Possibilities of Combinatorial Therapy: Insulin Dysregulation and the Growth Hormone Perspective on Neurodegeneration

Abstract

RTKs have been reported to be implicated in several neurodegenerative disorders and the roles of insulin receptor family have emerged as a key common pathway across diseases. Thus we focussed on the Insulin receptor family and discussed the irregulation from the growth hormone axis. The signaling, regulation and physiology of the production in liver and CNS has never been discussed in signaling perspectives and is extremely crucial for understanding the possibilities of IGF1 in neurodegeneration specifically. The commonalities across neurodegenerative diseases such as oxidative stress, mitochondrial dysfunction, and protein misfolding and insulin pathway anomalies have been elucidated and correlated with the insulin pathway. The crosstalk possibilities of the pathways, along with other regulatory modes for the development of combinatorial therapy have been discussed to visualize a common platform for neurodegenerative diseases including AD, PD, HD, ALS and FTD. Furthermore, the incretin based therapies that have gradually emerged as alternatives for insulin based therapy due to its inherent drawback of resistance has been briefly discussed.

Connecting the ends: signaling via receptor tyrosine kinases and cytoskeletal degradation in neurodegeneration

“…Alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib target several RTKs, including ALK, TRKA/B/C, ROS1, HGFR, IGF1R, Ret, and InsR [124]. The application of such targeted therapies toward downstream signaling pathways of RTKs, such as MEK, where binimetinib, colimetinib, and trametinib have been approved for cancer treatment [125], could be another viable option to target early events in dementia, including CCR, among others [126][127][128].…”