Improvement in Impaired Social Cognition but Not Seizures by Everolimus in a Child with Tuberous Sclerosis-Associated Autism through Increased Serum Antioxidant Proteins and Oxidant/Antioxidant Status

Abstract

We investigated the effect of the mammalian target of rapamycin (mTOR) inhibitor everolimus on tuberous sclerosis complex- (TSC-) associated autistic symptoms and focal seizures with impaired awareness in a female child with TSC. We further evaluated the relationship between improved autistic symptoms and seizures and increased the serum levels of the antioxidant proteins, ceruloplasmin (Cp) and transferrin (Tf), and oxidant-antioxidant status indicated by the oxidant marker oxidized low-density lipoprotein (ox-LDL) and the antioxidant marker total antioxidant power (TAP). Everolimus treatment improved impaired social cognition and autistic behaviors; however, seizure and epileptic activity persisted. Serum Cp and Tf levels gradually increased in response to improved autistic symptoms. Serum TAP levels gradually decreased from baseline to the lowest value at 16 weeks and then increased at 24 weeks, showing a trend toward decreased total score of the Aberrant Behavior Checklist. This study revealed that everolimus treatment improved impaired social cognition with increased serum levels of the copper mediator (Cp) and iron mediator (Tf) via homeostatic control of mTOR activity accompanied by overlap of the oxidant-antioxidant system. Everolimus had no effect on TSC-related epileptiform discharges, and thus, the autistic symptoms and epileptic activity may be two independent end results of a common central nervous system disorder including mTOR hyperactivity. This trial is registered with JMAS-IIA00258.

Target Discovery Using Deep Learning-Based Molecular Docking and Predicted Protein Structures With AlphaFold for Novel Antipsychotics

“…66 A case study has been reported in which everolimus also induced psychosis, 67 but in a previous study, the use of everolimus in children and adolescents with tuberous sclerosis resulted in a decrease in prepulse inhibition, an indicator of psychosis and sensorimotor gating. [68][69][70] In this study, high binding affinities between cyclosporine and everolimus, and the receptors found in this study, were discovered. Now, a study to develop drugs that bind to the corresponding receptors, but have the opposite action through pharmacodynamics, can be considered.…”

“…Everolimus, also an immunosuppressant, is a drug that acts on the mechanistic target of rapamycin and that affects the growth of neural stem cells [ 66 ]. A case study has been reported in which everolimus also induced psychosis [ 67 ], but in a previous study, the use of everolimus in children and adolescents with tuberous sclerosis resulted in a decrease in prepulse inhibition, an indicator of psychosis and sensorimotor gating [ 68 - 70 ]. In this study, high binding affinities between cyclosporine and everolimus, and the receptors found in this study, were discovered.…”

Νευροψυχιατρικές Και Συστηματικές Διαταραχές Σχετιζόμενες Με Οζώδη Σκλήρυνση

“…Ωστόσο τα τελευταία χρόνια υποστηρίζεται ότι η υπερλειτουργία και αποτελεσματικότητα των αναστολέων mTOR στη βελτίωση του νοητικού δυναμικού και ανάπτυξης των εν λόγω ασθενών 465,466. Ωστόσο υπάρχουν περιγραφές περιπτώσεων βελτίωσης συμπτωμάτων ΔΕΠΥ και αυτισμού σε ασθενείς με ΟΣ [467][468][469]. Σε επτά ασθενείς με ΟΣ και νεφρικά αγγειομυολιπώματα που συμμετείχαν σε μία κλινική μελέτη φάσης ΙΙ και λάμβαναν sirolimus παρατηρήθηκε βελτίωση στη μνήμη και τις διοικητικές δεξιότητες 470.…”