Antidepressant treatments regulate matrix metalloproteinases‐2 and ‐9 (MMP‐2/MMP‐9) and tissue inhibitors of the metalloproteinases (TIMPS 1–4) in the adult rat hippocampus

Benekareddy, Madhurima; Mehrotra, Purvi; Kulkarni, Vaishali A.; Ramakrishnan, Parvathy; Dias, Brian; Vaidya, Vidita A.

doi:10.1002/syn.20529

Cited by 25 publications

(20 citation statements)

References 53 publications

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“…In addition, we demonstrate that fluoxetine affected the conversion of Pro-TGF-β1 into active TGF-β1, likely through the activation of MMP-2. The involvement of MMP-2 in fluoxetine activity is in line with the suggestion that extracellular matrix modifying enzymes contribute to antidepressant-mediated structural plasticity in the hippocampus (Benekareddy et al, 2008; Lee et al, 2014). The evidence that inhibiting astrocytes MMP-2 resulted into a lack of neuroprotection against Aβ toxicity supported the role of MMP-2 in fluoxetine-induced TGF-β1 release.…”

Section: Discussionsupporting

confidence: 84%

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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Section: Discussionsupporting

confidence: 84%

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

et al. 2016

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“…It is actually possible that this high dose of Fluoxetine may be activating alternative immunomodulatory or antiinflammatory pathways that are responsible for the authors’ observations and that are overcoming the effects on serotonin metabolism. Indeed Branco-de-Almeida et al showed that Fluoxetine inhibited IL-1β and COX-2 mRNA and metalloprotease (MMP) 9 activity in their model, and, consistently with these findings, it has been reported that 5 mg/kg i.p Fluoxetine can reduce the expression of MMP 2 and 9 in rat hippocampus [58] and 10 mg/kg i.p. Fluoxetine inhibits the expression of MMP 2, 9 and 12 after spinal cord injury in mouse [59].…”

Section: The Wnt Connectionmentioning

confidence: 79%

Serotonin: a novel bone mass controller may have implications for alveolar bone

Galli

Macaluso

Passeri

2013

J Negat Results BioMed

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As recent studies highlight the importance of alternative mechanisms in the control of bone turnover, new therapeutic approaches can be envisaged for bone diseases and periodontitis-induced bone loss. Recently, it has been shown that Fluoxetine and Venlafaxine, serotonin re-uptake inhibitors commonly used as antidepressants, can positively or negatively affect bone loss in rat models of induced periodontitis. Serotonin is a neurotransmitter that can be found within specific nuclei of the central nervous system, but can also be produced in the gut and be sequestered inside platelet granules. Although it is known to be mainly involved in the control of mood, sleep, and intestinal physiology, recent evidence has pointed at far reaching effects on bone metabolism, as a mediator of the effects of Lrp5, a membrane receptor commonly associated with Wnt canonical signaling and osteoblast differentiation. Deletion of Lrp5 in mice lead to increased expression of Tryptophan Hydroxylase 1, the gut isoform of the enzyme required for serotonin synthesis, thus increasing serum levels of serotonin. Serotonin, in turn, could bind to HTR1B receptors on osteoblasts and stop their proliferation by activating PKA and CREB.Although different groups have reported controversial results on the existence of an Lrp5-serotonin axis and the action of serotonin in bone remodeling, there is convincing evidence that serotonin modulators such as SSRIs can affect bone turnover. Consequently, the effects of this drug family on periodontal physiology should be thoroughly explored.

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“…Our previous study showed that the serotonin-induced mitogenesis of PASMCs is mediated by SERT, in which the signal transduction for serotonin is dependent on the ERK1/2 pathway [14] . Benekareddy et al also reported that fluoxetine regulates MMP-2/ MMP-9 and TIMP1-4 in the adult rat hippocampus [31] . Taken this information and the present results together, we believe that fluoxetine-induced regulation of MMP-2, 9/TIMP-1, 2 is closely related to the inhibition of ECM remodeling, in which the serotonin intracellular signal pathway might be involved.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats

Wang

Yang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine on extracellular matrix (ECM) remodeling of the pulmonary artery and inflammation of the lungs in pulmonary arterial hypertension (PAH) induced by monocrotaline in rats. Methods: MCT-induced chronic PAH was established in Wistar rats. After treatment with fluoxetine for 3 weeks, pulmonary hemodynamic measurement and morphological investigation of lung tissues were undertaken. The main components of the ECM, elastin and collagen, were detected using Van Gieson stain and Orcein stain, respectively, or using Victoria-ponceau's double stain. The ECM proteolytic enzymes matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, were detected by Western blot. Inflammation of lung tissue was assayed using lung morphology and inflammatory cytokine expression. Results: Fluoxetine (2 and 10 mg/kg) significantly inhibited MCT-induced PAH, attenuated pulmonary arterial muscularization and ECM remodeling, and decreased MMP/TIMP expression. Fluoxetine also suppressed inflammatory responses in lung tissue and inhibited the expression of the inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP-1) and intercellular adhesion molecule-1 (ICAM-1). Conclusion: Fluoxetine inhibited MCT-induced ECM remodeling of the pulmonary artery and inflammation of lung tissue. These effects were related to its inhibition on MMPs/TIMPs and cytokine productions.Keywords: extracellular matrix; inflammation; pulmonary arterial hypertension; selective serotonin reuptake inhibitor Acta Pharmacologica Sinica (2011) 32: 217-222; doi: 10.1038/aps.2010 published online 10 Jan 2011 Original Article * To whom correspondence should be addressed. [11,12] . It was reported that the plasma concentration in serotonin was significantly increased in PAH patients [13] . We have previously reported that serotonin induced PASMCs mitogenesis in vitro, and serotonin selective reuptake inhibitor (SSRI) fluoxetine inhibited serotonininduced PASMCs proliferation via blocking SERT [14] . We have also found that SSRI fluoxetine and sertraline protected against pulmonary vascular remodeling by inhibiting pulmonary vascular muscularization in monocrotaline (MCT)-induced pulmonary hypertensive rats [15,16] . However, whether SSRI has a protective effect against ECM remodeling in the pulmonary artery remains unknown.Inflammatory mechanisms play an important role in the development of PAH. It has been demonstrated that lymphocytes and macrophages were present in the vicinity of remodeled pulmonary vessels and that cytokines such as interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) were increased in PAH patients [17][18][19][20] . We have also reported previously that chronic lung inflammation existed in MCT-induced PAH rats [21] . However, several studies have shown that...

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Antidepressant treatments regulate matrix metalloproteinases‐2 and ‐9 (MMP‐2/MMP‐9) and tissue inhibitors of the metalloproteinases (TIMPS 1–4) in the adult rat hippocampus

Cited by 25 publications

References 53 publications

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

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

Serotonin: a novel bone mass controller may have implications for alveolar bone

Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats

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