Stress-related symptoms are a global concern, impacting millions of individuals, yet effective and safe treatments remain scarce. Although multiple studies have highlighted the stress- alleviating properties of saffron extract, the underlying mechanisms remain unclear. This study employs the unpredictable chronic mild stress (CMS) animal model to investigate the impact of a standardized saffron extract, Affron^® (AFN), on hypothalamic–pituitary–adrenal (HPA) axis regulation and neuroplasticity in Wistar rats following repeated oral administration. The research evaluates AFN’s effects on various stress-related parameters, including hypothalamic gene expression, stress hormone levels, and the sucrose preference test. In animals subjected to continuous unpredictable CMS, repetitive administration of AFN at doses of 100 mg/kg and 200 mg/kg effectively normalized HPA axis dysregulation and enhanced neuroplasticity. Increased concentrations of AFN demonstrated greater efficacy. Following AFN oral administration, adrenocorticotropic and corticosterone hormone levels exhibited significant or nearly significant reductions in comparison to subjects exposed to stress only. These changes align with the alleviation of stress and the normalization of the HPA axis. These findings elucidate AFN’s role in stress mitigation, affirm its health benefits, validate its potential as a treatment for stress-related symptoms, confirm its physiological effectiveness, and emphasize its therapeutic promise.

Ko K, et al. J Vet Sci. 2024 May;25:e49. https://doi.org/10.4142/jvs.24076

Background/Objectives: Astrocytic redox-inflammatory signaling has been implicated in Parkinson’s disease (PD) pathology and may constrain hippocampal neurogenesis. We previously identified an astrocytic NOX4–MPO–OPN axis associated with impaired neurogenic capacity. Here, we tested whether a saffron-derived antioxidant (SDA; Crocus sativus extract) and Passiflora incarnata L. extract (PI) modulate this pathway in an MPTP-induced PD mouse model. Methods: Male C57BL/6J mice were randomized to Sham, MPTP, and treatment groups (n = 9/group for behavior; n = 4–5/group for histology/immunoblotting). SDA or PI (50 mg/kg/day, oral, 5 weeks) was administered, with resveratrol as a positive control. Behavioral, histological, and molecular analyses were performed by investigators blinded to group allocation where feasible. Results: SDA and PI were associated with reduced NOX4/MPO/OPN signals, mainly in GFAP-positive astrocytes, along with recovery of neurogenesis markers (Ki67, DCX, BrdU/NeuN) and synaptic markers (PSD95, synaptophysin), and improved motor performance. Mitochondrial and oxidative injury markers (TIM23, TOM20, OXPHOS subunits; 4-HNE) and apoptotic markers (Bax, cleaved caspase-3, Bcl-2) also shifted toward Sham levels. Given previous reports of Passiflora extracts’ sedative effects, we note that metabolic measures (body weight, food intake, and water intake) were similar across groups; however, specific tests for sedation or arousal were not conducted. Conclusions: These findings offer preclinical evidence that SDA and PI modulate redox-inflammatory and mitochondrial stress signatures and are associated with neurogenic, synaptic, and behavioral improvements in an acute MPTP model. Further validation in chronic/genetic PD models and pharmacokinetic/brain exposure studies will be necessary to confirm their translational potential.

Oxidative stress contributes to neuronal injury in Parkinson’s disease (PD), and the cerebellum is increasingly recognized as an affected region. We previously reported that Fetuin-A (alpha-2-HS-glycoprotein) is reduced in cerebellar Purkinje cells in human PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and that silencing it reduces Purkinje cell survival without apoptosis. We asked whether this reduction is pharmacologically modifiable by saffron-derived antioxidant (SDA) and Passiflora incarnata L. extract (PIE). SDA and PIE were administered orally at 50 mg/kg/day for 5 weeks to MPTP-treated C57BL/6J mice, with resveratrol (RES) as a comparator. In 1-methyl-4-phenylpyridinium (MPP⁺)-challenged primary cerebellar neurons, SDA and PIE were tested at 25 µg/mL and RES at 200 µg/mL. MPTP lowered nigral tyrosine hydroxylase immunoreactivity, grip strength, rotarod performance, Purkinje cell density and cerebellar Fetuin-A and raised cleaved caspase-3, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Fluoro-Jade C signals. SDA and PIE attenuated all these changes. In vitro, MPP⁺ raised 2′,7′-dichlorofluorescin diacetate (DCFDA) fluorescence and lowered Fetuin-A, and all three treatments reduced DCFDA fluorescence and restored Fetuin-A. Annexin V/propidium iodide (PI) profiling showed a substantial Annexin V⁻/PI⁺ necrotic component at 24 h, consistent with our earlier knockdown data. Cerebellar Fetuin-A emerges as a treatment-responsive correlate of Purkinje cell integrity.