Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials

Abstract

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood–brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer’s disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields

“…Researchers in the same field are presently attempting to repurpose antidiabetic medications with the aim of addressing dementia, characterized by the prevalence of insulin sensitizers and insulin substrates. Despite the initial appearance of promise and the potential for success, none of the clinical trials conducted thus far have achieved the desired outcome of mitigating the cognitive deterioration associated with late-onset dementia ( 71 ).…”

Role of the Insulin-like Growth Factor System in Neurodegenerative Disease

“…Shared pathological features include mitochondrial dysfunction, oxidative stress, and insulin resistance, along with the exacerbation of abnormalities of lipid metabolism [111][112][113]. Drugs targeting these pathways are therefore being considered in the management of AD and PD [114][115][116][117]. Protein expression in mice expressing human Aβ1-42 from a transgene shows overlapping expression patterns with diet-induced obesity, with effects on proteostasis, apoptosis and synaptic vesicles [118].…”

Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review

“…Aβ processing and synthesis-associated proteins are also potential markers for the diagnosis of AD. A disintegrin and metalloproteinase (ADAM10) is the major α-secretase in APP processing and prevents the accumulation of Aβ in neurons [ 91 ]; gelsolin (GSN) is an Aβ-binding that prevents Aβ aggregation [ 92 ]; insulin-like growth factor 1 (IGF-1) induces the release of neuron-bound Aβ oligomers and inhibits Tau phosphorylation [ 93 , 94 ]. These proteins are significantly reduced in exosomes from different sources of AD patients [ 89 , 95 , 96 ].…”