2026 ECNP Congress

PS03-3259

Pioglitazone alleviates post-weaning social isolation-induced cognitive impairments via PPAR-γ-Dependent BDNF upregulation in the prefrontal cortex and hippocampus of rats

Semil Selcen Gocmez — G. Celebi, S.H. Furat, G. Duruksu, Y. Yazir, T. Utkan · Kocaeli University Faculty of Medicine, Department of Pharmacology, Kocaeli, Türkiye

2026 ECNP Congress

Introduction

Post-weaning social isolation (SI) serves as a potent neurodevelopmental stressor that disrupts cognitive functions and neuroplasticity [1]. The Peroxisome Proliferator-Activated Receptor gamma (PPAR-γ) and Brain-Derived Neurotrophic Factor (BDNF) are critical mediators of neuronal survival and memory.

Aims

This study hypothesized that PPAR-γ activation via pioglitazone could rescue cognitive deficits induced by early-life SI by modulating the PPAR-γ/BDNF signaling axis in the prefrontal cortex (PFC) and hippocampus.

Methods

Post-weaned male Wistar rats were housed individually (SI) or in groups (Socially Reared - SR) for 8 weeks [2]. Rats were randomly assigned to four groups: SR, SI, SI+Pioglitazone, and SI+Pioglitazone+GW-9662. Pioglitazone (30 mg/kg/day, p.o.) was administered during the final 16 days of the 8-week isolation period. To evaluate the specific involvement of PPAR-γ, the selective antagonist GW-9662 (1 mg/kg/day, i.p.) was administered 30 minutes prior to each pioglitazone treatment. Spatial and emotional memories were assessed via Morris Water Maze (MWM) and the Passive Avoidance Test (PAT). Following behavioural assessments, rats were euthanized under deep anaesthesia. The right hemispheres (PFC and hippocampus) were snap-frozen for BDNF ELISA analysis, while the left hemispheres were immersion-fixed in 10% buffered formaldehyde for PPAR-γ and BDNF immunohistochemical (IHC) evaluations. Statistical analyses and graphical representations were performed using GraphPad Prism software, with p < 0.05 considered statistically significant.

Results

SI-reared rats exhibited significant spatial memory impairments in the MWM, evidenced by reduced time spent (p < 0.0001) and fewer entries (p < 0.0002) into the target quadrant. Regarding emotional memory, while there were no significant differences in PA acquisition latency on the first day (p = 0.8548), SI-reared rats showed a dramatic decrease in retention latency during the second day (p < 0.0001), indicating impaired memory consolidation. These deficits were associated with significantly lower PPAR-γ and BDNF IHC scores in both the PFC and hippocampus (p < 0.0001), alongside reduced BDNF levels in ELISA in the PFC (p = 0.0367) and hippocampus (p = 0.0059). Pioglitazone treatment successfully reversed behavioural impairments and restored molecular markers (p < 0.05). Importantly, the pre-administration of GW-9662 abolished the therapeutic effects of pioglitazone. Pearson correlation analysis revealed a strong and significant positive correlation between PPAR-γ and BDNF protein levels in both the PFC (r = 0.7419, p = 0.0002) and the hippocampus (r = 0.8465, p < 0.0001). The high correlation coefficients (R2values of 0.5504 and 0.7166, respectively) indicate that a substantial proportion of the variance in BDNF expression is explained by changes in PPAR-γ levels.

Conclusions

Our findings demonstrate that the PPAR-γ/BDNF pathway in the PFC and hippocampus is a key mediator of cognitive dysfunction resulting from post-weaning social isolation. The strong correlation between these markers and the blockade of pioglitazone’s effects by GW-9662 confirm that neuroprotection is specifically mediated through PPAR-γ-dependent neurotrophic support. The potent neuroprotective effect of pioglitazone highlights PPAR-γ as a promising pharmacological target for mitigating the long-term neurodevelopmental consequences of early-life psychosocial stress.

Acknowledgment: The present study received financial support from Scientific Research Projects of Kocaeli University (TDK-2022-3192).

Keywords: Social Isolation, Pioglitazone, PPAR-gamma, BDNF, Cognition, Prefrontal Cortex, Hippocampus.

References

  1. Fone, K.C.F. and Porkess M.V., 2008. Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders, Neurosci Biobehav Rev 32, 1087–1102. https://doi.org/10.1016/j.neubiorev.2008.03.003.
  2. Chmelova, M., Balagova, L., Marko, M., Vrankova, S., Cebova, M., Jezova, D., Riecansky, I., and Hlavacova, N., 2019. Behavioral alterations induced by post-weaning isolation rearing of rats are accompanied by reduced VGF/BDNF/TrkB signaling in the hippocampus, Neurochemistry International 129, 104473. https://doi.org/10.1016/j.neuint.2019.104473.