Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus)

Abstract

The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)—induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

Strengths and Weaknesses of the Gray Mouse Lemur (Microcebus murinus) as a Model for the Behavioral and Psychological Symptoms and Neuropsychiatric Symptoms of Dementia

“…The disruptive effect of SD on spatial memory retrieval thus constitutes an interesting validated challenge in investigating the impact of new drugs during both normal and pathological aging. The experiment was repeated in aged animals with similar conclusions, but the effects on memory retrieval (impairment) were stronger in aged animals (Rahman et al, 2017). In the Rahman study, two symptomatic AD drugs were tested to verify the validity of the model.…”

“…The progressive loss of limbic and neocortical cholinergic innervation (Hampel et al, 2018) and the dysfunction of somatostatin-positive interneurons associated with memory deficits have also not been clearly demonstrated (Dournaud et al, 1994). Nevertheless, the acetylcholinesterase inhibitor donepezil—and the N-methyl-D-aspartate antagonist memantine—prevent sleep deprivation (SD)–induced deficits in the retrieval of spatial memory both in young and aged mouse lemurs (Rahman et al, 2017) (see Sleep Deprivation to Induce Transient Cognitive Impairment Section for details). Anti-amyloid β immunotherapy induced an immune response, increased amyloid β 1–40 plasma levels, and elicited microhemorrhages and iron deposits in the choroid plexus (Joseph-Mathurin et al, 2013).…”

“…In the Rahman study, two symptomatic AD drugs were tested to verify the validity of the model. Both donepezil (an acetylcholinesterase inhibitor) and memantine (an N-methyl-D-aspartate antagonist), when administered 3 h before the memory session (during the last third of the SD period), prevented the deficits induced by SD in memory retrieval in both young and aged animals (Rahman et al, 2017). The effect was dose dependent (donepezil at 0.1 and 1 mg/kg was efficient, while memantine was efficient at 1 mg/kg and not at 0.1 mg/kg).…”

Evaluation of the effects of donepezil, memantine and α-lipoic acid combined administration in amnesia rats on impaired cognitive functions in terms of behavioural, apoptotic, cholinergic and glutamatergic systems

“…Scopolamine and memantine were dissolved in physiological saline (PS) to create a final injection volume of 1 ml/kg. Scopolamine, donepezil, memantine or saline was injected intraperitoneally (i.p) 3h before the onset of the cognitive function test (11). All antibodies were supplied from Santa Cruz Biotechnology, Inc (Santa Cruz, CA, USA).…”

“…This case constitutes the basic rationale of cholinergic replacement therapy in the treatment approach of AD patients. Despite the reported symptomatic and cognitive benefits of donepezil and memantine in AD patients, these drugs cannot stop or prevent AD progression (11)(12)(13).…”