24 25 Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is 26 a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition 27 properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in 28 VeroE6 cell line, with an EC 50 of 0.46±0.04 µM. Alisporivir inhibited a post-entry step of the 29 SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly 30 conducted with alisporivir in patients with SARS-CoV-2 infection. 31 32 33 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from 101 SARS-CoV-2 life cycle through mechanisms that remain to be unraveled. These results justify 102 that a proof-of-concept Phase 2 trial be rapidly conducted to assess the antiviral properties 103 and the effect of alisporivir on COVID-19 clinical outcomes in infected patients. 104 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from 6Alisporivir has been shown to be well tolerated when administered as a 105 monotherapy 12 . Preclinical pharmacology data indicate that, after oral administration, 106 alisporivir is widely distributed in the whole body, including the lungs, and that its EC 90 107 against SARS-CoV-2 in VeroE6 cells is clinically achievable in patients. In addition, because 108 alisporivir inhibits all cellular cyclophilins, it also blocks mitochondrial cyclophilin-D, a key 109 regulator of mitochondrial permeability transition pore (mPTP) opening, a mechanism 110
When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α‐Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein. Promotion of microglial glutamate release by αS aggregates (αSa) required concomitant engagement of TLR2 and P2X7 receptors. Downstream to cell surface receptors, the release process was mediated by activation of a signaling cascade sequentially involving phosphoinositide 3‐kinase (PI3K) and NADPH oxidase, a superoxide‐producing enzyme. Inhibition of the Xc‐ antiporter, a plasma membrane exchange system that imports extracellular l‐cystine and exports intracellular glutamate, prevented the release of glutamate induced by αSa, indicating that system Xc‐ was the final effector element in the release process downstream to NADPH oxidase activation. Of interest, the stimulation of glutamate release by αSa was abrogated by dopamine through an antioxidant effect requiring D1 dopamine receptor activation and PI3K inhibition. Altogether, present data suggest that the activation of microglial cells by αSa may possibly result in a toxic build‐up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in dopamine that characterizes this disorder may further aggravate this process in a vicious circle mechanism.
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