Unexpected Effects of Acetylcholine Precursors on Pilocarpine Seizure-Induced Neuronal Death

BACKGROUND: Choline alfoscerate (α-GPC) and Cytidine 5’-diphosphocholine (CDP-Choline) are both acetylcholine precursors and are considered to act as pro-cholinergic nootropic agents. Acetylcholine precursors have also recently found frequent use in the neurology clinic. Stroke and many types of dementia have been shown to respond favorably after treatment with these agents, not only in terms of cognitive dysfunction but also behavioral and psychological symptoms. The primary mechanisms of Acetylcholine precursors are the following: 1) Acetylcholine precursors themselves are used in the biosynthesis of acetylcholine and 2) byproducts like glycerophosphate have protective functions for neuronal phospholipids. However, whether acetylcholine precursors have a similar effect in treating cognitive impairment in patients with epilepsy remains controversial. METHODS: Our previous studies investigating acetylcholine precursors in seizure-experienced animals have produced variable results that were dependent on the timing of administration. RESULTS: Early administration of CDP-choline immediately after seizure increased neuronal death, blood-brain barrier (BBB) disruption and microglial activation in the hippocampus. However, administration of α-GPC starting 3 weeks after seizure (late administration) improved cognitive function through reduced neuronal death and BBB disruption, and increased neurogenesis in the hippocampus. CONCLUSION: These seemingly contradictory results may be attributed to both epileptogenic features and neuroprotective functions of several acetylcholine precursors.