Leukotriene Signaling as a Target in α-Synucleinopathies

Strempfl, Katharina; Unger, Michael S.; Flunkert, Stefanie; Zurl, Andrea; Reitsamer, Herbert A.; Hutter‐Paier, Birgit; Aigner, Ludwig

doi:10.3390/biom12030346

Cited by 9 publications

(3 citation statements)

References 143 publications

(238 reference statements)

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“…According, decreased astrogliosis in the 5lipoxygenase de cient mice was previously reported (Chou et al 2013). These ndings give su cient reason to hypothesize that the 5-lipoxygenase/LTB 4 pathway might be a key regulator of glial cell activation (Stremp et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Differential dopamine-mediated effects in the 5-lipoxygenase deficient mice

Issy,

Pedrazzi,

Nascimento

et al. 2024

Preprint

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The role of 5-lipoxygenase/leukotrienes on the central nervous system has been considered in both physiological end pathological states. Investigating the interaction between 5-lipoxygenase/leukotrienes and the dopaminergic system may provide better understanding of dopamine-related pathologies. This study aimed to investigate motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotrienes-deficient mice. Pharmacological challenges of the dopaminergic system included amphetamine, apomorphine and reserpine treatment along with their respective effects on prepulse inhibition (PPI) response, general motor activity, and oral involuntary movements. Reserpine-treated mice were also investigated for their striatal glial markers’ expression (GFAP and Iba-1). 5-lipoxygenase/leukotrienes-deficient mice exhibited increased spontaneous locomotor activity, including horizontal and vertical exploratory activity, and stereotyped-like behavior compared to wild-type mice. This condition was attenuated by acute apomorphine treatment. Despite the absence of altered basal responses in the PPI there was a significant and selective decreased in susceptibility in amphetamine-induced PPI disruption in 5-lipoxygenase/leukotrienes-deficient mice. However, there was an increased vulnerability to reserpine-induced involuntary movements. There was no alteration in the basal expression of striatal GFAP and Iba-1 positive cells in 5-lipoxygenase/leukotrienes-deficient mice compared to wild-type mice. Reserpine treatment induced a significant increase in GFAP immunoreactivity in wild-type mice but this effect was absent in the 5-lipoxygenase deficient mice. The percentage of activated microglia was found to be significantly increased in reserpine-treated wild-type mice. This effect was absent in the 5-lipoxygenase/leukotrienes-deficient mice. Our results support the conception of a unique dopaminergic pathway phenotype in 5-lipoxygenase/leukotrienes-deficient mice. These findings suggest that leukotrienes may interfere with the orchestration of dopamine-mediated responses.

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Section: Discussionmentioning

confidence: 99%

Differential dopamine-mediated effects in the 5-lipoxygenase deficient mice

Issy,

Pedrazzi,

Nascimento

et al. 2024

Preprint

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“…These mediators, especially their cysteinylated derivatives, are better known as the endogenous lipids involved in the pathogenesis of asthma, and the target of widely used drugs such as Montelukast, Pranlukast and Zafirlukast, which act as antagonists to CysLT1, the receptor engaging the cysteinylated derivative of leukotriene (LT) B4 [110]. However, these eicosanoids have also been recently involved in brain pathologies, including those deriving from misfolded αsyn; indeed, not only leukotrienes are strong activators of astrocytes and microglial cells (as reviewed in [111]), but an increase in the activity of 5-LOX, i.e., the enzyme catalyzing the rate-limiting step in leukotrienes synthesis, has also been found in patients and animal models of DLB [112]. Thus, recent papers have investigated the effect of the Montelukast in DLB, showing beneficial effects on the clinical phenotype and a reduction in the alphα-Syn load in the brains of DLB animal models [112].…”

Section: Eicosanoidsmentioning

confidence: 99%

Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies

Sanluca,

Spagnolo,

Mancinelli

et al. 2024

Metabolites

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The present review provides a comprehensive examination of the intricate dynamics between α-synuclein, a protein crucially involved in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease and multiple system atrophy, and endogenously-produced bioactive lipids, which play a pivotal role in neuroinflammation and neurodegeneration. The interaction of α-synuclein with bioactive lipids is emerging as a critical factor in the development and progression of neurodegenerative and neuroinflammatory diseases, offering new insights into disease mechanisms and novel perspectives in the identification of potential biomarkers and therapeutic targets. We delve into the molecular pathways through which α-synuclein interacts with biological membranes and bioactive lipids, influencing the aggregation of α-synuclein and triggering neuroinflammatory responses, highlighting the potential of bioactive lipids as biomarkers for early disease detection and progression monitoring. Moreover, we explore innovative therapeutic strategies aimed at modulating the interaction between α-synuclein and bioactive lipids, including the development of small molecules and nutritional interventions. Finally, the review addresses the significance of the gut-to-brain axis in mediating the effects of bioactive lipids on α-synuclein pathology and discusses the role of altered gut lipid metabolism and microbiota composition in neuroinflammation and neurodegeneration. The present review aims to underscore the potential of targeting α-synuclein-lipid interactions as a multifaceted approach for the detection and treatment of neurodegenerative and neuroinflammatory diseases.

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“…Moreover, many biological targets and signaling pathways are involved in the pathology of dementia. There is substantial literature that focuses on drug targets for AD [ 67 , 68 , 69 , 70 , 71 , 72 , 73 ], LBD [ 74 , 75 , 76 , 77 ], FTD [ 78 , 79 , 80 , 81 ], and VD [ 82 , 83 , 84 ]. As a result of a better understanding of the biochemical regulation of the mechanisms leading to dementia, new molecular targets have been introduced into clinical trials ( Table 3 ).…”

Section: Drug Discovery and Development For Dementiamentioning

confidence: 99%

Drug Discovery and Development Targeting Dementia

et al. 2023

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Dementia, most often associated with neurodegenerative diseases, affects millions of people worldwide, predominantly the elderly. Unfortunately, no treatment is still available. Therefore, there is an urgent need to address this situation. This review presents the state of the art of drug discovery and developments in targeting dementia. Several approaches are discussed, such as drug repurposing, the use of small molecules, and phosphodiesterase inhibitors. Furthermore, the review also provides insights into clinical trials of these molecules. Emphasis has been placed on small molecules and multi-target-directed ligands, as well as disease-modifying therapies. Finally, attention is drawn to the possibilities of applications of nanotechnology in managing dementia.

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Leukotriene Signaling as a Target in α-Synucleinopathies

Cited by 9 publications

References 143 publications

Differential dopamine-mediated effects in the 5-lipoxygenase deficient mice

Differential dopamine-mediated effects in the 5-lipoxygenase deficient mice

Interaction between α-Synuclein and Bioactive Lipids: Neurodegeneration, Disease Biomarkers and Emerging Therapies

Drug Discovery and Development Targeting Dementia

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