Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia among the elderly. The exact cause of the disease is not clearly known, and no existing therapies are able to prevent disease progression. Identification of the possible "impaired brain insulin signalling in AD" enriched the scope for "the repurposing of diabetic drugs in AD management." Among the different classes of diabetic drugs, pioglitazone (PIO), a PPARγ agonist classed as an insulin sensitizer, is of the highest interest for AD management. The drug is reported to have direct action on multiple targets involved in AD, independent of insulin signalling. Even though PIO has appeared to be a potent molecule in preclinical trials, limited success was observed in the clinical stage. The tentative reasons for the limited therapeutic success in the clinical stage are not clear. The main focus of the review is to discuss various factors that might limit the therapeutic success of PIO in clinical trials and possible approaches to overcome those limitations. The research articles, review articles, and patents containing information regarding the clinical and preclinical trials of PIO in AD have been reviewed thoroughly using the keywords related to diabetic drugs in AD, PIO for AD management and mechanism of PIO in AD. Literature search was conducted on PubMed, SCOPUS and EMBASE. Previous studies have indicated that the blood-brain barrier (BBB) is the biggest challenge to delivering PIO to the brain. Therefore, to attain a therapeutic concentration in the brain, a higher dose is needed, which is also supported by preclinical investigations in AD; however, in clinical studies, scientists have used the usual diabetic doses. This dose is inadequate to attain a therapeutic concentration in the brain and appears to be the primary reason for the limited success of PIO in clinical trials. The stage of drug intervention and the nature of the study population are also influential factors for the therapeutic response. The insufficient concentration of the drug reaching the brain appears to be the crucial factor that limits the therapeutic success of PIO in AD management. Since the administration of higher doses cannot be recommended due to safety issues, the current situation demands the use of novel tools to ensure a therapeutic concentration reaches the brain.