Pterostilbene Combating Cyclophosphamide-Induced Central Neuro-Inflammation in Rats: Effect on GFAP, PPAR- γ, NLRP3, COX-2 and Nrf2/HO-1 Pathway

Background/Objectives: The clinical efficacy of cyclophosphamide, a commonly used chemotherapeutic drug, is often restricted by off-target neurotoxicity, which is primarily caused by oxidative stress, neuroinflammation, and apoptosis. With the aim of finding natural neuroprotective agents, pterostilbene was investigated in this study, either in conventional form or when solubilized as a nanoemulsion, for its neuroprotective potential against cyclophosphamide-induced neurotoxicity. Methods: Female Wistar rats were orally administered pterostilbene, either in its conventional form (50 mg/kg p.o) or nanoemulsion form (25 and 50 mg/kg p.o), for 15 days. Cyclophosphamide was injected once on day 14 (200 mg/kg ip). Results: Our findings revealed that administering pterostilbene as a nanoemulsion or in its conventional powder form managed to counteract the cyclophosphamide-induced intoxication features via disrupting the oxidative stress–inflammasome–cytokine axis; by upregulating cortical and hippocampal PPAR-γ, Nrf2, HO-1, BCL2 levels and the BCL2/Bax ratio; and downregulating NLRP3, IL-1β, COX-2, Bax and GFAP levels. Further histopathological and immunohistochemical evaluation confirmed the improved neuronal morphology, reduced degeneration and apoptosis, restoration of cortical and hippocampal architecture, and normalization of GFAP expression levels, approaching those of the control group upon treatment with either conventional or nanoformulated pterostilbene. Conclusions: The promising nature of the nanoemulsion formulation, particularly when administered at the high dose level, was evidenced, hence emphasizing the important role of proper formulation of natural bioactives such as pterostilbene in maximizing their therapeutic potential.