Ibuprofen and Glutathione Conjugate as a Potential Therapeutic Agent for Treating Alzheimer's Disease

<jats:title>Abstract</jats:title><jats:p>Non‐steroidal anti‐inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, we synthesized a molecular combination of glutathione (GSH) and ibuprofen (IBU) via an amide bond and investigated its potential for targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation are related to AD. Evaluation of its physicochemical and <jats:italic>in‐vitro</jats:italic> antioxidant properties indicated that compound <jats:bold>1</jats:bold> exhibits good stability toward human plasma enzymatic activity, and, like GSH, displays <jats:italic>in‐vitro</jats:italic> free radical scavenging activity in a time and concentration‐dependent manner. The new compound was also assessed by infusion in a rat model for Alzheimer's disease for its potential to antagonize the deleterious structural and cognitive effects of β‐amyloid(1‐40). In behavioral tests of long‐term spatial memory, animals treated with codrug <jats:bold>1</jats:bold> performed significantly better than those treated with β‐amyloid (Aβ) peptide. Histochemical findings confirmed the behavioral data, revealing that Aβ protein was less expressed in cerebral cortex treated with <jats:bold>1</jats:bold> than that treated with IBU. Taken together, the present findings suggest that conjugate <jats:bold>1</jats:bold> treatment may protect against the oxidative stress generated by reactive oxygen species (ROS) and the cognitive dysfunction induced by intracerebroventricular (i.c.v.) infusion of Aβ(1‐40) in rats, and thus that codrug <jats:bold>1</jats:bold> could prove useful as a tool for controlling AD induced cerebral amyloid deposits and behavioral deterioration.</jats:p>