Isoflurane-Induced Spatial Memory Impairment in Mice is Prevented by the Acetylcholinesterase Inhibitor Donepezil

Abstract

Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg) or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2%) for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE), choline acetylase (ChAT) and α7 nicotinic receptor (α7-nAChR) were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or α7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

Donepezil Is Ineffective in Promoting Motor and Cognitive Benefits after Controlled Cortical Impact Injury in Male Rats

“…For example, chronic intragastric donepezil (5 mg/kg/day) had no effects on whole-brain AChE protein levels, but it did increase levels of choline acetyltransferase (ChAT), the rate-limiting enzyme for the synthesis of acetylcholine, and it reversed spatial learning deficits in aged mice. 54 Similarly, we reported an attenuation of CCI-induced ChAT( + ) medial septal cell loss at 3 weeks post-injury that correlated with improved cognitive performance. 40 Furthermore, Pike and Hamm showed an attenuation of fluid percussion (FP) injury-induced reduction of basal forebrain ChAT immunoreactivity after chronic administration of Lu 25-109-T, a partial M1 muscarinic receptor agonist and presynaptic M2 autoreceptor antagonist.…”

Neuroprotective effects of donepezil against cholinergic depletion

“…In fact, though spatial change detection implies efficient spatial mapping, novelty detection implies recognition of the salient object, thus minimizing the effect of the spatial and contextual factors [38,48,49]. Interestingly, the preserved abilities in detecting spatial change of Don-Sap rats reveal the specific neuroprotective effect of donepezil on a subtle spatial deficit induced by the cholinergic lesion and are in agreement with donepezil neuroprotective properties on spatial mnesic performances in different brain damage models [12-14,26,27]. …”

Alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigates isoflurane-induced cognitive impairment in aged rats

“…In contrast to the changes of proinflammatory cytokines, the tendency of increased apoptosis in the hippocampal CA1 region of the rats exposed to 1.3% isoflurane is in agreement with the impaired performance of these rats in the water maze test. Because hippocampal neuronal apoptosis [5,10,11,25], amyloid pathology [26], cholinergic dysfunction [27], and synaptic ultrastructure impairments [5,10,11,28], and so forth were postulated to be associated with isoflurane-induced cognitive dysfunction, the phenomenon may be caused by detrimental effects of isoflurane in the early phase, such as acute neuroinflammation, so that the previously mentioned events subsequently occur and lead to the delayed cognitive dysfunction.…”