EFEITOS DA GRANDISINA E SEU ANÁLOGO ISOXAZÓLICO SOBRE A PERFORMANCE COGNITIVA E ESTRESSE OXIDATIVO EM UM MODELO IN VIVO DA DOENÇA DE ALZHEIMER

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation and deposition of the beta-amyloid protein (βA) in the brain. Pharmacological treatments currently available show limited effectiveness in slowing cognitive decline, making the search for new therapeutic options essential. Research indicates the potential of multi-target compounds capable of modulating underlying pathways such as neuroinflammation and oxidative stress. In this context, tetrahydrofuran neolignans, such as grandisin (GRA), have shown anti-inflammatory and antioxidant potential. In previous studies, the triazolic derivative of GRA produced aneuroprotective effects against βA injection in animals. Given such results, the present study evaluated the effect of repeated treatment with GRA and its isoxazolic derivative (AIG) in an animal model of AD, with emphasis on the memory related response under different routes of administration. The study used C57/BL6 mice (CEUA protocol: 1.272/2023), which were subjected to intracerebroventricular (i.c.v.) injection of βA or vehicle (10% DMSO). They were divided into the following groups: i.c.v. Control/Vehicle (oral or i.p.), i.c.v. βA/Vehicle (oral or i.p.), i.c.v. βA/GRA (oral or i.p.; 1 mg/kg), and i.c.v. βA/AIG (oral or i.p.; 1 mg/kg). Treatment lasted seven days, beginning one day after surgery. 24 hours after the end of the treatment, the animals were submitted to the Object Recognition Test (ORT) to calculate the discrimination index (d2). In summary, only GRA prevented cognitive impairment when the compounds were administered via the i.p. route. However, when administered orally, both GRA and AIG showed neuroprotective effects, with AIG presenting a significantly higher d2 value than GRA. These results suggest that AIG requires metabolic activation, characteristic of a prodrug.