The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data.
Aigli G VakrakouAnastasia AlexakiMaria-Evgenia BriniaMaria C AnagnostouliLeonidas StefanisPanos StathopoulosPublished in: International journal of molecular sciences (2022)
This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects.
Keyphrases
- multiple sclerosis
- cell proliferation
- immune response
- mass spectrometry
- randomized controlled trial
- signaling pathway
- clinical trial
- ms ms
- white matter
- oxidative stress
- endothelial cells
- dendritic cells
- induced apoptosis
- big data
- cell death
- transcription factor
- bone marrow
- stem cells
- systematic review
- spinal cord injury
- pi k akt
- epithelial mesenchymal transition
- acute myeloid leukemia
- study protocol
- cell cycle arrest
- brain injury
- case report
- cancer therapy
- lipopolysaccharide induced
- deep learning
- data analysis