Unlocking the Neuroprotective Effect of Quercetin Against Cadmium-Induced Hippocampal Damage in Rats: PPARγ Activation as a Key Mechanism.

Background: This study investigates the effects of cadmium chloride (CdCl(2)) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 rats per group as follows: control, CdCl(2) (0.5 mg/kg), CdCl(2) + PPARγ agonist (Pioglitazone, 10 mg/kg), CdCl(2) + QUR (25 mg/kg), and CdCl(2) + QUR + PPARγ antagonist (GW9662, 1 mg/kg). Treatments were administered orally for 30 days. At the end of the experiment, behavioral memory tests, hippocampal histology, markers of cholinergic function, neuroplasticity, oxidative stress, inflammation, and apoptosis, as well as transcription levels of some genes were carried out. Results: CdCl(2) exposure significantly reduced hippocampal PPARγ mRNA and DNA binding potential and nuclear levels. Additionally, CdCl(2) impaired spatial, short-term, and recognition memory, decreased granular cell density in the dentate gyrus (DG), and reduced levels of neuroprotective factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and several antioxidant enzymes including heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD), as well as reduced glutathione (GSH). Conversely, CdCl(2) elevated levels of oxidative stress, inflammation, and apoptosis markers such as interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), and cleaved caspase-3. QUR and Pioglitazone reversed these effects, restoring expression and PPARγ activation, improving memory, and modulating antioxidant and anti-inflammatory pathways. In contrast, blocking PPARγ with GW9662 negated the neuroprotective effects of QUR, exacerbating oxidative stress and inflammation by reversing all their beneficial effects. Conclusions: Activation of PPARγ by QUR or Pioglitazone offers a promising therapeutic strategy for mitigating CdCl(2)-induced neurotoxicity.