Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.
Mitochondrial encephalopathies are fatal, infantile neurodegenerative disorders caused by a deficit of mitochondrial functioning, for which there is urgent need to identify efficacious pharmacological treatments. Recent evidence shows that rapamycin administered both intraperitoneally or in the diet delays disease onset and enhances survival in the Ndufs4 null mouse model of mitochondrial encephalopathy. To delineate the clinical translatability of rapamycin in treatment of mitochondrial encephalopathy, we evaluated the drug's effects on disease evolution and mitochondrial parameters adopting treatment paradigms with fixed daily, oral doses starting at symptom onset in Ndufs4 knockout mice. Molecular mechanisms responsible for the pharmacodynamic effects of rapamycin were also evaluated. We found that rapamycin did not affect disease development at clinically-relevant doses (0.5 mg kg-1). Conversely, an oral dose previously adopted for intraperitoneal administration (8 mg kg-1) delayed development of neurological symptoms and increased median survival by 25%. Neurological improvement and lifespan were not further increased when the dose raised to 20 mg kg-1. Notably, rapamycin at 8 mg kg-1did not affect the reduced expression of respiratory complex subunits, as well as mitochondrial number and mtDNA content. This treatment regimen however significantly ameliorated architecture of mitochondria cristae in motor cortex and cerebellum. However, reduction of mTOR activity by rapamycin was not consistently found within the brain of knockout mice. Overall, data show the ability of rapamycin to improve ultrastructure of dysfunctional mitochondria and corroborate its therapeutic potential in mitochondrial disorders. The non-clinical standard doses required, however, raise concerns about its rapid and safe clinical transferability.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy. Electronic address: roberta.felici@ed.ac.uk.
Roberta
R
Felici
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Daniela
D
Buonvicino
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Mirko
M
Muzzi
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Leonardo
L
Cavone
Department of Experimental and Clinical Medicine, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
Daniele
D
Guasti
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Andrea
A
Lapucci
Department of Experimental and Clinical Medicine, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
Sara
S
Pratesi
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Francesco
F
De Cesaris
General Laboratory Unit (Pharmacology Unit), Careggi University Hospital, Florence, Italy.
Francesca
F
Luceri
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
Alberto
A
Chiarugi
D000284:Administration, Oral; D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004272:DNA, Mitochondrial / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000648:ultrastructure; D017237:Mitochondrial Encephalomyopathies / Q000188:drug therapy* / Q000473:pathology*; D009044:Motor Cortex / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; C534449:Ndufs4 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D042967:Electron Transport Complex I; D020123:Sirolimus
Mitochondria; Mitochondrial diseases; Mitochondrial encephalopathy; Ndufs4 knockout mice; Rapamycin