Vascular endothelial cell injury and platelet embolism in Duchenne muscular dystrophy at the preclinical stage

Miike, Teruhisa; Sugino, Shigeto; Ohtani, Yoshinobu; Taku, Keiichi; Yoshioka, Ken

doi:10.1016/0022-510x(87)90007-4

Cited by 43 publications

(35 citation statements)

References 21 publications

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“…Global ischemic models and human clinicopathological material suggest that CA1 pyramidal neurons are particularly vulnerable to hypoxia and ischemiainduced cell injury and death (33)(34)(35) and that these pathologic reactions are associated with marked memory deficits (32) that are prominent in DMD patients (1)(2)(3). Individuals with DMD may be at increased risk for hypoxic and ischemic neuronal injury because they exhibit a CNS vasculopathy (17) and profound sleep-associated episodes of arterial oxygen desaturation (18,19). The enhanced neuronal loss may be cumulative and could contribute to the cognitive deficits that are associated with DMD patients.…”

Section: Discussionmentioning

confidence: 99%

“…Pathological studies of brains of cognitively impaired DMD patients have shown reductions in brain weight, preferential loss of neuronal populations that normally express dystrophin, and small cortical ischemic infarcts (16). In addition, DMD patients may be at increased risk for pathological periods of hypoxia during development because of the presence of a CNS vasculopathy (17) and profound sleep-associated episodes of arterial 02 desaturation (18,19). Therefore, we tested the hypothesis that absence of functional dystrophin may heighten the sensitivity of susceptible neuronal populations to hypoxia-induced neuronal injury, as assessed by the loss of synaptic transmission during hypoxia and the extent of recovery following reoxygenation.…”

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confidence: 99%

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Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

Mehler

Haas

Kessler

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CAl pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxiainduced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodiumdependent action potentials and low-threshold transient calcium conductances. These rindings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable.Duchenne muscular dystrophy (DMD) is a common, allelic, X chromosome-linked recessive neuromuscular disorder in which patients also exhibit significant cognitive and behavioral disabilities, including attention deficit disorders and infantile autism (1-3). In skeletal muscle, dystrophin, the DMD gene product, is a component of a multiunit protein complex that links intrinsic sarcolemmal proteins to the actin-based cytoskeleton (4-6). Significant alterations in calcium channel physiology and elevated intracellular calcium concentrations have been demonstrated in DMD myocytes and in the mdx mouse strain, a dystrophin-deficient genetic mouse model (7-10). In the central nervous system (CNS), a distinct dystrophin mRNA is transcribed from a separate upstream promoter (11-13), and the protein is confined to specific regions of neuronal somata and proximal dendrites (14). This suggests that dystrophin may serve a regional modulatory role in relation to specific ligand receptors or ion channel subclasses. Sustained increases in intracellular calcium concentrations have been proposed as a final common element in excitotoxic cascades leading to neuronal injury and death following periods of hypoxia or ischemia (15). Pathological studies of brains of cognitively impaired DMD patients have shown reductions in brain weight, preferential loss of neuronal populations that normally express dystrophin, and small cortical ischemic infarcts (16). In addition, DMD patients may be at increased risk for pathological periods of hypoxia during development because of the presence of a CNS vasculopathy (17) and profound sleep-associated episodes of arteria...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

Mehler

Haas

Kessler

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…A reduction in dystrophin induces deep alterations in muscular cells. Autoptic and clinical observations have established that visceral (see review by Nowak et al 1982) and vascular (Matsuishi et al 1982;Miike et al 1987) smooth muscle cells can also be affected during Duchenne muscular dystrophy. The availability of mdx mouse (Bulfield et al 1984), the genetic homologue of DMD, offers a useful opportunity to investigate the pathophysiology of this disease.…”

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confidence: 99%

Mechanical Properties of Smooth Muscle Portal Vein in Normal and Dystrophin‐Deficient (MDX) Mice

Mancinelli

Tonali

Romani

et al. 1999

Experimental Physiology

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Mechanical properties of the vascular smooth muscle from normal and dystrophin-deficient (mdx) mice were examined. Changes in resting and developed tensions in response to stretch were recorded in isolated portal vein. The vascular segments were elongated in 5 % increments of the 'in situ' length (Lr) up to 1.30Lr. The resting length-tension curves in male mdxmice were similar to normal mice, while a marked decrease in the slope of the curve was noted in female mdx mice. These findings were not affected by atropine, phentolamine, tetrodotoxin or [Ca2+] in the surrounding media. At Lr, the tension of isolated portal vein was characterized by spontaneous synchronized uniform force waves in normal mouse. In contrast, in mdxmouse portal veins an irregular motor pattern characterized by desynchronized force waves with a decrease of amplitude and an increase in frequency was recorded. Extension of the length of the portal vein segment did not increase the spontaneous phasic activity developed in female mdx mice although this was noted with male mdx mice and normal mice. Experiments with chemical depolarizing agents indicated that spontaneous myogenic excitation activated the great majority of vascular smooth muscle cells in normal mouse portal vein, whereas in mdx mice only a reduced number of these cells were excited suggesting that in the mdx mouse the intercellular electronic coupling is altered. In conclusion this study provides the first description of the mechanical activities of portal vein longitudinal muscle and shows that in mdx mice the motor activity is severely disrupted.

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“…Previous studies have demonstrated that NO-cGMP signalling, along with other vasoregulatory molecules, controls local blood flow in the muscle [486,487] and that lack of dystrophin and the associated DAPC causes a defect in blood flow to the muscle [484,488] that strongly correlates with the reduction in nNOS activity [467,484,488]. In addition to the widely studied muscular defects, various studies have also reported alterations in vascular pathology, vasodilative response and signalling downstream of nNOS in DMD [467,[489][490][491][492][493][494]. Irrespective of whether the attenuated blood flow is a cause or consequence of the initial membrane damage in DMD, the vasodilatory effects of PDE5 inhibitors could enhance blood flow to the muscle providing an additional angle through which to oppress the complex secondary pathology of DMD.…”

Section: No/cgmpmentioning

confidence: 95%

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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Vascular endothelial cell injury and platelet embolism in Duchenne muscular dystrophy at the preclinical stage

Cited by 43 publications

References 21 publications

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

Mechanical Properties of Smooth Muscle Portal Vein in Normal and Dystrophin‐Deficient (MDX) Mice

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

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