Xanthatin-13-(Pyrrolidine-2-Carboxylic Acid), a Sesquiterpene Lactone Isolated From Burdock Leaf, Attenuated AβToxicity and Memory Deficits in a Pharmacological Mouse Model of Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) is a severe form of dementia, which occurrence increases with age and lifestyle conditions. It is characterized by amyloid protein accumulation forming senile plaques, hyperphosphorylated tau protein forming neurofibrillary tangles, neuroinflammation, and oxidative stress, leading to synapse loss and cell death. Pharmacological alternatives to conventional treatments include alkaloids with anti-inflammatory and antioxidant properties. Sesquiterpene lactones, such as Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc) from burdock leaf, show promise due to their antioxidant activity targeting glucose-6-phosphate dehydrogenase. This study evaluated XPc's protective effects in vivo using Aβ-treated mice, a pharmacological AD model, and explores its synergistic potential with neuroprotective agents like TSPO activators or sigma-1 receptor agonists. Mice were administered Aβpeptide (9 nmol ICV) and XPc (0.3-3 mg/kg) daily for 4 days. Behavioral tests assessed memory deficits and anxiety. Post-sacrifice, brains were analyzed for neuroinflammation and oxidative stress markers. Combination studies involved XPc with the TSPO activator PK11195 or the sigma-1 receptor agonist PRE-084, with memory evaluated in two behavioral tests. Combination indices were calculated to assess synergy. XPc (1-3 mg/kg) prevented Aβ-induced memory impairments and anxiety. It reduced astroglial reaction, blocked microglial activation, and confirmed antioxidant activity by lowering lipid peroxidation and protein nitrosylation. Combinations with PK11195 or PRE-084 showed synergistic protection in memory tests. XPc is a potent neuroprotective agent against AD-like toxicity in this murine model, effective alone or in synergistic combinations with other drugs.