Manganese Dipyridoxyl Diphosphate: MRI Contrast Agent with Antioxidative and Cardioprotective Properties?

Brurok, Heidi; Ardenkjær-Larsen, Jan Henrik; Hansson, Georg; Skarra, Sissel; Berg, Kirsti; Karlsson, Jan; Laursen, I.; Jynge, Per

doi:10.1006/bbrc.1998.0131

Cited by 63 publications

(44 citation statements)

References 20 publications

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“…Furthermore, ONC may cause the release of free radicals that cause oxidative stress and cellular damage (37). Mn 2ϩ has the ability to act as a scavenger, protecting RGCs against oxidative stress (38,39). Since more RGCs survive after serial intravitreal injection of 150 nmol MnCl 2 at 0 and 20 dpl than after ONC alone, it seems that MEMRI safely can be used to study regeneration in the ON after ONC in the manner presented here.…”

Section: ؉ Toxicity On Rgc Survival After Onc and Png Implantationmentioning

confidence: 88%

Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Thuen

Olsen

Berry

et al. 2008

Magnetic Resonance Imaging

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Purpose:To evaluate manganese (Mn 2ϩ )-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) as tools for detection of axonal injury and regeneration after intravitreal peripheral nerve graft (PNG) implantation in the rat optic nerve (ON). Materials and Methods:In adult Fischer rats, retinal ganglion cell (RGC) survival was evaluated in Flurogold (FG) back-filled retinal whole mounts after ON crush (ONC), intravitreal PNG, and intravitreal MnCl 2 injection (150 nmol) at 0 and 20 days post lesion (dpl). MEMRI and echoplanar DTI (DTI-EPI) was obtained of noninjured ON one day after intravitreal MnCl 2 injection, and at 1 and 21 dpl after ONC, intravitreal PNG, and intravitreal MnCl 2 injections given at 0 and 20 dpl. GAP-43 immunohistochemistry was performed after the last MRI.Results: ONC reduced RGC density in retina by 94% at 21 dpl compared to noninjured ON without MnCl 2 injections. Both intravitreal PNG and intravitreal MnCl 2 injections improved RGC survival in retina, which was reduced by 90% (ONCϩMnCl 2 ), 82% (ONCϩPNG), and 74% (ONCϩPNGϩMnCl 2 ) compared to noninjured ON. DTIderived parameters (fractional anisotropy [FA], mean diffusivity, axial diffusivity , and radial diffusivity Ќ ) were unaffected by the presence of Mn 2ϩ in the ON. At 1 dpl, CNR MEMRI and were reduced at the injury site, while at 21 dpl they were increased at the injury site compared to values measured at 1 dpl. GAP-43 immunoreactive axons were present in the ON distal to the ONC injury site. Conclusion:MEMRI and DTI enabled detection of functional and structural degradation after rat ON injury, and there was correlation between the MRI-derived and immunohistochemical measures of axon regeneration. UNLIKE AXONS IN THE PERIPHERAL NERVOUS SYS-TEM, those in the central nervous system (CNS) of adult mammals do not regenerate after injury (1,2). Failure to regenerate is attributed to a combination of axon growth arrest by myelin-associated and scar-derived inhibitory molecules (3,4), and to the absence of growth-promoting neurotrophic factors in the adult CNS (5). Several therapeutic interventions have been tested in animal models to try to promote axon regeneration in the adult mammalian CNS, including neutralizing inhibitory molecules by bacterial enzyme chondroitinase ABC (6) and administration of growthpromoting factors released, for example, from olfactory ensheathing cells and stem cells (7,8). One method that has been shown to have an effect in an optic nerve (ON) animal model is the intravitreal implantation of a peripheral nerve graft (PNG) after ON transection. Schwann cells in the PNG produce trophic factors that promote both retinal ganglion cell (RGC) survival and axon growth through the putative inhibitory environment of the injured ON, as documented in several studies (9 -11). Most studies detect regenerating axons in the CNS using traditional axon tracing techniques (e.g.,

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Section: ؉ Toxicity On Rgc Survival After Onc and Png Implantationmentioning

confidence: 88%

Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Thuen

Olsen

Berry

et al. 2008

Magnetic Resonance Imaging

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“…Mangafodipir has pharmacological effects, including anti-oxidant [4,9,14], antitumour [8,9] and anti-apoptotic activities [10]. Additionally, the mangafodipir metabolites MnPLED and Dp-dp have also been shown to possess anti-oxidant and metal ion-chelating effects [7].…”

Section: Discussionmentioning

confidence: 99%

“…Potential use of mangafodipir for cardiovascular MRI was suggested, as it exerts pharmacological effects such as vascular relaxation and protection against oxidative stress [4]. Mangafodipir was marketed as Teslascan and supplied as sterile aqueous solution with a recommended adult dose of 5 µmol/kg body weight [5].…”

Section: Introductionmentioning

confidence: 99%

Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7β-Hydroxycholesterol-Induced Cell Death

Laskar¹,

Andersson

Li³

2013

Pharmacology

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Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7β-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 µm), MnPLED (100 µmol/l) or Dp-dp (100 µmol/l) for 8 h and then exposed to 7β-OH (28 µmol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7β-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7β-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7β-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7β-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.

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“…Therefore, the use of a Mn 2+ -releasing contrast agents such as Mn-DPDP may be a promising multipurpose approach. In addition to the suggested therapeutic effects of antioxydative myocardial protection (Brurok et al 1999;Karlsson et al 2001), with noninvasive MRI, more functional information about myocardial metabolism and MV might be acquired by depicting differential patterns of T1 relaxation changes in relation to regional coronary flow, cellular cation uptake and retention, ion channel function and metabolism in patients with coronary heart disease. However, all these encouraging outcomes are still experimental.…”

Section: Intracellular Contrast Agentsmentioning

confidence: 99%

MR Contrast Agents for Cardiac Imaging

2011

Clinical Cardiac MRI

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Manganese Dipyridoxyl Diphosphate: MRI Contrast Agent with Antioxidative and Cardioprotective Properties?

Cited by 63 publications

References 20 publications

Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7β-Hydroxycholesterol-Induced Cell Death

MR Contrast Agents for Cardiac Imaging

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Manganese Dipyridoxyl Diphosphate: MRI Contrast Agent with Antioxidative and Cardioprotective Properties?

Cited by 63 publications

References 20 publications

Combination of Mn2+‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Combination of Mn2+‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7β-Hydroxycholesterol-Induced Cell Death

MR Contrast Agents for Cardiac Imaging

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Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Combination of Mn²⁺‐enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve