Rapamycin and FK506 derivative TH2849 could ameliorate neurodegenerative diseases through autophagy with low immunosuppressive effect

Abstract

Summary Autophagy is an essential cellular process concern with cellular homeostasis down‐regulated by mTOR, whose activity can be modulated by rapamycin, a kind of lipophilic macrolide antibiotic, through forming a complex with immunophilin FKBP12 essential for mTOR regulation to induce autophagy. Therefore, rapamycin is normally used as a neuron protective agent. The immunophilin FKBP12 binding ligand FK506 is well known as an immunosuppressive agent by inhibiting the calcineurin expression. In this study, we synthesized a series of modified compounds based on the FKBP12 binding moiety to as same as the binding structure of rapamycin and FK506 particularly. We removed the other binding regions of the complex that has the property of immunosuppression. We found that a novel small molecule named TH2849 from these derivative compounds has a significant binding connection with mTOR by comparing to calcineurin. The effects of TH2849 on calcineurin/NFAT were not as significant as FK506, and weak effects on IL2/p34cdc2/cyclin signaling pathway were also found. Moreover, TH2849 also shows mitochondrial protective effect through stabilizing the mitochondrial structure and transmembrane potential (ΔΨm) and could rescue dopaminergic neurons in MPTP‐treated zebrafishes as well as mice models with less immunosuppressive effect. Our present study shows that TH2849 works as a neuroprotective agent possibly by inducing autophagy and low immunosuppressive effect.

Emerging Potential Role of Autophagy to Modulate Aggresome Formation: Insights Molecular Treatment of Alzheimer’s Disease

“…Autophagy enhancers that can be utilized for the potential treatment of neurodegenerative diseases is receiving growing attention in recent studies [9,18,93,94]. It has been shown that the inactivation of mTOR by the lipophilic macrolide antibiotic rapamycin promotes the induction of autophagy [95]. Furthermore, long-term administration of rapamycin can reduce amyloid load in mouse models of AD and improve cognitive function as well as the pathology of tauopathy [96,97].…”

Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions

“…The specific mTORC1 inhibitor, rapamycin, and its derivatives (rapalogs) demonstrated to alleviate neuropathology and neurodegeneration in several transgenic models of pathogenic proteins, including models of HD (mutant HTT) ( Ravikumar et al., 2004 ; Sarkar and Rubinsztein, 2008 ), AD (mutant APP) ( Spilman et al., 2010 ; Caccamo et al., 2010 ), SCA type 3 ( Menzies et al., 2010 ), and PD (mutant α-synuclein) ( Webb et al., 2003 ). Rapamycin decreases neuronal death in MPTP-mediated PD animal models ( Ding et al., 2019 ; Liu et al., 2013a ). Furthermore, rapamycin diminishes muHTT fragments toxicity in cellular and mice models ( Ravikumar et al., 2004 ).…”

“…In another mouse model with the expression of a mutated APP, long-term rapamycin treatment decreases Aβ levels and alleviates the AD phenotype ( Spilman et al., 2010 ). Likewise, beneficial effects over neurodegeneration are observed with new rapalog compounds such as TH2849 which is an FKBP12-FK506 derivative ( Ding et al., 2019 ). Despite the promissory results of rapamycin and rapalogs, they cannot be generalized to all neurodegenerative diseases since mixed data are obtained for ALS.…”

Intelligent lesion blood–brain barrier targeting nano-missiles for Alzheimer's disease treatment by anti-neuroinflammation and neuroprotection

“…So it is necessary to use neuroprotective drugs additionally. Calcineurin inhibitor (tacrolimus, FK506), the most effective neuroprotective drug in central nervous system diseases, can maintain intracellular calcium homeostasis to improve neuronal repair and regeneration 21 , 22 , 23 , 24 , 25 , 26 . Moreover, the amelioration of AD-like behavior has been observed in patients taking FK506 21 , 24 , 26 .…”

“…Calcineurin inhibitor (tacrolimus, FK506), the most effective neuroprotective drug in central nervous system diseases, can maintain intracellular calcium homeostasis to improve neuronal repair and regeneration 21 , 22 , 23 , 24 , 25 , 26 . Moreover, the amelioration of AD-like behavior has been observed in patients taking FK506 21 , 24 , 26 . To sum up, we combined ibuprofen and FK506 for AD treatment, which could not only inhibit neuroinflammation mediated by NF- κ B pathway, but also exert neuroprotective effects.…”