Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats

Abstract

Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aβ) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aβ accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg(-1)) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

“…Furthermore, thiazolidinedione drugs are insulin sensitizers and deficits in the insulin pathway are co-morbid with cognitive impairment in AD (Gad et al, 2015; Sato et al, 2011; Perez & Quintanilla, 2015; Rodriguez-Rivera et al, 2011; Jahrling et al, 2014; Xu et al, 2014; Cowley et al, 2012; Bosco et al, 2011; Escribano et al, 2010; Escribano et al, 2009). Based on this evidence, we posited that genetic deletion of FGF14 could affect the insulin pathway.…”

“…Epidemiological studies have demonstrated a link between insulin signaling, cognition, and risk for AD. Supporting this link, the class of insulin-sensitizing drug known as the thiazolidinediones, which includes rosiglitazone (RSG) and pioglitazone (PIO), and are potent and selective agonist of the peroxisome proliferator-activated receptor gamma (PPARγ), has shown efficacy in patients with MCI (Mild Cognitive Impairment) and concomitant insulin resistance (Risner et al, 2006; Harrington et al, 2007; Watson et al, 2005; Gad et al, 2015; Sato et al, 2011; Perez & Quintanilla, 2015). Likewise, RSG treatment rescues hippocampus-dependent cognitive function in the Tg2576 AD mouse model (Rodriguez-Rivera et al, 2011; Denner et al, 2012) by a mechanism that involves normalized intrinsic excitability and synaptic function of granule neurons in the dentate gyrus (DG), a critical location for new memory formation (Nenov et al, 2015).…”

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

“…Therefore, the blockade of PPARα and PPARβ/δ may be impairing the formation of a new memory upon reexposure to the conditioned arena. Most studies investigating the role of PPARs in memory have investigated their role in models of mnemonic impairment, such as diabetes-induced cognitive dysfunction [35,36], morphine-induced mnemonic dysfunction [13], scopolamine-induced memory…”

“…Therefore, the blockade of PPARα and PPARβ/δ may be impairing the formation of a new memory upon re-exposure to the conditioned arena. Most studies investigating the role of PPARs in memory have investigated their role in models of mnemonic impairment, such as diabetes-induced cognitive dysfunction [35,36], morphine-induced mnemonic dysfunction [13], scopolamine-induced memory impairment [37][38][39] and others [40][41][42][43]. There are studies showing that the modulation of PPARs may also affect memory in subjects whose mnemonic abilities were preserved.…”

Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration

“…Clinical studies indicate that in patients with cognitive impairment or AD in early stages, thiazolidinediones improve long‐term memory functioning (Galimberti & Scarpini, ) . Also, in murine models, it is evident that the treatment with this drug improves synaptic transmission and reduces neuronal damage, in response to a toxicity (Gad, Zaitone, & Moustafa, ). However, further studies are needed to demonstrate that thiazolidinediones are one more option for the treatment of AD.…”