Histone Deacetylase Inhibitor Combined with Rosiglitazone Improves Cognitive Function via Microglial Polarization and Increased Mature/pro-BDNF in Alzheimer’s Disease.

Alzheimer’s disease (AD) is characterized with impaired brain metabolism, cognitive impairments, neural loss, astrogliosis, and microgliosis. We hypothesized that co-administration of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, and a histone deacetylase (HDAC) inhibitor would enhance cognitive function in an AD model. Methods: Forty adult male Wistar rats were randomly assigned into five groups (n = 8 per group): (1) Control group receiving saline, (2) AD model group (induced by i.c.v injection of Streptozocin), (3) AD + Rosiglitazone (ROSI) (4) AD+MS-275, and (5) AD + combined ROSI and MS-275 group. Cognitive functions was evaluated using the passive avoidance test and the Morris water maze (MWM). Microglial polarization was assessed by flow cytometry, and protein expression was analyzed by western blotting. Results: Data analyzed by one-way ANOVA and post hoc Tukey for (MWM) showed a significant decrease in latency to the target quadrant both in working and reference memories, and a significant increase in total time spent (TTS) in the target quadrant for reference memory in the group of STZ + ROSI + MS-275 (p < 0.000). Kruskal-Wallis H test revealed a significant increase in the M2/M1 ratio for ROSI + MS-275 + STZ group compared with the STZ + Saline group (p = 0.001). Conclusion: These findings suggest that co-administration of Rosiglitazone and MS-275 improves cognitive function in AD rats, potentially through shifting microglial polarization from the M1 to the M2 phenotype and enhancing synaptic strength via an increased mature brain-derived neurotrophic factor (BDNF)/pro-BDNF ratio.