The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies

Marschallinger, Julia; Altendorfer, Barbara; Rockenstein, Edward; Holztrattner, Miriam; Julia, Garnweidner-Raith; Pillichshammer, Nadine; Leister, Iris; Hutter‐Paier, Birgit; Strempfl, Katharina; Unger, Michael S.; Chishty, Mansoor; Felder, Thomas K.; Johnson, Mary Ann; Attems, Johannes; Masliah, Eliezer; Aigner, Ludwig

doi:10.1007/s13311-020-00836-3

Cited by 25 publications

(32 citation statements)

References 80 publications

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“…Montelukast alleviated damage, restored fiber connectivity, and improved neurological function in an animal model of acute stroke (Gelosa et al, 2019). It reduced seizures and restored blood-brain-barrier function in an animal model of epilepsy (Lenz et al, 2014), and reduced the alpha-synuclein load and restored memory in an animal model of Lewy-Body dementias (Marschallinger et al, 2020), In an animal model of multiple sclerosis, montelukast reduced T-cell chemotaxis and restored integrity of the blood-brain-barrier (Wang et al, 2011).…”

Section: Montelukast In Covid-19-a Therapy Beyond Lung?mentioning

confidence: 99%

The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic

Aigner

Pietrantonio²,

Sousa

et al. 2020

Front. Mol. Biosci.

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The emergence and global impact of COVID-19 has focused the scientific and medical community on the pivotal influential role of respiratory viruses as causes of severe pneumonia, on the understanding of the underlying pathomechanisms, and on potential treatment for COVID-19. The latter concentrates on four different strategies: (i) antiviral treatments to limit the entry of the virus into the cell and its propagation, (ii) anti-inflammatory treatment to reduce the impact of COVID-19 associated inflammation and cytokine storm, (iii) treatment using cardiovascular medication to reduce COVID-19 associated thrombosis and vascular damage, and (iv) treatment to reduce the COVID-19 associated lung injury. Ideally, effective COVID-19 treatment should target as many of these mechanisms as possible arguing for the search of common denominators as potential drug targets. Leukotrienes and their receptors qualify as such targets: they are lipid mediators of inflammation and tissue damage and well-established targets in respiratory diseases like asthma. Besides their role in inflammation, they are involved in various other aspects of lung pathologies like vascular damage, thrombosis, and fibrotic response, in brain and retinal damages, and in cardiovascular disease. In consequence, leukotriene receptor antagonists might be potential candidates for COVID-19 therapeutics. This review summarizes the current knowledge on the potential involvement of leukotrienes in COVID-19, and the rational for the use of the leukotriene receptor antagonist montelukast as a COVID-19 therapeutic.

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Section: Montelukast In Covid-19-a Therapy Beyond Lung?mentioning

confidence: 99%

The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic

Aigner

Pietrantonio²,

Sousa

et al. 2020

Front. Mol. Biosci.

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“…The effect of MTK on cognition might be more pronounced in older animals, as the behavioral deficits of transgenic 5xFAD mice increase with age [ 74 ]. Beneficial effects of MTK have been reported in various animal models of neurodegenerative diseases, including a model of kainic acid-induced loss of memory function, an acute Huntington’s disease model of quinolinic acid and malonic acid injection-induced degeneration of striatal neurons, a beta-amyloid injection model of AD, which was accompanied by inhibition of neuroinflammation and reduced neuronal cell death, and a mouse model of dementia with Lewy bodies [ 37 , 42 , 65 , 75 ]. Cognitive improvements after MTK were also demonstrated in an aging rat model [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…A 6-week oral treatment of aged rats, resembling a model for mild cognitive impairment, with MTK elevated hippocampal neurogenesis, reduced neuroinflammation, reconstituted the BBB and, most importantly, improved spatial learning and memory [ 27 ]. Furthermore, MTK has shown beneficial effects on cognition and autophagy in a mouse model for dementia with Lewy bodies [ 42 ]. MTK might indeed prevent disease and/or improve cognitive function in AD patients, which has been suggested in a retrospective analysis of the Norwegian Prescription Database (NorPD), and data from the Tromsö study [ 43 , 44 ].…”

Section: Introductionmentioning

confidence: 99%

The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice

Michael

Zirknitzer

Unger

et al. 2021

IJMS

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Alzheimer’s disease (AD) is the most common form of dementia. In particular, neuroinflammation, mediated by microglia cells but also through CD8+ T-cells, actively contributes to disease pathology. Leukotrienes are involved in neuroinflammation and in the pathological hallmarks of AD. In consequence, leukotriene signaling—more specifically, the leukotriene receptors—has been recognized as a potential drug target to ameliorate AD pathology. Here, we analyzed the effects of the leukotriene receptor antagonist montelukast (MTK) on hippocampal gene expression in 5xFAD mice, a commonly used transgenic AD mouse model. We identified glial activation and neuroinflammation as the main pathways modulated by MTK. The treatment increased the number of Tmem119+ microglia and downregulated genes related to AD-associated microglia and to lipid droplet-accumulating microglia, suggesting that the MTK treatment targets and modulates microglia phenotypes in the disease model compared to the vehicle. MTK treatment further reduced infiltration of CD8+T-cells into the brain parenchyma. Finally, MTK treatment resulted in improved cognitive functions. In summary, we provide a proof of concept for MTK to be a potential drug candidate for AD and provide novel modes of action via modulation of microglia and CD8+ T-cells. Of note, 5xFAD females showed a more severe pathology, and in consequence, MTK treatment had a more pronounced effect in the females compared to the males. The effects on neuroinflammation, i.e., microglia and CD8+ T-cells, as well as the effects on cognitive outcome, were dose-dependent, therefore arguing for the use of higher doses of MTK in AD clinical trials compared to the approved asthma dose.

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“…Secondly, we analyzed pharmacokinetics of MTK in a transgenic mouse model of AD, because recently it was shown that pharmacological inhibition of leukotriene signaling had beneficial effects in several mouse models of AD [ 30 , 31 , 32 , 33 , 34 ]. The leukotriene receptor antagonist MTK has been proposed as an interesting candidate for drug repurposing in AD patients [ 13 , 14 , 15 ], due to its potential to modulate neuroinflammation and improve memory in animal models of stroke [ 35 ], epilepsy [ 36 , 37 ] and Lewy body dementia [ 38 ]. However, the cellular and molecular mechanisms underlying MTK action on CNS remain yet poorly understood, and pre-clinical experiments are needed to shade light onto its efficacy to modulate cognitive function.…”

Section: Discussionmentioning

confidence: 99%

Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice

Michael

Sousa

Conway³

et al. 2020

Pharmaceutics

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The leukotriene receptor antagonist Montelukast (MTK) is an approved medication for the treatment of asthma and allergic rhinitis. The existing marketed tablet forms of MTK exhibit inconsistent uptake and bioavailability, which partially explains the presence of a significant proportion of MTK low- and non-responders in the population. Besides that, tablets are suboptimal formulations for patients suffering from dysphagia, for example, seen in patients with neurodegenerative diseases such as Alzheimer’s disease, a disease with increasing interest in repurposing of MTK. This, and the need for an improved bioavailability, triggered us to reformulate MTK. Our aim was to develop a mucoadhesive MTK film with good safety and improved pharmacological features, i.e., an improved bioavailability profile in humans as well as in a mouse model of Alzheimer’s disease. We tested dissolution of the MTK mucoadhesive film and assessed pharmacoexposure and kinetics after acute and chronic oral application in mice. Furthermore, we performed a Phase I analysis in humans, which included a comparison with the marketed tablet form as well as a quantitative analysis of the MTK levels in the cerebrospinal fluid. The novel MTK film demonstrated significantly improved bioavailability compared to the marketed tablet in the clinical Phase 1a study. Furthermore, there were measurable amounts of MTK present in the cerebrospinal fluid (CSF). In mice, MTK was detected in serum and CSF after acute and chronic exposure in a dose-dependent manner. The mucoadhesive film of MTK represents a promising alternative for the tablet delivery. The oral film might lower the non-responder rate in patients with asthma and might be an interesting product for repurposing of MTK in other diseases. As we demonstrate Blood-Brain-Barrier (BBB) penetrance in a preclinical model, as well as in a clinical study, the oral film of MTK might find its use as a therapeutic for acute and chronic neurodegenerative diseases such as dementias and stroke.

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The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies

Cited by 25 publications

References 80 publications

The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic

The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic

The Leukotriene Receptor Antagonist Montelukast Attenuates Neuroinflammation and Affects Cognition in Transgenic 5xFAD Mice

Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice

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