Imatinib mesylate ameliorates the dystrophic phenotype in exercised mdx mice

Bizário, João Carlos da Silva; Cerri, Daniel Giuliano; Rodrigues, Lílian Cataldi; Oliveira, Gislane Lelis Vilela de; Nomizo, Auro; Araújo, Daniela; Fukuhara, Paula Sakemi; Caldas, Juliana; Castro, Fabíola Attié de; Costa, María

doi:10.1016/j.jneuroim.2009.05.006

Cited by 29 publications

(26 citation statements)

References 50 publications

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“…Such effects appear to depend on the inhibition exerted by the drug on the activation of both c-Abl and PDGFR on both peritoneal macrophages and muscleresident fibroblasts (Huang et al, 2009). Similar observations have been independently reported by another group (Bizario et al, 2009). Both reports suggest that treatment with IM exerts a marked anti-inflammatory effect, lowering the levels of proinflammatory cytokines.…”

Section: Wwwintechopencomsupporting

confidence: 92%

“…The results show that while able to improve muscle phenotype in mdx mice (Bizario et al, 2009;Huang et al, 2009), IM is ineffective in preventing muscle wasting in tumor-bearing animals, although it likely exert an anti-inflammatory action, as shown by the protection against spleen hypertrophy. These observations may suggest that the tyrosine kinases blocked by IM might not be involved in the pathogenesis of muscle wasting in cancer cachexia.…”

Section: Wwwintechopencommentioning

confidence: 84%

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Protein Kinases in the Pathogenesis of Muscle Wasting

Penna¹,

Costamagna²,

Camperi³

et al. 2012

Advances in Protein Kinases

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Section: Wwwintechopencomsupporting

confidence: 92%

Section: Wwwintechopencommentioning

confidence: 84%

Protein Kinases in the Pathogenesis of Muscle Wasting

Penna¹,

Costamagna²,

Camperi³

et al. 2012

Advances in Protein Kinases

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“…Treatment of rats with imatinib after bleomycin administration results in a strong reduction in TGF-β1 gene expression [35]. Bizario et al [36] showed that imatinib treatment reduces the levels of TGF-β cytokine and mRNA in mdx mice. In a murine lupus model, renal TGF-β expression was reduced by imatinib treatment [37].…”

Section: Discussionmentioning

confidence: 99%

Effect of Imatinib on Airway Smooth Muscle Thickening in a Murine Model of Chronic Asthma

Rhee

Kim

Park

et al. 2011

Int Arch Allergy Immunol

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Background: Asthma is characterized by airway hyperresponsiveness (AHR), inflammation and remodeling. The tyrosine kinase inhibitor imatinib mesylate was developed to inhibit BCR-ABL kinase activity; however, it also has potent inhibitory activity against the c-Kit and platelet-derived growth factor receptors. The present study aimed to determine whether imatinib suppresses airway smooth muscle (ASM) remodeling and whether its effect is associated with growth factors such as transforming growth factor (TGF)-β1 and stem cell factor (SCF). Methods: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with imatinib during the OVA challenge. Results: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and AHR compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of imatinib significantly inhibited the development of AHR, eosinophilic inflammation and, importantly, ASM remodeling in mice chronically exposed to OVA. Imatinib treatment significantly reduced the levels of interleukin-4, -5 and -13. In addition, TGF-β1 and SCF were significantly reduced in the imatinib-treated animals. Conclusions: These results suggest that imatinib administration can prevent not only airway inflammation, but also airway remodeling associated with chronic allergen challenge. Imatinib may provide a clinically attractive therapy for chronic severe asthma.

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“…It is an orally administered drug with antineoplastic, anti-inflammatory and antifibrotic capabilities that has been shown to be well tolerated by adults in the treatment of many cancers [312,313]. Two studies in mdx mice have demonstrated that Imatinib could be beneficial in reducing necrosis, inflammation, fibrosis, and improving muscle strength [249,314].…”

Section: Tgf-mentioning

confidence: 99%

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Fairclough

Perkins²,

Davies³

2012

CGT

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DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy. Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restricted to management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 with the discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology of DMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towards the identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition to gene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacological approaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs are also being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect, including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue, utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB, TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements. There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulating Ca2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tackling the complex pathogenesis of this multifaceted disorder.

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Imatinib mesylate ameliorates the dystrophic phenotype in exercised mdx mice

Cited by 29 publications

References 50 publications

Protein Kinases in the Pathogenesis of Muscle Wasting

Protein Kinases in the Pathogenesis of Muscle Wasting

Effect of Imatinib on Airway Smooth Muscle Thickening in a Murine Model of Chronic Asthma

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

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