Neuroprotective effects of N-acetylcysteine-amide (AD4) in a Survival Mouse Model of Paraoxon Intoxication: Targeting Oxidative Stress, Neuroinflammation and Memory Impairments.

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.