Brosimine B and the Biphasic Dose-Response: Insights into Hormesis and Retinal Neuroprotection

Susanne Suely Santos da Fonseca ^1,2* Natacha Medeiros de Souza Port's ³ Gisele Priscila Soares de Aguiar ³ Eliã Pinheiro Botelho ³ Nádia Miléo Garcês de Couto ⁴ Wandson Braamcamp de Souza Pinheiro ⁴ André Salim Khayat ⁵ Elizabeth Sumi Yamada ⁶ Edmar Tavares da Costa ⁶ Chubert Bernardo Castro de Sena ⁷ Mara Silvia Pinheiro Arruda ⁴ Carlomagno Pacheco Bahia ³ Antonio Pereira ²

• ¹ Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Brazil
• ² Institute of Technology, Federal University of Pará, Belém, Pará, Brazil
• ³ Laboratory of Neuroplasticity, Institute of Health Sciences, Federal University of Pará, Belém, Pará, Brazil
• ⁴ Central Extraction Laboratory, Federal University of Pará, Belém, Pará, Brazil
• ⁵ Oncology Research Center, Hospital University João of Barros Barreto, Belém, Brazil
• ⁶ Laboratory of Experimental Neuropathology, Hospital University João of Barros Barreto, Federal University of Pará, Belém, Brazil
• ⁷ Laboratory of Structural Biology, Federal University of Pará, Belém, Brazil

The biphasic dose-response behavior, also known as hormesis, is a characteristic feature of numerous natural products. Beneficial effects at low concentrations and toxicity at higher doses define it. This study investigates the hormetic effects of Brosimine B, a flavonoid derived from Brosimum acutifolium, on retinal cell viability under oxidative stress. Using an oxygen-glucose deprivation (OGD) model to simulate ischemic conditions, we observed that Brosimine B at 10 µM significantly enhanced cell viability and reduced reactive oxygen species (ROS) production, likely through modulation of oxidative stress-protective enzymes such as catalase. However, higher concentrations (>10 µM) induced cytotoxic effects. To characterize this biphasic response, we applied a computational modelling approach with a hormetic (inverted U-shaped) model, which provided biologically interpretable parameters, including the peak response at 10.2 µM and the hormetic zone width (σ = 6.5 µM) (R² = 0.984). The results confirm that Brosimine B exhibits hormetic neuroprotective effects within a well-defined concentration window, supporting its potential as a therapeutic agent for oxidative stress-related retinal damage. This study underscores the value of computational modeling in optimizing dose-response analyses, providing a framework for refining natural product therapies and predicting toxicological thresholds in pharmacological applications.