Improved Sleep, Memory, and Cellular Pathological Features of Tauopathy, Including the NLRP3 Inflammasome, after Chronic Administration of Trazodone in rTg4510 Mice

Oliveira, Paula de; Cella, Claire V.; Locker, Nicolas; Ravindran, Kiran Kumar Guruswamy; Mendis, Agampodi; Wafford, Keith A.; Gilmour, Gary; Dijk, Derk‐Jan; Winsky‐Sommerer, Raphaèlle

doi:10.1523/jneurosci.2162-21.2022

Cited by 13 publications

(11 citation statements)

References 72 publications

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“…These results illustrate the fact that antidepressants of all classes exert inhibitory effects on neuroinflammation, and these effects are directly linked to the pathophysiology of neurodegenerative disorders in many cases [63,65,68,69,73,[78][79][80][81]. These central anti-inflammatory effects are mediated through multiple signaling pathways, including pro-and anti-inflammatory cytokines, intracellular and paracrine signaling cascades, and reductions in oxidative stress and pathological protein deposits [62,64,71,73,75,77].…”

Section: Antidepressants As Anti-inflammatory and Neuroprotective Agentsmentioning

confidence: 74%

“…Citalopram does not bind significantly to this receptor, which may explain its ineffectiveness in this context [81].…”

Section: Venlafaxinementioning

confidence: 98%

“…Tranylcypromine Reduces LPS-induced expression of IL-1β IL-6, reduces p-STAT3 and NF-κB nuclear translocation, and reduces TLR4/ERK signaling in mouse microglia; downregulates Aβ-induced microglial activation in a mouse model of AD [75] Tianeptine Reduces gp120-induced apoptosis and stimulation of caspase-3, suppresses NOS, and inhibits NF-κB transcription in human astroglial cells [76] Inhibits expression of plasminogen activator inhibitor-1 (Serpine-1) and reduces lipid peroxidation and apoptosis in mouse cortical neurons exposed to oxygenglucose deprivation [77] Trazodone Reduces microglial NLRP3 inflammasome expression, phosphorylated p38 MAPK and ATF4 levels, and tau levels in a mouse model of tauopathy; improves sleep and memory [81] Vortioxetine Restores levels of TGF-β and inhibits Aβ-induced oxidative stress in a mouse model of AD; protects against behavioral changes and memory deficits [69] Reduces caspase-3 expression and α-synuclein deposition in a rotenone-induced rat model of PD; improves motor, cognitive, and behavioral functioning [78] Others Agomelatine Reduces expression of aging-related proteins, caspase-3, and glutamate-included excitotoxicity; stabilizes endoplasmic reticulum and mitochondrial membranes in a rat model of aging [79] Aβ: amyloid-beta protein; ATF4: activating transcription factor 4; CXCL1: chemokine ligand 1; ERK: extracellular signalregulated kinase; gp120: glycoprotein 120; HD: Huntington's disease; IFN-γ: interferon-gamma; MAPK: mitogen-activated protein kinase; LPS: lipopolysaccharide; MSA: multiple systems atrophy; NF-κB: nuclear factor kappa B; NLRP3: Nod-like receptor protein 3; NO: nitric oxide; NOS: NO synthase; PD: Parkinson's disease; p-STAT3: phosphorylated signal transducer and activator of transcription protein 3; TGF-β: transforming growth factor-beta; TLR4: toll-like receptor 4…”

Section: Venlafaxinementioning

confidence: 99%

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Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

Rajkumar

2024

Explor Neuroprot Ther

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Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.

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Section: Antidepressants As Anti-inflammatory and Neuroprotective Agentsmentioning

confidence: 74%

“…Citalopram does not bind significantly to this receptor, which may explain its ineffectiveness in this context [81].…”

Section: Venlafaxinementioning

confidence: 98%

Section: Venlafaxinementioning

confidence: 99%

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Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

Rajkumar

2024

Explor Neuroprot Ther

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“…Other possibilities include direct or indirect activation of NLRP1 inflammasome due to cell stress caused by the AD pathological changes [ 23 , 30 ], predisposition given by certain gene polymorphisms [ 28 ], and prior activation of NLRP3 inflammasome in microglia [ 33 ]. One of the latest reports demonstrated that trazodone, an antidepressant with hypnotic efficacy in dementia, can reduce disease-related cellular pathways, including the NLRP3 inflammasome expression, and improve memory and sleep in male rTg4510 mice with a tauopathy-like phenotype [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

Španić

Horvat

Ilić

et al. 2022

Cells

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Neuroinflammation is one of the core pathological features of Alzheimer’s disease (AD) as both amyloid β (Aβ) and tau monomers and oligomers can trigger the long-term pro-inflammatory phenotype of microglial cells with consequent overactivation of the inflammasomes. To investigate the NLRP1 inflammasome activation in AD, we analyzed the expression of NLRP1, ASC, cleaved gasdermin (cGSDMD), and active caspase-6 (CASP-6) proteins in each hippocampal subdivision (hilar part of CA3, CA2/3, CA1, subiculum) of postmortem tissue of 9 cognitively healthy controls (HC) and 11 AD patients whose disease duration varied from 3 to 7 years after the clinical diagnosis. The total number of neurons, along with the total number of neurofibrillary tangles (NFTs), were estimated in Nissl- and adjacent modified Bielschowsky-stained sections, respectively, using the optical disector method. The same 9 HC and 11 AD cases were additionally semiquantitatively analyzed for expression of IBA1, HLA-DR, and CD68 microglial markers. Our results show that the expression of NLRP1, ASC, and CASP-6 is present in a significantly greater number of hippocampal formation neurons in AD brains compared to controls, suggesting that the NLRP1 inflammasome is more active in the AD brain. None of the investigated inflammasome and microglial markers were found to correlate with the age of the subjects or the duration of AD. However, besides positive correlations with microglial IBA1 expression in the subiculum and with microglial CD68 expression in the CA1 field and subiculum in the AD group, the overall NLRP1 expression in the hippocampal formation was positively correlated with the number of NFTs, thus providing a causal link between neuroinflammation and neurofibrillary degeneration. The accumulation of AT8-immunoreactive phosphorylated tau proteins that we observed at nuclear pores of large pyramidal neurons of the Ammon’s horn further supports their role in the extent of neuronal dysfunction and degeneration in AD. This is important because unlike fibrillar amyloid-β deposits that are not related to dementia severity, total NFTs and neuron numbers in the hippocampal formation, especially in the CA1 field, are the best correlates of cognitive deterioration in both human brain aging and AD. Our findings also support the notion that the CA2 field vulnerability is strongly linked to specific susceptibilities to different tauopathies, including primary age-related tauopathy. Altogether, these findings contrast with reports of nonsignificant microglial activation in aged nonhuman primates and indicate that susceptibility to inflammasome activation may render the human brain comparatively more vulnerable to neurodegenerative changes and AD. In conclusion, our results confirm a key role of NLRP1 inflammasome in AD pathogenesis and suggest NLRP1 as a potential diagnostic marker and therapeutic target to slow or prevent AD progression.

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“…It is noted that different kinases are responsible for the hyperphosphorylation of Tau protein in response to various stimuli. For example, ischemia/reperfusion injury induced Tau phosphorylation through cyclin-dependent kinase 5 (CDK5) [33]; sleep disturbances-associated Tau phosphorylation was mediated via p38 mitogen-activated protein kinase (p38MAPK) [34]; virus infection enhanced Tau phosphorylation by doublestranded RNA-dependent protein kinase [35]; sepsis triggered Tau phosphorylation through GSK-3β [36]; and metal dysregulation activated rapamycin/ribosomal S6 protein kinase and thus caused Tau phosphorylation [37]. In a previous study, streptozotocin was intracranially injected into the rats to induce neuroinflammation, and it was revealed that plasma TNF-α release was increased and p-Tau was induced by GSK-3β in the hippocampus area [38].…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

Zhang

Song

Ding

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Neuroinflammation-induced phosphorylated Tau (p-Tau) deposition in central nervous system contributes to neurodegenerative disorders. Propofol possesses neuroprotective properties. We investigated its impacts on tumor necrosis factor-α (TNF-α)-mediated p-Tau deposition in neurons. Methods. Mouse hippocampal neurons were exposed to propofol followed by TNF-α. Cell viability, p-Tau, mitophagy, reactive oxygen species (ROS), NOD-like receptor protein 3 (NLRP3), antioxidant enzymes, and p62/Keap1/Nrf2 pathway were investigated. Results. TNF-α promoted p-Tau accumulation in a concentration- and time-dependent manner. TNF-α (20 ng/mL, 4 h) inhibited mitophagy while increased ROS accumulation and NLRP3 activation. It also induced glycogen synthase kinase-3β (GSK3β) while inhibited protein phosphatase 2A (PP2A) phosphorylation. All these effects were attenuated by 25 μM propofol. In addition, TNF-α-induced p-Tau accumulation was attenuated by ROS scavenger, NLRP3 inhibitor, GSK3β inhibitor, or PP2A activator. Besides, compared with control neurons, 100 μM propofol decreased p-Tau accumulation. It also decreased ROS and NLRP3 activation, modulated GSK3β/PP2A phosphorylation, leaving mitophagy unchanged. Further, 100 μM propofol induced p62 expression, reduced Keap1 expression, triggered the nuclear translocation of Nrf2, and upregulated superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) expression, which was abolished by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Consistently, the inhibitory effect of 100 μM propofol on ROS and p-Tau accumulation was mitigated by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Conclusions. In hippocampal neurons, TNF-α inhibited mitophagy, caused oxidative stress and NLRP3 activation, leading to GSK3β/PP2A-dependent Tau phosphorylation. Propofol may reduce p-Tau accumulation by reversing mitophagy and oxidative stress-related events. Besides, propofol may reduce p-Tau accumulation by modulating SOD and HO-1 expression through p62/Keap1/Nrf2 pathway.

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Improved Sleep, Memory, and Cellular Pathological Features of Tauopathy, Including the NLRP3 Inflammasome, after Chronic Administration of Trazodone in rTg4510 Mice

Abstract: Improved sleep, memory, and cellular pathological features of tauopathy, including the NLRP3 inflammasome, after chronic administration of trazodone in rTg4510 mice

Cited by 13 publications

References 72 publications

Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

The Mechanism of TNF-α-Mediated Accumulation of Phosphorylated Tau Protein and Its Modulation by Propofol in Primary Mouse Hippocampal Neurons: Role of Mitophagy, NLRP3, and p62/Keap1/Nrf2 Pathway

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