Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

Liang, Li‐Ping; Huang, Jie; Fulton, Ruth; Pearson-Smith, Jennifer N.; Day, Brian J.; Patel, Manisha

doi:10.1016/j.taap.2017.04.004

Cited by 13 publications

(18 citation statements)

References 46 publications

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“…2A ) resulted safe and well tolerated in a Phase I clinical trial on Amyotrophic Lateral Sclerosis patients and is now pursued as a radioprotector by the pharmaceutical company Aeolus Pharmaceuticals [ 87 ]. More importantly in the context of PD, the same company is currently working on optimization of manufacturing process and formulation of another Mn-porphyrin, AEOL 11114, which shows promise in PD, being protective in a MPTP-based mouse model of PD [ 88 ]. Very interestingly, the molecule has been demonstrated to be orally active, to have relatively long plasma half-life, rapid absorption by the gastrointestinal tract, ability to penetrate the BBB, and can achieve therapeutically active concentrations in the brain [ 88 ].…”

Section: Superoxide Radical Dismutation and Therapeutic Implicationsmentioning

confidence: 99%

Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease

Lazzari¹,

Bubacco²,

Whitworth³

et al. 2018

Aging and disease

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Aging is the biggest risk factor for developing many neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). PD is still an incurable disorder and the available medications are mainly directed to the treatment of symptoms in order to improve the quality of life. Oxidative injury has been identified as one of the principal factors involved in the progression of PD and several indications are now reported in the literature highlighting the prominent role of the superoxide radical in inducing neuronal toxicity. It follows that superoxide anions represent potential cellular targets for new drugs offering a novel therapeutic approach to cope with the progression of the disease. In this review we first present a comprehensive overview of the most common cellular reactive oxygen and nitrogen species, describing their cellular sources, their potential physiological roles in cell signalling pathways and the mechanisms through which they could contribute to the oxidative damage. We then analyse the potential therapeutic use of SOD-mimetic molecules, which can selectively remove superoxide radicals in a catalytic way, focusing on the classes of molecules that have therapeutically exploitable properties.

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Section: Superoxide Radical Dismutation and Therapeutic Implicationsmentioning

confidence: 99%

Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease

Lazzari¹,

Bubacco²,

Whitworth³

et al. 2018

Aging and disease

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show abstract

“…Nanozyme is one type of nanomaterials with enzyme-like characteristics [162,163]. SOD and catalase mimics can detoxify various ROS, such as superoxide anion (O 2− ) and H 2 O 2 , which have been used in oxidative stress associated diseases [164][165][166]. Metalloporphyrin can imitate catalase, SOD, and other natural antioxidant enzymes [166].…”

Section: Nanozyme For Therapy Of Acute Liver Failurementioning

confidence: 99%

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

Jin

Wang

et al. 2020

Nano-Micro Lett.

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Highlights This review focuses on the therapeutic mechanisms, targeting strategies of various nanomaterials in acute liver failure, and recent advances of diverse nanomaterials for acute liver failure therapy, diagnosis, and imaging. This review provides an outlook on the applications of nanomaterials, especially on the new horizons in acute liver failure therapy, and inspires broader interests across various disciplines. Abstract Acute liver failure (ALF), a fatal clinical disease featured with overwhelming hepatocyte necrosis, is a grand challenge in global health. However, a satisfactory therapeutic option for curing ALF is still absent, other than liver transplantation. Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF. The liver can sequester most of nanoparticles from blood circulation, which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases. Nanobiomaterials can enhance the bioavailability of free drugs, thereby significantly improving the therapeutic effects in ALF. Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells. In addition, stimuli-responsive, optical, or magnetic nanomaterials exhibit great potential in the therapeutical, diagnostic, and imaging applications in ALF. Therefore, therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy, diminish adverse systemic effects, and offer a multifunctional theranostic platform. Nanobiomaterial holds excellent significance and prospects in ALF theranostics. In this review, we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF. We highlight recent developments of diverse nanomedicines for ALF therapy, diagnosis, and imaging. Furthermore, the challenges and future perspectives in the theranostics of ALF are also discussed.

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“…All reagents, including 6-OHDA hydrochloride were purchased from Sigma Aldrich (Sigma-Aldrich Corp., St. Louis, MO). AEOL11207 and AEOL11114 (see Figure 1) were characterized as previously described (Liang et al, 2007;Liang et al, 2017).…”

Section: Reagentsmentioning

confidence: 99%

“…Sections were counterstained with cresyl violet following TH staining. The number of TH-positive neurons at every fourth section was quantified with stereological analysis following previously described methods (West, 1999;Liang et al, 2007;Liang et al, 2017). Stereological method was used to determining the number of DA neurons using a computer-assisted were measured using a rat multiplex pro-inflammatory cytokine array kit (V-PLEX) from…”

Section: Tyrosine Hydroxylase Immunohistochemistry Staining and Sterementioning

confidence: 99%

“…Meso-porphyrin metalloporphyrins are synthetic small molecule catalytic antioxidants with at least four distinct antioxidant properties due to their ability to scavenge O2 -• , H2O2, ONOO − and lipid peroxides (Day, 2004). Our laboratory has previously shown that lipophilic metalloporphyrins such as AEOL11207 and AEOL11114, protect against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mouse model (Liang et al, 2007;Liang et al, 2017). The acute MPTP mouse model replicates many features of PD and is one of the classical models used to elucidate the pathogenesis of dopaminergic neuronal death.…”

Section: Introductionmentioning

confidence: 99%

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Optimization of Lipophilic Metalloporphyrins Modifies Disease Outcomes in a Rat Model of Parkinsonism

Liang

Fulton

Bradshaw‐Pierce

et al. 2021

J Pharmacol Exp Ther

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Oxidative stress plays a crucial role in the pathogenesis of Parkinson's disease (PD) and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e. disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114 was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24 % and 25 %, respectively at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA) induced neurotoxic damage, including dopamine depletion, cytokine production and microglia activation in the striata, dopaminergic neuronal loss in the substantial nigra, oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity one to three days post-lesioning suggesting disease-modifying properties and translational potential for PD.

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Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

Cited by 13 publications

References 46 publications

Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease

Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

Optimization of Lipophilic Metalloporphyrins Modifies Disease Outcomes in a Rat Model of Parkinsonism

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