Waiting for PARIS—A Biological Target in Search of a Drug

Wyse, Richard K.H.; Stott, Simon; Mursaleen, Leah; Matthews, Helen; Dawson, Valina L.; Dawson, Ted M.

doi:10.3233/jpd-212945

Cited by 3 publications

(2 citation statements)

References 76 publications

(51 reference statements)

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“…An early review of MAO-A/B inhibitory compounds in tobacco smoke identified several compounds that are reversible and either selective or non-selective inhibitors, including 2,3,6-trimethyl- 1,4-naphthoquinone; 2-naphthylamine; norharman; harman; farnesol, and farnesylacetone ( Sari and Khalil, 2015 ). While there has been some discussion of the potential role of these MAO-inhibiting substances on diseases such as Parkinson’s ( Dome et al, 2010 ; Wyse et al, 2021 ) via changes in dopaminergic systems ( Abuhamdah et al, 2016 ); there have been few studies to date that demonstrate reliable cognitive effects of those specific compounds found in tobacco products.…”

Section: Resultsmentioning

confidence: 99%

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms

Taylor

Carrasco

et al. 2022

Front. Neurosci.

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Attention-deficit/hyperactivity disorder (ADHD) is a relatively commonly occurring neurodevelopmental disorder affecting approximately 5% of children and young people. The neurobiological mechanisms of ADHD are proposed to particularly center around increased dopamine receptor availability related to associated symptoms of reduced attention regulation and impulsivity. ADHD is also persistent across the lifespan and associated with a raft of impulsive and health-risk behaviors including substance abuse and smoking. Research highlighting the potentially significant levels of monoamine oxidase (MAO) inhibitory properties in tobacco smoke and e-cigarettes may provide a mechanism for increased tobacco smoke dependence among those with ADHD, in addition to the role of nicotine.AimThis scoping review aimed to establish evidence for the above neurobiological pathway between smoking and ADHD symptom-alleviation or “self-medication” with the inclusion of the mechanism of MAO-inhibitors indirect increasing dopamine in the brain.MethodologyScoping review methodologies were employed in this review selected to synthesize multiple sources of empirical research to identify current gaps in the knowledge base and identify key characteristics of research data related to a phenomenon. Databases searched included OVID MEDLINE(R), Embase, Cochrane, PsycINFO and SCOPUS limited to 2000 onward and empirically validated, peer-reviewed research.FindingsThere is support for the role of MAO-inhibition on greater reinforcement of smoking for individuals with ADHD through a greater impact on dopaminergic availability than nicotine; potentially moderating ADHD symptoms.ConclusionGreater support for a “self-medication” model of ADHD and smoking includes not only nicotine but also MAO-inhibitors as dopamine agonists contained in cigarettes and e-cigarettes.

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Section: Resultsmentioning

confidence: 99%

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms

Taylor

Carrasco

et al. 2022

Front. Neurosci.

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“…The parkin-interacting substrate (PARIS) plays an important role in the reduction of mitochondrial mass and activity by repressing the transcriptional expression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) [ 273 , 274 ]. It also contributes to the pathologic α-synuclein-induced degeneration, thus accelerating the loss of dopamine neurons.…”

Section: Neuroprotective Potential Of β-Caryophyllene and Carnosic Ac...mentioning

confidence: 99%

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

2022

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Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

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Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons

Wang

Chen

Xiao

et al. 2023

Preprint

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Mutations and loss of activity in the protein kinase PINK1 play a role in the pathogenesis of Parkinsons disease (PD). PINK1 regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy), fission, fusion, transport, and biogenesis. Defects in mitophagy are though to play a predominant role in the loss of dopamine (DA) neurons in PD. Here we show that, although there are defects in mitophagy in human DA neurons lacking PINK1, mitochondrial deficits induced by the absence of PINK1 are primarily due to defects in mitochondrial biogenesis. Upregulation of PARIS and the subsequent down regulation of PGC-1 alpha accounts for the mitochondrial biogenesis defects. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without impacting the deficits in mitophagy due to the absence of PINK1. These results highlight the importance mitochondrial biogenesis in the pathogenesis of PD due to inactivation or loss of PINK1 in human DA neurons.

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Waiting for PARIS—A Biological Target in Search of a Drug

Cited by 3 publications

References 76 publications

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons

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