Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2

Thau, Nadine; Jungnickel, Julia; Knippenberg, Sarah; Ratzka, Andreas; Dengler, Reinhard; Petri, Susanne; Grothe, Claudia

doi:10.1016/j.nbd.2012.04.008

Cited by 33 publications

(42 citation statements)

References 68 publications

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“…The whole ventral horn of the spinal cord was photographed at 20× magnification using a Zeiss Axioskop 2 microscope. Large neurons, with a cell body area ≥200 μm 2 and a definable cytoplasm with a nucleus and nucleolus (Thau et al, 2012) were then counted using Neurolucida software (MBF Bioscience, USA).…”

Section: Methodsmentioning

confidence: 99%

Spinal cord pathology is ameliorated by P2X7 antagonism in SOD1-G93A mouse model of amyotrophic lateral sclerosis

Apolloni¹,

Amadio²,

Parisi

et al. 2014

Disease Models &Amp; Mechanisms

109

115

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In recent years there has been an increasing awareness of the role of P2X7, a receptor for extracellular ATP, in modulating physiopathological mechanisms in the central nervous system. In particular, P2X7 has been shown to be implicated in neuropsychiatry, chronic pain, neurodegeneration and neuroinflammation. Remarkably, P2X7 has also been shown to be a ‘gene modifier’ in amyotrophic lateral sclerosis (ALS): the receptor is upregulated in spinal cord microglia in human and rat at advanced stages of the disease; in vitro, activation of P2X7 exacerbates pro-inflammatory responses in microglia that have an ALS phenotype, as well as toxicity towards neuronal cells. Despite this detrimental in vitro role of P2X7, in SOD1-G93A mice lacking P2X7, the clinical onset of ALS was significantly accelerated and disease progression worsened, thus indicating that the receptor might have some beneficial effects, at least at certain stages of disease. In order to clarify this dual action of P2X7 in ALS pathogenesis, in the present work we used the antagonist Brilliant Blue G (BBG), a blood-brain barrier permeable and safe drug that has already been proven to reduce neuroinflammation in traumatic brain injury, cerebral ischemia-reperfusion, neuropathic pain and experimental autoimmune encephalitis. We tested BBG in the SOD1-G93A ALS mouse model at asymptomatic, pre-symptomatic and late pre-symptomatic phases of disease. BBG at late pre-onset significantly enhanced motor neuron survival and reduced microgliosis in lumbar spinal cord, modulating inflammatory markers such as NF-κB, NADPH oxidase 2, interleukin-1β, interleukin-10 and brain-derived neurotrophic factor. This was accompanied by delayed onset and improved general conditions and motor performance, in both male and female mice, although survival appeared unaffected. Our results prove the twofold role of P2X7 in the course of ALS and establish that P2X7 modulation might represent a promising therapeutic strategy by interfering with the neuroinflammatory component of the disease.

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Section: Methodsmentioning

confidence: 99%

Spinal cord pathology is ameliorated by P2X7 antagonism in SOD1-G93A mouse model of amyotrophic lateral sclerosis

Apolloni¹,

Amadio²,

Parisi

et al. 2014

Disease Models &Amp; Mechanisms

109

115

View full text Add to dashboard Cite

show abstract

“…qRT-PCR was performed with cDNA from 50 ng total RNA and TaqMan®Fast Universal Master Mix (Applied Biosystems) on a StepOnePlus instrument (Applied Biosystems) under the following standard conditions: 95°C for 20 s, followed by 40 cycles of 95°C for 1 s and 60°C for 20 s. The relative gene expression was calculated via the comparative Ct method as previously described by K. Livak (Applied Biosystems User Bulletin #2, 2001). Ct values were normalized to Hrtp1 and used to calculate the relative gene expression using the 2 −ΔΔCt method [29].…”

Section: Methodsmentioning

confidence: 99%

“…Based on previous studies assessing MSC effects in vitro and in vivo , we therefore aimed to find out, whether expression of growth factors, cytokines and chemokines previously found to be modified by MSC and of particular interest with regard to ALS pathophysiology and therapy was influenced by MSC CM in our in vitro models [10], [12], [23], [24], [25]. Protective effects of growth factors, such as CNTF (ciliary neurotrophic factor), GDNF (glial cell line-derived neurotrophic factor), IGF-1 (insulin-like growth factor 1), FGF2 (basic fibroblast growth factor 2) and VEGF (vascular endothelial growth factor) [26], [27], [28], [29], [30] have been shown in rodent models of ALS. We therefore studied whether MSC CM could induce their expression in astrocytes and NSC-34 cells.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

et al. 2013

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Administration of mesenchymal stromal cells (MSC) improves functional outcome in the SOD1G93A mouse model of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) as well as in models of other neurological disorders. We have now investigated the effect of the interaction between MSC and motor neurons (derived from both non-transgenic and mutant SOD1G93A transgenic mice), NSC-34 cells and glial cells (astrocytes, microglia) (derived again from both non-transgenic and mutant SOD1G93A ALS transgenic mice) in vitro. In primary motor neurons, NSC-34 cells and astrocytes, MSC conditioned medium (MSC CM) attenuated staurosporine (STS) - induced apoptosis in a concentration-dependent manner. Studying MSC CM-induced expression of neurotrophic factors in astrocytes and NSC-34 cells, we found that glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) gene expression in astrocytes were significantly enhanced by MSC CM, with differential responses of non-transgenic and mutant astrocytes. Expression of Vascular Endothelial Growth Factor (VEGF) in NSC-34 cells was significantly upregulated upon MSC CM-treatment. MSC CM significantly reduced the expression of the cytokines TNFα and IL-6 and iNOS both in transgenic and non-transgenic astrocytes. Gene expression of the neuroprotective chemokine Fractalkine (CX3CL1) was also upregulated in mutant SOD1G93A transgenic astrocytes by MSC CM treatment. Correspondingly, MSC CM increased the respective receptor, CX3CR1, in mutant SOD1G93A transgenic microglia. Our data demonstrate that MSC modulate motor neuronal and glial response to apoptosis and inflammation. MSC therefore represent an interesting candidate for further preclinical and clinical evaluation in ALS.

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“…The whole ventral horn of the spinal cord was photographed at ×20 magnification with Zeiss Axioskop 2 microscope. Large neurons, with cell bodies ≥200 μm 2 and a definable cytoplasm with a nucleus and nucleolus [25] were then counted using Neurolucida software (MBF Bioscience, USA), and the data were normalized with respect to wild-type mice, where the number of healthy motor neurons was assumed as 100 %.…”

Section: Nissl Stainingmentioning

confidence: 99%

Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2014

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Mutations in the Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) gene underlie 14-23 % of familial and 1-7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1(G93A) mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic clemastine administration in SOD1(G93A) mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, clemastine is able to modify several activation parameters of SOD1(G93A) microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.

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Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2

Cited by 33 publications

References 68 publications

Spinal cord pathology is ameliorated by P2X7 antagonism in SOD1-G93A mouse model of amyotrophic lateral sclerosis

Spinal cord pathology is ameliorated by P2X7 antagonism in SOD1-G93A mouse model of amyotrophic lateral sclerosis

Therapeutic Potential of Mesenchymal Stromal Cells and MSC Conditioned Medium in Amyotrophic Lateral Sclerosis (ALS) - In Vitro Evidence from Primary Motor Neuron Cultures, NSC-34 Cells, Astrocytes and Microglia

Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

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