Rapamycin

0 efect

Neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics

Resulting in the lack of efficacy for increasing the survival
Not able to detect any consistent sign of microgliosis in this mouse model
In the transcriptomics analysis were related to the proliferation of astrocytes and not to the proliferation of microglia

Some of the key inflammatory genes downregulated by rapamycin in Ndufs4-/- mice (Tlr2, Cxcl10, Ccl5 and Aif1) were not picked up in our transcriptomics analysis

Low or high doses, does not result in therapeutic benefits in a mouse model of mitochondrial encephalopathy due to CoQ deficiency

Oral administration of rapamycin, either at low (28 ppm) or high dose (225 ppm), did not produce any therapeutic benefits in Coq9R239X mice
Group of animals with the high dose of rapamycin experienced an aggravation on the brain lesions, resulting in a mild decrease in the survival, which

Could be attributed to the reported side effects of this drug, e.g. thrombocytopenia and hyperlipidemia, impaired wound healing, nephrotoxicity, and altered insulin sensitivity

Four studies the underlying mitochondrial dysfunction was not mitigated, and the mechanism by which rapamycin produced the therapeutic outcomes was not sufficiently elucidated
www.thelancet.com/article/S2352-3964(19)30165-3/fulltext

Low dose induced a very mild inhibition only in heart and liver
Rapamycin dramatically reduced the gliosis and the histopathological signs on a mouse model of Leigh syndrome due to mitochondrial complex I deficiency (Ndufs4-/- model), thus increasing the survival
Oral administration of different doses of rapamycin, starting from 42 ppm of dietary administration, delayed the development of neurological symptoms and extended the lifespan in Ndufs4-/- mice

Induce morphological and phenotypic improvements with survival increase in Ndufs4-/- mice in a dose-dependent manner
Inhibition of mTORC1, rapamycin was able to lessen the microgliosis and downregulate microglia-related inflammatory genes in Ndufs4-/- mice

Mouse model of mtDNA depletion and encephalopathy due to thymidine kinase 2 (TK2) deficiency (the Tk2H126N model), low doses of oral rapamycin induced a very mild increase in lifespan without any improvement in the morphological features
Mouse model of mitochondrial myopathy with COX deficiency due to the muscle-specific ablation of the Cox15 gene (the Cox15sm/sm model), the i.p. administration of high doses of rapamycin improved the locomotor activity, corrected the histopathological features and increased the COX activity in muscle
Late-onset mitochondrial myopathy due to a defect in the helicase Twinkle (the Twnkdup model), the i.p. administration of high doses of rapamycin downregulated the components of the integrated mitochondrial stress response, thus reversing the myopathy progression
www.thelancet.com/article/S2352-3964(19)30165-3/fulltext

Rapamycin-mediated therapeutic mechanism is the inhibition of the integrated mitochondrial stress response, which includes the repression of the mitochondrial unfolded protein response (UPRmt). However, the deleterious effect of the induction of UPRmt has been only identified in the model Twnkdup of mitochondrial myopathy
https://www.thelancet.com/article/S2352-3964(19)30165-3/fulltext

Partial bypass of the OXPHOS defect by tapping into alternative energy reserves, such as amino acids and lipids