Diverse Effects of an Acetylcholinesterase Inhibitor, Donepezil, on Hippocampal Neuronal Death after Pilocarpine-Induced Seizure

Abstract

Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer’s disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.

Effects of Cerebrolysin on Hippocampal Neuronal Death After Pilocarpine-Induced Seizure

“…It is well-established that neuronal death occurs in the brain after a seizure (Kim et al, 2012;Jeong et al, 2017;Lee S. H. et al, 2018), but the mechanisms through which this injury occurs remain elusive. When neuronal death occurs, an inflammatory response is initiated to restore tissue homeostasis and remove dead cells (Chapkin et al, 2009;Karin and Clevers, 2016).…”

“…Seizure is one of the most common neurological diseases, but methods for preventing the cell death mechanisms that occur post-seizure and repairing this injury after a seizure remain uncertain. Seizures cause serious damage to the hippocampus, and neuronal death is ultimately caused by a series of cell death cascades involving excessive inflammation, glial activation, apoptosis, oxidative stress, and zinc accumulation ( Kim et al, 2012 ; Jeong et al, 2017 ). Here, we focused on the rescue of seizure-induced neurological damage with cerebrolysin.…”

“…We next performed staining for NeuN, a specific marker of live neurons, and cleaved caspase-3, a specific marker for apoptotic cells, to confirm the effects of cerebrolysin on neuronal death after pilocarpine-induced seizure. It is already well known that the number of live neurons decreases after a seizure ( Kim et al, 2012 ; Jeong et al, 2017 ; Lee S. H. et al, 2018 ). Also, it is already well established that the number of apoptotic cells increases after a seizure ( Lee J. M. et al, 2018 ; Li et al, 2019 ).…”

“…Thus, if the hippocampus is damaged by seizure, damage to the neuronal cells and changes in metabolic processes can result in the hippocampus failing to function normally (Holmes, 1991;Najm et al, 1998;Pitkanen and Sutula, 2002;Haut et al, 2004;Lukoyanov et al, 2004;Vingerhoets, 2006). Cognitive impairment and neuronal injury in epileptic patients remain important medical problems (Jeong et al, 2017;Lee S. H. et al, 2018). Various animal models have been developed to help identify therapeutic interventions to prevent these negative epileptic outcomes (Xie et al, 1995;Smolders et al, 2002;Remy et al, 2003).…”

Donepezil increases resistance to induced seizures in a mouse model of Dravet syndrome

“…Although the effect of donepezil on spontaneous seizures was not examined, it was recently demonstrated that administration of donepezil following pilocarpine‐induced SE protected against hippocampal neuron loss . Furthermore, donepezil also protects against glutamate neurotoxicity .…”