Selected article for: "cell proliferation and immune cell"
Author: Courtney R. Sullivan; Catharine A. Mielnik; Sinead M. O’Donovan; Adam J. Funk; Eduard Bentea; Erica A.K. DePasquale; Zhexing Wen; Vahram Haroutunian; Pavel Katsel; Amy J. Ramsey; Jarek Meller; Robert E. McCullumsmith
Title: Connectivity analyses of bioenergetic changes in schizophrenia: Identification of novel treatments
  • Document date: 2018_6_5
    • ID: ltb6l5xz_63
    Snippet: We divided the top 12 unique perturbagens from our signature connectivity analysis into 5 groups: PPAR agonists, PI3K inhibitors, antipsychotic drugs, HDAC inhibitors, and other (Table 4 ). PI3K inhibitors constituted 2 of the drugs that may "reverse" our disease signature. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint These antitumor drugs inhi.....
    Document: We divided the top 12 unique perturbagens from our signature connectivity analysis into 5 groups: PPAR agonists, PI3K inhibitors, antipsychotic drugs, HDAC inhibitors, and other (Table 4 ). PI3K inhibitors constituted 2 of the drugs that may "reverse" our disease signature. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/338392 doi: bioRxiv preprint These antitumor drugs inhibit PI3K enzymes, which are part of the PI3K/AKT/mTOR signaling pathway and play critical roles in many cellular functions such as cellular proliferation, metabolism, and immune cell activation (93) (94) (95) . Recent work has linked schizophrenia pathology to the PI3K-AKT-mTOR signaling cascade (74, 96, 97) . Additionally, PI3K signaling can modulate synaptic formation and plasticity, and has been implicated in both schizophrenia and autism disorder (reviewed in (98, 99) ). Previous work demonstrated pharmacological inhibition of the catalytic subunit of PI3K blocks amphetamine induced psychosis in mice, highlighting PI3K inhibitors as therapeutic targets for the treatment of psychiatric disorders (100) . However, PI3K inhibition may be more suitable for "positive symptoms," as PI3K inhibition results in diminished insulin-stimulated glucose uptake by inhibiting translocation of GLUT4 glucose transporters to the plasma membrane (101) . Three of our drug discovery analysis hits were typical antipsychotics, which also treat positive symptoms of schizophrenia via dopamine receptor D2 antagonism (102) . It is possible that the glycolytic knockdown signatures used to generate these perturbagens could cause transcriptional changes in L1000 genes involved in the regulation of dopaminergic synapses, suggesting dopamine and metabolic systems could be connected in schizophrenia. This is not entirely surprising as antipsychotics have well documented metabolic effects (103) .

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