Diabetic Theory in Anti-Alzheimer’s Drug Research and Development - Part 1: Therapeutic Potential of Antidiabetic Agents

Abstract

: Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder that affects over 46 million people worldwide. It is characterized by a decline in cognitive abilities, including memory and thinking skills. AD patients also suffer from behavioral and psychological symptoms of dementia of which depression is the most prevalent. Currently available drugs provide modest symptomatic relief and do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of AD. Studies suggest that AD is a type of diabetes manifested in the brain. Although AD and diabetes are currently classified as separate disease entities, they share common pathophysiological mechanisms. One of them is an increased level of cytokines involved in the inflammation and the regulation of metabolic, regenerative, and neural processes. The purpose of this review was to update the most recent reports on the discovery and development of antidiabetic agents as promising drugs for the symptomatic and disease-modifying treatment of AD. We collected the results of in vitro and in vivo studies, and recent reports from clinical trials suggesting the utility of antidiabetic agents in memory-enhancing therapy of AD. Their beneficial effects on chronic neuroinflammation, pathological hallmarks, and neuropsychiatric symptoms co-occurring with cognitive deficits are also presented. Antidiabetic agents refer to the diabetic and inflammatory hypotheses of AD and provide hope to find an effective drug for comprehensive therapy of the disease.

The Contribution of Type 2 Diabetes to Parkinson’s Disease Aetiology

“…Thiazolidinediones Thiazolidinediones (also known as glitazones) are used for the treatment of T2D. These drugs are PPAR-γ agonists that (a) increase adipokine-elicited insulin sensitivity [245] and (b) attenuate inflammation by inhibition of NF-κB and NLRP3 and activation of MAPK signalling pathways [444,445]. In animal models of PD, the aggregate effects of pioglitazone and rosiglitazone were improved motor cognitive functions, reduced dopaminergic neurodegeneration with improved dopamine levels, improved MT function, and attenuated microglial and astroglial cytokine inflammatory responses [446][447][448][449][450][451][452][453][454].…”

Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation

“…TZDs have been reported to block NF-κB-dependent gene expression, which includes the inhibition of pro-inflammatory cytokines, chemokines, COX-2, iNOS, and matrix metallopeptidases (Daynes and Jones, 2002;Straus and Glass, 2007). Furthermore, the anti-inflammatory activity of TZDs may be also mediated by the inhibition of pyrin domain-containing protein 3 (NLRP3) inflammasome, the expression of mitogen activated protein kinases (MAPK) phosphatase 1 and the activation of the caveolin-1-dependent pathway (Jankowska et al, 2019).…”

NM101 Phase III Study of NE3107 in Alzheimer’s Disease: rationale, Design and Therapeutic Modulation of Neuroinflammation and Insulin Resistance

“…Up to 81% of AD subjects have IGT or T2D [9]. Currently antidiabetic agents are being examined for activity in AD [10][11][12].…”