Protective Effects of Pioglitazone on Cognitive Impairment and the Underlying Mechanisms: A Review of Literature

Abstract

Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is known to have anti-inflammatory and anti-oxidant effects on the brain, and its clinical potential in the treatment of cognitive impairment in diseases such as Alzheimer's disease (AD) and Parkinson disease (PD) is currently being explored. This review focused on the reported beneficial effects of pioglitazone on cognitive dysfunction and summarized the associated mechanisms associated with pioglitazone-induced improvement in cognitive dysfunction. Our review of the relevant literature indicated that there is conclusive evidence of the effect of pioglitazone on improving cognitive impairment via its agonistic effect on PPAR-γ. Further, several mechanisms of action have been reported, and these include enhanced NF-kB and p38 activity; regulation of the pro-inflammatory cytokines IL-1, IL-6, and TNF-α; inhibition of Aβ production; alterations in the levels of mitochondrial proteins such as mitoNEET; regulation of protein kinases such as CDK5 and JNK; regulation of ROS and MDA levels and the levels of the antioxidant proteins TRX1 and PON2; and increased expression of thyroid hormone receptors. Despite these promising findings, pioglitazone treatment is also associated with cardiovascular risks, such as weight gain and edema, which subsequently increase the risk of mortality. Further, it has been documented that pioglitazone may be unable to cross the blood–brain barrier when administered in certain forms, and it can also cause cell death when administered at high concentrations. Therefore, further research is required to explore the effects of acute and chronic pioglitazone treatment on memory function and the associated risks, in order to determine its clinical applicability in the treatment of cognitive disorders. Nonetheless, the current literature does demonstrate that pioglitazone promotes the function of PPAR receptors in ameliorating inflammation, oxidative stress, amyloidogenesis, and hypothyroidism, and enhancing neurogenesis, synaptic plasticity, and mitochondrial function. Therefore, these mechanisms of PPAR receptors warrant further investigation in order to establish the clinical applicability of pioglitazone in the treatment of cognitive disorders, such as PD and AD, and neuronal impairment in conditions such as diabetes.

Establishment of a chronic insomnia rat model of sleep fragmentation using unstable platforms surrounded by water

“…The Morris water maze test can be used to study dysfunction of learning and memory ability ( 35-40 ). Increased expression levels of pro-inflammatory factors contribute to dysfunction of learning and memory ability ( 26 , 27 ). In the present study, the night-time Morris water maze training and test experiment indicated that the memory dysfunction in the model rats was accompanied by a longer escape latency and reduced number of times crossing the target regions.…”

“…It has been reported that the levels of inflammatory cytokines, namely IL-1, IL-6, TNF-α and IL-10, are affected by insomnia (25). The abnormal levels of these cytokines further affect brain function, such as learning and memory (26,27). Furthermore, orexin A and its receptors play important roles in the regulation of food intake, circadian rhythms, arousal and sleep (28)(29)(30)(31)(32).…”

Structural Biology Inspired Development of a Series of Human Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Ligands: From Agonist to Antagonist

“…Thus, novel hPPARγ-modulating agents that activate hPPARγ moderately, not fully, clearly need to be developed. Phosphorylation of Ser245 of hPPARγ with cyclin-dependent kinase 5 (Cdk5) is an important post-translational modification of hPPARγ [ 10 ]. CDK5 does not alter its adipogenic activity but dysregulated a specific set of genes with important roles in obesity and diabetes.…”

Targeting immunometabolic pathways for combination therapy in Alzheimer's disease

“…It has been suggested that failure to cross the BBB limits efficacy for these agents, or that off-target cardiovascular adverse effects offset potential benefits. 51 In summary, there is limited human evidence that the insulin sensitizers tested to date enhance brain insulin sensitivity or can act as effective therapeutic agents in AD in isolation. However, the important question of whether such agents provide additive benefit when combined with anti-amyloid treatment is still viable.…”

“…A phase III placebo‐controlled trial of pioglitazone to delay the onset of MCI and AD was terminated early due to lack of efficacy (NCT01931566). It has been suggested that failure to cross the BBB limits efficacy for these agents, or that off‐target cardiovascular adverse effects offset potential benefits 51 …”