Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models

Balducci, Claudia; Santamaria, Giulia; Vitola, Pietro La; Brandi, Edoardo; Grandi, Federica; Viscomi, Arturo R.; Beeg, Marten; Gobbi, Marco; Salmona, Mario; Ottonello, Simone; Forloni, Gianluigi

doi:10.1016/j.neurobiolaging.2018.06.002

Cited by 65 publications

(48 citation statements)

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“…This suggests that other properties of doxycycline might be at play, in accordance with the drug's pleiotropic activities (Stoilova et al, 2013). In fact, the positive cognitive effects of doxycycline in AD mice were not associated with any reduction of the Ab plaque load, but there was a significant normalization effect on glial cells, whose activation in the AD mouse brain contributes to the memory impairment (Balducci et al, 2017), thus highlighting an important contribution of the drug's anti-inflammatory effects (Balducci et al, 2018). It has also been shown that the inhibitory effect of doxycycline on poly (ADP-ribose) polymerase-1 (PARP-1), involved in microglial activation, inflammation, and cell death (Kauppinen and Swanson, 2005), also induced by Ab (Kauppinen et al, 2011), occurs at submicromolar concentrations (Alano et al, 2006), consistently with the concentrations actually measured in the brain of our mice.…”

Section: Brainmentioning

confidence: 96%

“…In addition, the drug concentrations reached in the brain under specific treatment conditions may help identify the mechanism(s) of action of the central in vivo effects of doxycycline in mice. For example, it was recently shown (Balducci et al, 2018) that memory deficits in APP/PS1Tg mice are significantly rescued by single or repeated intraperitoneal doses of 10 mg/kg doxycycline, which results in brain concentrations always lower than 1 mM, i.e., lower than the concentrations required for antiaggregating effects in vitro ($10 mM) (Forloni et al, 2001(Forloni et al, , 2002Cardoso et al, 2003;Giorgetti et al, 2011;Ward et al, 2011;De Luigi et al, 2015;Gonzalez-Lizarraga et al, 2017). This suggests that other properties of doxycycline might be at play, in accordance with the drug's pleiotropic activities (Stoilova et al, 2013).…”

Section: Brainmentioning

confidence: 99%

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Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice

Lucchetti

Fracasso

Balducci

et al. 2018

J Pharmacol Exp Ther

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Repurposing doxycycline for the treatment of amyloidosis has recently been put forward because of the antiaggregating and anti-inflammatory properties of the drug. Most of the investigations of the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g., prion and Alzheimer disease (AD), have been carried out in mouse models, but surprisingly no data are available regarding the concentrations reached in the brain after systemic administration. We filled this gap by analyzing the pharmacokinetic profile of doxycycline in plasma and brain after single and repeated intraperitoneal injections of 10 and 100 mg/kg, in wild-type mice and the APP23 mouse model of AD. The main outcomes of our study are: 1) Peak plasma concentrations ranged from 2 to10 mg/ml, superimposable to those in humans; 2) brain-to-plasma ratio was ∼0.2, comparable to the cerebrospinal fluid/serum ratios in humans; 3) brain C max 4-6 hours after a single dose was ∼0.5 (10 mg/kg) and ∼5 mM (100 mg/kg). Notably, these concentrations are lower than those required for the drug's antiaggregating properties as observed in cell-free studies, suggesting that other features underlie the positive cognitive effects in AD mice; 4) elimination half-life was shorter than in humans (3-6 vs. 15-30 hours), therefore no significant accumulation was observed in mouse brain following repeated treatments; and 5) there were no differences between doxycycline concentrations in brain areas of age-matched wildtype and APP23 mice. These data are useful for planning preclinical studies with translational validity, and to identify more reliably the mechanism(s) of action underlying the central in vivo effects of doxycycline.

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Section: Brainmentioning

confidence: 96%

Section: Brainmentioning

confidence: 99%

Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice

Lucchetti

Fracasso

Balducci

et al. 2018

J Pharmacol Exp Ther

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“…More recently, Balducci and coworkers [16,17] demonstrated that doxycycline could counteract the deleterious actions of β-amyloid oligomers (AβOs), recognized as the main detrimental species of Alzheimer's disease (AD), on memory. Such effect was associated with an anti-inflammatory action in both an AβO-induced acute mouse model, and in the APP/ PS1dE9 chronic mouse model of AD.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Doxycycline in the R6/2 Mouse Model of Huntington’s Disease

et al. 2019

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Mechanisms of tissue damage in Huntington's disease involve excitotoxicity, mitochondrial damage, and inflammation, including microglia activation. Immunomodulatory and anti-protein aggregation properties of tetracyclines were demonstrated in several disease models. In the present study, the neuroprotective and anti-inflammatory effects of the tetracycline doxycycline were investigated in the mouse model of HD disease R6/2. Transgenic mice were daily treated with doxycycline 20 mg/kg, starting from 4 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that doxycycline-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the saline-treated ones. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and the negative modulation of microglial reaction revealed a neuroprotective effect of the compound. Doxycycline provided a significantly increase of activated CREB and BDNF in the striatal neurons, along with a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings show that doxycycline treatment could be considered as a valid therapeutic approach for HD.

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“…Although AbOs induce memory impairment through glial activation, assessing the anti-inflammatory action of 96, we found that in both the AbOtreated and APP/PS1 mice, the memory recovery was associated with a lower neuroinflammation. Our data promote 96 as a hopeful repositioned drug counteracting crucial neuropathological AD targets [166].…”

Section: Figure 3 Chemical Structures Of Drugs Repurposed For Cancermentioning

confidence: 64%

A medicinal chemistry perspective of drug repositioning: Recent advances and challenges in drug discovery

Pillaiyar

Meenakshisundaram²,

Manickam

et al. 2020

European Journal of Medicinal Chemistry

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Drug repurposing is a strategy consisting of finding new indications for already known marketed drugs used in various clinical settings or highly characterized compounds despite they can be failed drugs. Recently, it emerges as an alternative approach for the rapid identification and development of new pharmaceuticals for various rare and complex diseases for which lack the effective drug treatments. The success rate of drugs repurposing approach accounts for approximately 30% of new FDA approved drugs and vaccines in recent years.This review focuses on the status of drugs repurposing approach for various diseases including skin diseases, infective, inflammatory, cancer, and neurodegenerative diseases.Efforts have been made to provide structural features and mode of actions of drugs.Keywords: Cancer, drug repositioning, drug reprofiling, recycling of drugs, drug discovery, inflammation, neurodegenerative diseases, skin diseases. since clinical and pre-clinical studies of the re-purposed candidates are already being documented in the original indication(s). Thus, it reduces the time and cost needed to reach the market and risk intrinsic to any research and development program. Moreover, the risk of clinical failure is also low. As an added advantage, this approach gives a possibility to widen the market and to prolong the application of the patent life of a drug. There are mainly two ways to proceed drug-repositioning approach such as experimental strategies and computational strategies.Experimental repurposing strategies include binding assays and phenotypic screening methods, which can be to find binding interactions of drug molecules to assay components and to identify lead compounds from a vide range of compound libraries, respectively [10].Computational approaches are categorized into target-/mechanism based, knowledge-based, pathway-and network-based approaches. These approaches are proven economic in discovering novel therapeutic ligands. Most notably, computational methods augment the drug discovery process by effectively utilizing cheminformatics, bioinformatics, network biology and systems biology. More specifically, these methods exploit known targets, drugs, disease biomarkers or pathways to establish novel methods and accelerate the planning of crucial clinical trials [11].In this perspective, we focused on the status of drugs repurposing approaches for various diseases including skin diseases, infective, inflammatory, cancer, and neurodegenerative diseases. Efforts have been made to provide structural features, and modes of action of drugs, which are exclusively small molecules, peptidomimetics, and macrocyclic compounds.Antibodies, vaccines, and any other biological drugs are not discussed. Drugs repositioning for skin whitening activity.Melanin is a collection of natural pigments that primarily determine the skin, hair and hair color of the human. Melanocytes, which are found in the basal layer of the epidermis, produce melanin by the process called melanogenesis upon the skin exposure to the ultra...

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Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models

Cited by 65 publications

References 64 publications

Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice

Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice

Neuroprotective Effects of Doxycycline in the R6/2 Mouse Model of Huntington’s Disease

A medicinal chemistry perspective of drug repositioning: Recent advances and challenges in drug discovery

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