Stimulating effect of thyroid hormones in peripheral nerve regeneration:research history and future direction toward clinical therapy

Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.

Remembering your A, B, C’s: Alzheimer’s disease and ABCA1

The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.The risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and inflammation.Upregulation of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory signaling.Various strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHR)agonists.These agonists display beneficial preclinical effects;however,important side effects have limited development.In particular,ligands that bind liver X receptor(LXR),the primary NHR that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often observed.The longstanding approach,focusing on LXRβvs.LXRa selectivity,is over-simplistic and has failed.Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.