Anti-neuroinflammatory effects of DPTP, a novel synthetic clovamide derivative in in vitro and in vivo model of neuroinflammation

Lim, Hyung-Woo; Park, Jeong-In; More, Sandeep Vasant; Park, Ju‐Young; Kim, Byungwook; Jeon, Saebom; Yun, Yang; Park, Eun-Jung; Yoon, Seo Hyun; Choi, Dong‐Kug

doi:10.1016/j.brainresbull.2015.01.004

Cited by 21 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies employing the MPTP animal model of PD have also shown NADPH oxidase activation, increased iNOS expression and elevated pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α (Nagatsu et al, 2000; Wang et al, 2009; Lofrumento et al, 2011; Lim et al, 2015). Moreover, nitric oxide ( • NO) generated by iNOS and derived from activated glial cells is believed to contribute to neurodegenerative diseases such as AD, PD, HIV-associated dementia, HD and ALS (Galea et al, 1992; Ghosh et al, 2009).…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…[27][28][29][30][31] Its expression can be induced by specific treatment, such as jasmonic acid, 32 and, finally, the molecule can be synthetized. 16,[33][34][35] Herein we have demonstrated that clovamide treatment of hCPCs could decrease the levels of ROS accumulated within the CPCs after an oxidative stress, which are then responsible for cell apoptosis. ROS, namely O 2 .-, H 2 O 2 , and OH, are produced in biological systems because of the redox reactions and are now considered second messengers, being responsible for the maintenance of the physiological cellular redox balance, governing cellular homeostasis.…”

Section: Discussionmentioning

confidence: 89%

Clovamide protects cardiac progenitor cells from H2O2-induced oxidative stress

Antonini¹,

Colangelo²,

Oltolina³

et al. 2018

JABB

View full text Add to dashboard Cite

show abstract

“…LPS activation renders microglia ameboid, induces several pro-and antiinflammatory signaling molecules (Lim et al, 2015;Zhu et al, 2014) and neurotoxic substances through binding to the CD14/MD-2/Toll-like receptor 4-complex (Fricker et al, 2012;Tokes et al, 2011), and gives rise, among others, to cell spreading by interfering with the organization of the actin cytoskeleton through the alteration of integrin clustering (Abram and Lowell, 2009). Microglia activation was shown to involve the signaling pathways nuclear factor B and p38 mitogenactivated protein kinase (Bachstetter et al, 2007;Cao et al, 2014;Kaushal et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Calmodulin inhibition regulates morphological and functional changes related to the actin cytoskeleton in pure microglial cells

Szabó

Dulka

Gulya

2016

Brain Research Bulletin

View full text Add to dashboard Cite

The roles of calmodulin (CaM), a multifunctional intracellular calcium receptor protein, as concerns selected morphological and functional characteristics of pure microglial cells derived from mixed primary cultures from embryonal forebrains of rats, were investigated through use of the CaM antagonists calmidazolium (CALMID) and trifluoperazine (TFP). The intracellular localization of the CaM protein relative to phalloidin, a bicyclic heptapeptide that binds only to filamentous actin, and the ionized calcium-binding adaptor molecule 1 (Iba1), a microglia-specific actin-binding protein, was determined by immunocytochemistry, with quantitative analysis by immunoblotting. In unchallenged and untreated (control) microglia, high concentrations of CaM protein were found mainly perinuclearly in ameboid microglia, while the cell cortex had a smaller CaM content that diminished progressively deeper into the branches in the ramified microglia. The amounts and intracellular distributions of both Iba1 and CaM proteins were altered after lipopolysaccharide (LPS) challenge in activated microglia. CALMID and TFP exerted different, sometimes opposing, effects on many morphological, cytoskeletal and functional characteristics of the microglial cells. They affected the CaM and Iba1 protein expressions and their intracellular localizations differently, inhibited cell proliferation, viability and fluid-phase phagocytosis to different degrees both in unchallenged and in LPS-treated (immunologically challenged) cells, and differentially affected the reorganization of the actin cytoskeleton in the microglial cell cortex, influencing lamellipodia, filopodia and podosome formation. In summary, these CaM antagonists altered different aspects of filamentous actin-based cell morphology and related functions with variable efficacy, which could be important in deciphering the roles of CaM in regulating microglial functions in health and disease.

show abstract

Anti-neuroinflammatory effects of DPTP, a novel synthetic clovamide derivative in in vitro and in vivo model of neuroinflammation

Cited by 21 publications

References 61 publications

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

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

Clovamide protects cardiac progenitor cells from H2O2-induced oxidative stress

Calmodulin inhibition regulates morphological and functional changes related to the actin cytoskeleton in pure microglial cells

Contact Info

Product

Resources

About