Antidépresseur tricyclique | EPFL Graph Search

vignette|Structure de la tienopramine Les antidépresseurs tricycliques (abréviation ATC ou ADT) sont une classe d'antidépresseurs utilisés pour la première fois vers la fin des années 1950. Leur nom vient de leurs structures moléculaires composées de trois anneaux d'atomes, tout comme les antidépresseurs tétracycliques, à la différence qu'eux en ont quatre. Mode d'action La majorité des antidépresseurs tricycliques vont agir principalement comme inhibiteur de la recapture de la sérotonine et de la noradrénaline. Cela a pour conséquence d'augmenter la concentration de ces neurotransmetteurs dans la fente synaptique, ce qui améliore la neurotransmission. Les antidépresseurs tricycliques ont par contre un impact presque nul sur la recapture de la dopamine. Il a été démontré que la sérotonine et la noradrénaline jouent un rôle clé dans la dépression, ainsi, l'augmentation de la concentration de ces deux neurotransmetteurs favorise un état psychologique «normal». Les tricycli

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit

Douglas Hanahan, Aristea Massaras, Ksenya Shchors

The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y(12), potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y(12) inhibitors may have applicability for treating glioma.

Elsevier2015

Highly Sensitive Detection of the Antidepressant Fluoxetine With an Extended Gate Field Effect Transistor

Mihai Adrian Ionescu, Shokoofeh Sheibani

Fluoxetine (FL) is one of the selective serotonin reuptake inhibitors, which is used as an anti-depressant, as well as anti-panic drug. In this work, a sensor for label-free recognition of trace amounts of FL is introduced, which is based on an extended gate field-effect transistor (EGFET). This sensor enables the detection and accurate measurement of FL concentrations over wide dynamic range. The sensing part of the device is a Pt electrode covered by a sensitive polyvinyl chloride (PVC) membrane. The functionalized Pt electrode acting as an extended gate of the EGFET, is connected to the internal gate of a MOSFET transducer. The sensing element of the PVC membrane is the insoluble ion-pair of FL cation and tetraphenylborate anion. The sensor performance for detection of FL was characterized in different ionic strengths of the matrix solution. Then, the sensor capability to operate in physiological phosphate-buffered saline (PBS) was assessed, where the sensor indicated two linear dynamic ranges of its response, with different sensitivities in 10(-11) -10(-5) M and 10(-5) -10(-3) M ranges. Also the calculated detection limit for the sensor was 2.63x10(-12) M. Moreover, the selectivity of the sensor was examined and validated in the presence of Citalopram, which is another anti-depressant drug with a similar structure to FL. We proposed a comprehensive analytical mapping of current sensitivity in all working regimes of the EGFET, providing a guide to the design of optimized sensors in any integrated systems of interest. Finally, the sensor was successfully exploited to assay citalopram in its pharmaceutical formulation.

IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC2022

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018