A Novel Mitochondrially-Targeted Apocynin Derivative Prevents Hyposmia and Loss of Motor Function in the Leucine-Rich Repeat Kinase 2(LRRK2R1441G) Transgenic Mouse Model of Parkinson’s Disease

Dranka, Brian P.; Gifford, Alison; McAllister, Donna; Zielonka, Jacek; Joseph, Joy; Kalyanaraman, Balaraman

doi:10.1016/j.freeradbiomed.2013.10.494

Cited by 2 publications

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“…Using the same rationale of boosting the antioxidant capacity of mitochondria, Dranka and colleagues tested a mitochondrial‐permeable form of the antioxidant apocynin (mito‐apocynin) in the transgenic mouse model of PD (Dranka et al ., ). Significant deterioration in physical ability and increased hyposmia in the mice was prevented by treatment with mito‐apocynin (3 mg·kg −1 ) three times a week.…”

Section: Mitochondrial Dysfunction As a Source Of Ros And Rnsmentioning

confidence: 97%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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Section: Mitochondrial Dysfunction As a Source Of Ros And Rnsmentioning

confidence: 97%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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“…To determine whether mice exhibited hyposmia, a promising marker for PD severity (Roos et al, 2019), mice were tested on the buried treat test (Dranka et al, 2014). Three days prior to testing, mice were habituated to fruit-scented cereal treats.…”

Section: Buried Treat Testmentioning

confidence: 99%

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

Mazza

Nguyen

Beilina

et al. 2020

Preprint

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Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson's disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 month Rab29 -/and double (Lrrk2 -/-/Rab29 -/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Significance statement:Genetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson's disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects across in vivo and post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.

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A Novel Mitochondrially-Targeted Apocynin Derivative Prevents Hyposmia and Loss of Motor Function in the Leucine-Rich Repeat Kinase 2(LRRK2R1441G) Transgenic Mouse Model of Parkinson’s Disease

Cited by 2 publications

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Redox‐based therapeutics in neurodegenerative disease

Redox‐based therapeutics in neurodegenerative disease

Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo

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