Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling

Vandresen-Filho, Samuel; Martins, Wagner C.; Bertoldo, Daniela Bohn; Rieger, Débora Kurrle; Maestri, Mariana; Leal, Rodrigo Bainy; Tasca, Carla I.

doi:10.1007/s11064-016-1913-1

Cited by 9 publications

(4 citation statements)

References 84 publications

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“…Although a similar effect of the parent molecule ATV on glutamate uptake has been recently reported in vivo (Vandresen‐Filho et al . ), this might well be as a result of a specific effect of the o‐ATV metabolite, which is rapidly generated in a whole animal physiology system. The effect of o‐ATV increasing the association of EAAC1 with lipid rafts we observed fits with the previously reported specific effect of o‐ATV preserving the lipid organization in the membrane (Mason et al .…”

Section: Discussionmentioning

confidence: 99%

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Guirao

Martí-Sistac

DeGregorio-Rocasolano

et al. 2017

Journal of Neurochemistry

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The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD.

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Section: Discussionmentioning

confidence: 99%

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Guirao

Martí-Sistac

DeGregorio-Rocasolano

et al. 2017

Journal of Neurochemistry

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“…ATV are widely known for their lipid regulation in vivo and extensive used in clinical practice, which being explored for potential benefits in depression [24,25]. To assess the anti-depression effect of ATV, the CUMS model mice were treated with ATV for 40 d, and FLU was used as positive drug (Fig.…”

Section: Atv Treatment Rescued Choric Stress Induced Depressive Behav...mentioning

confidence: 99%

“…Interestingly, some studies reported the neuroprotective action of ATV. ATV prevents ischemia induced cell death [24], and protects neurons against glutamatergic excitotoxicity [25]. Clinical studies have report that ATV improved psychological well-being on depressive patients [26].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin prevents depressive behavior improving the sphingolipid metabolism and triggering neurovascular coupling via Apolipoprotein E

song

Lai

et al. 2022

Preprint

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Depression is a common mental disorder, but classical antidepressants have many adverse reactions in clinical application. Many clinical studies show that lipid metabolism plays an important role in depression. In this study, chronic unpredictable mild stress (CUMS) model was established to evaluate the antidepressant activity and mechanism of classic lipid regulating drugs - atorvastatin (ATV) by ethology and multichannel electrophysiology etc., Laser speckle flow imaging and Doppler ultrasound measurement showed that ATV increased the cerebral blood flow and carotid blood flow of depressed mice. At the same time, ApoE-/- mice were compared to verify the important role of Apolipoprotein E (ApoE) in ATV antidepressant mechanism. Lipomics and Western blot showed that ATV administration could inhibit the increase of synaptic plasma membrane acidic sphingomyelinase (ASMase) stimulated by CUMS. Through further analysis of immunofluorescence and primary cell culture technology etc., it was found that ATV administration can inhibit the decrease of neuronal glutamate caused by the disorder of nerve sphingolipid, and increase the expression of metabotropic glutamate receptor (mGluR) and IP3 receptor (IP3R) in astrocytes. These findings suggest that ATV can regulate ApoE protein in central cortex, regulate sphingolipid metabolism in cortical synaptic plasma membrane, and alleviate the decline of cerebral blood flow in depressed mice through neurovascular coupling mechanism (NVC), so as to improve depression like symptoms. This means that atorvastatin may be a potential candidate for the treatment of depression. At the same time, it also provides a basis for lipid metabolism to become an antidepressant target.

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“…Specifically, atorvastatin significantly reduced QA-induced clonic and/or tonic seizures and prevented cell death induced by QA in the hippocampus [ 127 ]. Atorvastatin also counteracts the decrease in glutamate uptake triggered by QA and prevents the QA-induced decrease in protein kinase B (PKB, or Akt) phosphorylation [ 128 ].…”

Section: Introductionmentioning

confidence: 99%

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder

et al. 2021

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Objective Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood–brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors. Methods We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129. Results Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins. Conclusion The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

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Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling

Cited by 9 publications

References 84 publications

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Atorvastatin prevents depressive behavior improving the sphingolipid metabolism and triggering neurovascular coupling via Apolipoprotein E

Lipophilic vs. hydrophilic statins and psychiatric hospitalizations and emergency room visits in US Veterans with schizophrenia and bipolar disorder

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