Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

leads to severe brain damage and cognitive impairments. Although current treatments

alleviate acute cholinergic symptoms, they fail to address secondary neurotoxicity. This

study investigated the therapeutic potential of N-acetylcysteine-amide (AD4), a blood–

brain-barrier permeable antioxidant, in a survival mouse model of acute POX intoxication.

Male Swiss CD-1 mice received POX (4 mg/kg) followed by standard emergency therapy

(atropine, pralidoxime and diazepam). AD4 (150 mg/kg) was administered 2 and 6 h

post-exposure. AD4 treatment effectively prevented oxidative stress by reducing lipid

peroxidation and restoring the expression in hippocampus (HP) and/or prefrontal cortex

(PFC) of key antioxidant enzymes such as glutathione peroxidase-1 (GPx-1) and catalase

(CAT) suppressed by POX acute exposure. Moreover, AD4 attenuated neuroinflammation

in specific hippocampal subregions, as evidenced by reduced Glial Fibrillary Acidic Protein

(GFAP) and Ionized Calcium Binding Adaptor Molecule 1 (Iba-1) immunoreactivity. Im-

portantly, AD4 also rescued recognition memory deficits, as assessed by the Novel Object

Recognition Test (NORT). In summary, these findings demonstrate that AD4 mitigates

oxidative stress, neuroinflammation, and cognitive dysfunction following acute POX in-

toxication, supporting its potential as an adjuvant therapy for mitigating the secondary

neurotoxicity derived from organophosphorus poisoning.

function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide,

and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined

effects remain poorly understood. Apolipoprotein E (APOE) genotype influences vulnerability to cognitive

decline, with the ε4 allele being a major risk factor for neurodegenerative diseases. This study assessed the

interplay between APOE genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male

and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during

postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body

weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results

indicate that HFD-driven weight gain was influenced by sex and APOE genotype. All groups acquired the spatial

learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in

females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed

improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired

long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and

environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public

health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized

but tailored to individual profiles to optimize cognitive health and disease prevention.<