The Organic Cation Transporter 2 Inhibitor Quinidine Modulates the Neuroprotective Effect of Nerve Growth Factor and Memantine on Cholinergic Neurons of the Basal Nucleus of Meynert in Organotypic Brain Slices.

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain characterized by degeneration of cholinergic neurons which is directly linked to cognitive decline. Nerve growth factor (NGF) is the most potent protective factor for cholinergic neurons, additionally the NMDA antagonist memantine blocks glutamate-mediated excitotoxic activity. Quinidine is an inhibitor of organic cation transporter 2 (OCT2). OCT2 is located on cholinergic neurons and plays a role in presynaptic reuptake and recycling of acetylcholine in the brain. We hypothesize that quinidine can modulate the protective effects of NGF and memantine on cholinergic neurons in organotypic brain slices of the nucleus basalis of Meynert (nBM). Organotypic brain slices of nBM were incubated with 100 ng/mL NGF, 10 µM memantine, 10 µM quinidine, and combinations of these treatments for 2 weeks. Cholinergic neurons were immunohistochemically stained for choline acetyltransferase (ChAT). Our data show that NGF as well as memantine counteracted the cell death of cholinergic nBM neurons. Quinidine alone had no toxic effect on cholinergic neurons but inhibited the protective effect of NGF and memantine when applied simultaneously. Our data provide evidence that quinidine modulates the survival of cholinergic nBM neurons via OCT2.