rats that received a spirulina- enhanced diet concomitant to neuroprotection. The increase in CX3CR1 in the groups that received spirulina, suggests a potential mechanism of action

Effect of AAV9-synuclein treatment on the LC.

<p>Quantification of TH immunohistochemistry in the locus coeruleus using unbiased stereological techniques. Graph shows that 4 months following α-synuclein gene transfer there is a significant loss of TH positive cells in the LC (2-way ANOVA did not show a significant interaction, but did reveal main effects of diet and treatment, and bonferonni post-hoc revealed a difference between the α-synuclein control and diet treated groups, p<0.01). Treatment with spirulina was able to prevent the loss of TH positive cells in the locus coeruleus. Asterisk denotes significance (**p<0.01 vs control GFP; *p<0.05 vs control α-synuclein).</p

Gene transfer efficiency is not affected by spirulina.

<p>Quantification of GFP positive cells in the SN. Stereological estimates of the number of GFP positive cells in the SN one month after gene transfer. There was no significant effect of the spirulina diet on numbers of GFP transduced cells (Student’s two-talied t-test).</p

Effect of spirulina on TH immunoreactive cells in the SNpc.

<p>TH positive cells in the SNpc after 1 or 4 months of α-synuclein expression. Cells were counted using unbiased stereological counting techniques. (A) One month after α-synuclein gene transfer, there was a significant decrease in TH positive cells as compared to GFP control (N = 12–18/group). The spirulina diet group lesioned with α-synuclein (N = 12) had greater numbers of TH positive cells compared to the control diet group lesioned with α-synuclein (N = 18). There was a diet by vector group interaction in the two way ANOVA analysis [F = 5.569, p<0.01]. (B) Results at four months were similar. There was a similar loss of TH positive cells and protective effect of spirulina. Two-way ANOVA yielded a main effect of diet (F = 81.3), and a main effect of vector group (F = 45.5; p<0.01), although without a significant interaction. Bonferonni post-hoc tests comparing NIH 31 GFP (N = 10) vs NIH 31 synuclein (N = 8) and NIH31 synuclein vs spirulina synuclein (N = 8) groups were significant). Asterisk denotes significance (*P<0.05; **p<0.01).</p

Effect of spirulina on NeuN immunoreactive cells in the SNpc.

<p>NeuN positive cells in the SNpc after 1 or 4 months of α-synuclein expression. At 1 month, there was a decrease in NeuN positive cells in the SN, mirroring the loss of TH positive cells in Fig. 1. This confirms cell loss rather than loss of TH expression. The effect was similar at 4 months of expression (B). There was neuroprotection in the groups that received a diet enhanced with spirulina at both intervals. Two-way ANOVA yielded a significant interaction of diet and vector treatment at both time points [1 month F = 6.931, df = 1; 4 months F = 8.899 df = 1]. (*p<0.05; **p<0.01) after Bonferonni's post-hoc.</p