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Metalloporphyrin in CNS Injuries

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Redox-Active Therapeutics

Abstract

This chapter discusses the therapeutic potential of cationic Mn(III)-substituted N-pyridyl- and N,N’-imidazolylporphyrins (MnPs) for improving neurological function and histological outcome after central nervous system (CNS) injuries including ischemic and hemorrhagic stroke and traumatic brain and spinal cord injury. Reactive oxygen and nitrogen species are induced during CNS injuries and activate various cellular signals. As such, they are major factors leading to DNA fragmentation, lipid peroxidation, and cell death and significantly impact recovery. MnPs have a biologically compatible metal-centered reduction potential, which allow them to couple with redox-based signaling species acting as both oxidant and antioxidants; in either case they produce therapeutic effects. Such MnPs catalytically remove superoxide, i.e., oxidize it and reduce it, while mimicking superoxide dismutase (SOD) enzymes. They are also able to reduce other species including peroxynitrite, hypochlorite, carbonate anion, and lipid radicals. Yet, they oxidize cellular reductants; in particular oxidation of thiols may be relevant for their impact on signaling pathways in suppressing post-injury activation of cellular transcription factors and subsequent inflammatory responses. MnPs are currently the most effective antioxidants. The therapeutic window for efficacious treatment onset is wide in animal studies of transient cerebral ischemia. MnP efficacy was evident even when treatment began 6 h after reperfusion, which would be particularly important in clinical settings. Moreover, long-term efficacy was detected at 8 weeks in a survival study with continuous treatment for 1 week. The data on MnPs presented in this chapter were generated in multiple preclinical studies. These findings are expected to be pivotal to the development of MnP-based treatment for patients with CNS injury.

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Abbreviations

CO3 ∙− :

Carbonate anion radical

CNS:

Central nervous system

ECSOD:

Extracellular superoxide dismutase

EMSA:

Electromobility shift essay

FeP:

Fe(III) porphyrin

FeTE-2-PyP5+ :

Fe(III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin

FeTM-4-PyP5+ :

Fe(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin

FeTnHex-2-PyP5+ :

Fe(III) meso-tetrakis (N-N-hexylpyridinium-2-yl) porphyrin

FeTSPP3− :

Fe(III) meso-tetrakis(4-sulfonatophenyl)porphyrin

∙OH:

Hydroxyl radicals

8-OHdG:

8-Hydroxy-2′-deoxyguanosine

H2O2 :

Hydrogen peroxide

HClO:

Hypochlorous acid

ICV:

Intracerebroventricular

IL-6:

Interleukin-6

IP:

Intraperitoneal

IT:

Intrathecal

IV:

Intravenous

LDH:

Lactate dehydrogenase

MAP:

Mean arterial blood pressure

MCAO:

Middle cerebral artery occlusion

MnP:

Mn(III)-substituted N-pyridyl- and N,N′-imidazolylporphyrin

MnTDE-2-ImP5+ :

Mn(III) meso-tetrakis (N,N′-diethylimidazolium-2-yl) porphyrin

MnTE-2-PyP5+ :

Mn(III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin

MnTnHex-2-PyP5+ :

Mn(III) meso-tetrakis (N-n-hexylpyridinium-2-yl) porphyrin

MnTnOct-2-PyP5+ :

Mn(III) meso-tetrakis (N-n-octylpyridinium-2-yl) porphyrin

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor -kappa-B

∙NO:

Nitric oxide radical

∙NO2 :

Nitrogen dioxide radical

O2 ∙− :

Superoxide anion radical

OGD:

Oxygen glucose deprivation

ONOO− :

Peroxynitrite

PBS:

Phosphate-buffered saline

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SAH:

Subarachnoid hemorrhage

SOD:

Superoxide dismutase

Sq:

Subcutaneous

TNF-α:

Tumor necrosis factor α

tPA:

Tissue plasminogen activator

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Authors and Affiliations

  1. Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, NC, 27710, USA

    Huaxin Sheng & David S. Warner

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  1. Huaxin Sheng
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  2. David S. Warner
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Correspondence to Huaxin Sheng .

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Editors and Affiliations

  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Sheng, H., Warner, D.S. (2016). Metalloporphyrin in CNS Injuries. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_24

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