Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1–42)-induced toxicity

Caraci, Filippo; Pappalardo, Giuseppe; Basile, Livia; Giuffrida, Alessandro; Copani, Agata; Tosto, Rita; Sinopoli, Alessandro; Giuffrida, Maria Laura; Pirrone, Emanuele; Drago, Filippo; Pignatello, Rosario; Guccione, Salvatore

doi:10.1016/j.ejphar.2015.07.015

Cited by 14 publications

(11 citation statements)

References 40 publications

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“…Finally, we examined the neuroprotective activity of carnosine in mixed neuronal cultures containing both neurons (35–40%) and glial cells (astrocytes and microglia; 60–65%) challenged with oAβ1-42 (2 µM). We have previously demonstrated that mixed neuronal cultures treated with oAβ1-42 represent an established experimental model of Aβ-induced neurodegeneration, where oAβ1-42 show a faster kinetics compared to pure neuronal cultures, with a substantial increase in the number of dead neurons (about 100%) being detected after 48 h of exposure to Aβ oligomers [55].…”

Section: Resultsmentioning

confidence: 99%

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1

Caruso

Fresta

Musso

et al. 2019

Cells

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Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer’s disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O2−• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects.

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Section: Resultsmentioning

confidence: 99%

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1

Caruso

Fresta

Musso

et al. 2019

Cells

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“…Under these conditions, neurons exposed to Aβ oligomers die showing an apoptotic phenotype (Copani et al, 1999; Caraci et al, 2015b). Exposure to Aβ 1-42 oligomers (1 μM) was toxic in a time dependent manner, inducing apoptotic neuronal death in about 20–25% of neuronal population at 24 h, and 35–45% at 48 h. Fluoxetine or sertraline were co-applied with Aβ 1-42 for 48 h at the concentrations (100 nM–10 μM) observed in depressed patients treated with these drugs.…”

Section: Resultsmentioning

confidence: 99%

Fluoxetine Prevents Aβ1-42-Induced Toxicity via a Paracrine Signaling Mediated by Transforming-Growth-Factor-β1

et al. 2016

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Selective reuptake inhibitors (SSRIs), such as fluoxetine and sertraline, increase circulating Transforming-Growth-Factor-β1 (TGF-β1) levels in depressed patients, and are currently studied for their neuroprotective properties in Alzheimer’s disease. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against β-amyloid (Aβ)-induced neurodegeneration. In the present work, the SSRI, fluoxetine, was tested for the ability to protect cortical neurons against 1 μM oligomeric Aβ1-42-induced toxicity. At therapeutic concentrations (100 nM–1 μM), fluoxetine significantly prevented Aβ-induced toxicity in mixed glia-neuronal cultures, but not in pure neuronal cultures. Though to a lesser extent, also sertraline was neuroprotective in mixed cultures, whereas serotonin (10 nM–10 μM) did not mimick fluoxetine effects. Glia-conditioned medium collected from astrocytes challenged with fluoxetine protected pure cortical neurons against Aβ toxicity. The effect was lost in the presence of a neutralizing antibody against TGF-β1 in the conditioned medium, or when the specific inhibitor of type-1 TGF-β1 receptor, SB431542, was added to pure neuronal cultures. Accordingly, a 24 h treatment of cortical astrocytes with fluoxetine promoted the release of active TGF-β1 in the culture media through the conversion of latent TGF-β1 to mature TGF-β1. Unlike fluoxetine, both serotonin and sertraline did not stimulate the astrocyte release of active TGF-β1. We conclude that fluoxetine is neuroprotective against Aβ toxicity via a paracrine signaling mediated by TGF-β1, which does not result from a simplistic SERT blockade.

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“…For example, Park et al recently reported that injection of the newly synthesized reversible MAO-B inhibitor KDS2010 in APP/PS1 mice (a mouse model of AD) significantly suppresses astrocytic GABA upregulation and astrogliosis and rescues learning and memory [ 48 ]. Interestingly, a recent study reported that tranylcypromine has neuroprotective effects against Aβ 1-42 -induced neuronal cell death and neurodegeneration in primary rat cortical neurons [ 24 ]. However, whether tranylcypromine alters Aβ oligomer-induced neuroinflammatory responses in vitro and in vivo is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Another study found that tranylcypromine downregulates LPS-induced TNF-α, IL-1β, and IL-6 levels in a rat model of depression [ 23 ]. Moreover, tranylcypromine inhibits Aβ-induced toxicity in primary cortical neurons [ 24 ]. However, whether tranylcypromine can alter Aβ- and/or LPS-induced neuroinflammatory responses in the brain and its mechanisms of action remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

Park

Jeon

Lee

et al. 2020

Cells

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Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.

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Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1–42)-induced toxicity

Cited by 14 publications

References 40 publications

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1

Fluoxetine Prevents Aβ1-42-Induced Toxicity via a Paracrine Signaling Mediated by Transforming-Growth-Factor-β1

The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD

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