Unleashing the power of golden berry leaves to counteract cyclophosphamide's toll with antioxidant, anti-inflammatory, anti-apoptotic, and neurotransmitter boosting effects

Abstract

Ethnopharmacological relevance: Golden berries (Physalis peruviana) are esteemed for their healing properties and widespread use in traditional medicine, particularly for their neuroprotective benefits.

Aim of the study: This work aims to evaluate the neuroprotective effect of golden berry total leaf extract cultivated in Egypt (TLE) against cyclophosphamide (CP)-induced neurotoxicity and to identify the chemical composition of different organs of P. peruviana from both Egypt and USA.

Material and methods: Metabolite profiling of TLE was conducted using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). In the animal model experiment, CP (100 mg/kg, i.p.) was administered once weekly for four weeks to induce neurocognitive dysfunction. Concurrently, TLE (500 mg/kg, orally) was administered twice weekly throughout the four weeks to evaluate its effectiveness in alleviating CP-induced neuronal deficits. Behavioral assessments, Morris water maze and passive avoidance tests, were conducted, followed by, histological evaluations of brain tissue samples. Additionally, biochemical analyses were performed on hippocampal tissue samples, examining the following markers, acetylcholinesterase activity (AChE), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) activity, nuclear factor kappa B (p-NF-κB p65) (Ser536), Interleukin 1β (IL-1β), Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), and Bax (Bcl-2-associated X) levels.

Results: TLE significantly preserved hippocampal neurons and improved cognitive performance in behavioral tests. TLE achieved these beneficial effects by suppressing AChE activity, diminishing the oxidative stress and restoring redox balance via inhibiting p-NFκB/IL-1β,/TNFα/IL-6 cascades. Leaf extract revealed the highest total phenolic content (TPC) (2.7 ± 6.41 mg GAE/g extract) and total flavonoid content (TFC) (0.37 ± 1.19 mg QE/g) and the strongest antioxidant effects in Ferric Reducing Antioxidant Power (FRAP) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays with IC₅₀ values of 21.13 ± 1.48 and 18.19 ± 1.29 μg/mL, respectively. UHPLC-QTOF-MS/MS analysis resulted in the tentative identification of 20 metabolites including phenolic acids, flavonoids, hydroxycinnamic acid amides, and alkyl resorcinols.

Conclusions: Findings verify for the first time the neuroprotective potential of golden berry leaf, currently discarded as agricultural waste, and highlight its multifaceted mechanism of neuroprotection in CP-induced neurotoxicity, suggesting its suitability as a promising therapeutic agent for neurotoxicity management.

Keywords: Anti-apoptotic; Cyclophosphamide; Neuroprotective; Physalis peruviana, golden berry; UHPLC–QTOF-MS/MS.