Dose Formulation and Analysis of Diapocynin

Luchtefeld, Ron; Luo, Rensheng; Stine, Keith J.; Alt, Mikaela L.; Chernovitz, Patricia A.; Smith, Robert E.

doi:10.1021/jf072792n

Cited by 35 publications

(37 citation statements)

References 13 publications

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“…Recent studies have shown conversion of apocynin to diapocynin (apocynin dimer) in vivo, which prevents the assembly and activation of the NADPH oxidase complex [13]. Additionally, diapocynin is 13-fold more lipophilic than apocynin [22]. Here, we show that diapocynin inhibits MPTP-induced activation and expression of both iNOS and gp91phox in activated glial cells, suggesting that diapocynin has anti-inflammatory properties against neurotoxic stress.…”

Section: Discussionmentioning

confidence: 54%

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Ghosh

Joseph

Anantharam

et al. 2012

J Neuroinflammation

107

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BackgroundParkinson’s disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.MethodsBoth pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin.ResultsOral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD.ConclusionsCollectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.

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Section: Discussionmentioning

confidence: 54%

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Ghosh

Joseph

Anantharam

et al. 2012

J Neuroinflammation

107

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“…Recently, we have shown that diapocynin (apocynin dimer) reduced neuroinflammation and protected dopaminergic neurons in the MPTP mouse model of PD (Ghosh et al, 2012b) by preventing the assembly and activation of the NADPH oxidase complex. Diapocynin is 13-fold more lipophilic than the monomer apocynin (Luchtefeld et al, 2008). Later, we demonstrated that diapocynin successfully prevented motor deficits in the leucine-rich repeat kinase 2 (LRRK2 R1441G ) transgenic mouse (Dranka et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

Ghosh

Langley

Harischandra

et al. 2016

J Neuroimmune Pharmacol

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Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.

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“…One such compound listed as NADPH oxidase inhibitor is apocyanin, (4-hydroxy-3-methoxyacetophenone), a plantderived antioxidant originally isolated from the medicinal plant Picrorhiza kurroa [16]. It is lipophyllic in nature and can easily cross cell membrane [17]. Being a selective inhibitor of NADPH oxidase, it can block the production of superoxide and oxygen free radicals that typically accompany inflammation.…”

Section: Introductionmentioning

confidence: 99%

Apocyanin, a Microglial NADPH Oxidase Inhibitor Prevents Dopaminergic Neuronal Degeneration in Lipopolysaccharide-Induced Parkinson’s Disease Model

Sharma

Nehru

2015

Mol Neurobiol

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Microglia-associated inflammatory processes have been strongly implicated in the development and progression of Parkinson's disease (PD). Specifically, microglia are activated in response to lipopolysaccharide (LPS) and become chronic source of cytokines and reactive oxygen species (ROS) production. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex is responsible for extracellular as well as intracellular production of ROS by microglia and its expression is upregulated in PD. Therefore, targeting NADPH oxidase complex activation using an NADPH oxidase inhibitor, i.e., apocyanin seems to be an effective approach. The aim of present study was to investigate the neuroprotective effects of apocyanin in a LPS-induced PD model. LPS (5 μg) was injected intranigral and apocyanin was administered daily at a dose of 10 mg/kg b.wt (i.p.) during the experiment. LPS when injected into the substantia nigra (SN) reproduced the characteristic hallmark features of PD in rats. It elicited an inflammatory response characterized by glial cell activation (Iba-1, GFAP). Furthermore, LPS upregulated the gene expression of nuclear factor-κB (NFκB), iNOS, and gp91PHOX and resulted in an elevated total ROS production as well as NADPH oxidase activity. Subsequently, this resulted in dopaminergic loss as depicted by decreased tyrosine hydroxylase (TH) expression with substantial loss in neurotransmitter dopamine and its metabolites, whereas treatment with apocyanin significantly reduced the number of glial fibrillary acidic protein (GFAP) and Iba-1-positive cells in LPS-treated animals. It also mitigated microglial activation-induced inflammatory response and elevation in NADPH oxidase activity, thus reducing the extracellular as well as intracellular ROS production. The present study indicated that targeting NADPH oxidase can inhibit microglial activation and reduce a broad spectrum of toxic factors generation (i.e., cytokines, ROS, and reactive nitrogen species [RNS]), thus offering a hope in halting the progression of PD.

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Dose Formulation and Analysis of Diapocynin

Cited by 35 publications

References 13 publications

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

Apocyanin, a Microglial NADPH Oxidase Inhibitor Prevents Dopaminergic Neuronal Degeneration in Lipopolysaccharide-Induced Parkinson’s Disease Model

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