Cinnamaldehyde Regulates Insulin and Caspase-3 Signaling Pathways in the Sporadic Alzheimer's Disease Model: Involvement of Hippocampal Function via IRS-1, Akt, and GSK-3β Phosphorylation.

Insulin signaling disruption and caspase-3 cleavage play a pathologic role in Alzheimer's disease (AD). Evidence suggested that cinnamaldehyde (Cin), the major component of cinnamon, has the ability to act as a neuroprotective agent. However, little evidence is available to demonstrate its effectiveness in regulating the insulin and caspase-3 signaling pathways and underlying molecular mechanisms. Therefore, the present study was conducted to correlate the molecular mechanisms of these signaling pathways and Cin treatment on animal behavioral performance in an intracerebroventricular (ICV)-streptozotocin (STZ, 3 mg/kg) model. The sporadic AD rat model was treated with Cin (10 and 100 mg/kg; intraperitoneal, i.p) daily for 2 weeks. Novel object recognition (NOR), Morris water maze (MWM), and elevated plus maze (EPM) tests were performed to assess recognition/spatial memory and anxiety-like behavior, respectively. Hippocampal Aβ aggregation was assessed using Congo red staining. The activity of hippocampal caspase-3 and IRS-1/Akt/GSK-3β signaling pathways were analyzed using the Western blot technique. The results revealed that Cin (100 mg/kg, effective dose) improved recognition/spatial memory deficits and anxiety-like behavior. In addition, Cin negated the effects of STZ on Aβ aggregation and caspase-3 cleavage in the hippocampus. Furthermore, the Western blot method showed that hippocampal IRS-1/AKT/GSK-3β phosphorylation was altered in ICV-STZ animal model, while Cin modulated this signaling pathway through decreasing Phospho.IRS-1Ser307/Total.IRS-1 ratio and also increasing Phospho.AktSer473/Total.Akt and Phospho.GSK-3βSer9/Total.GSK-3β ratios. These findings suggest that Cin is involved in the regulation of hippocampal IRS-1/AKT/GSK-3β and caspase-3 pathways in a sporadic AD model, and modulation of these signaling pathways also influences the animal behavioral performance.