title: Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration.
abstract: Memantine, a non-competitive NMDA receptor antagonist, is used for the treatment of Alzheimer's disease (AD) and off-label as an anti-depressant. Here we investigated possible anti-depressant, cognitive enhancing and neuroprotective effects of memantine in the olfactory bulbectomized (OBX) rat. OBX is used as a screening model for antidepressants and shows cognitive disturbances. In Experiment I, memantine treatment started 14 days after OBX surgery (this setup is similar to what we use for screening of potential antidepressants) and 2 days before surgery in experiment II. In both experiments, memantine (20 mg/kg, p.o) was administered once daily for 28 days. Animals were tested in the open field (locomotor activity), passive avoidance (fear learning and memory), and holeboard (spatial acquisition and memory) before and after the bulbectomy. Memantine, when administered before surgery, prevented OBX-induced hyperactivity and partly fear memory loss. These behavioral effects were present for at least 3 weeks after cessation of treatment. Memantine, however did not improve spatial memory. When administered 2 weeks after OBX surgery, memantine was ineffective in normalizing open field hyperactivity and improving cognitive deficits. Interestingly, after the animals were retrained in passive avoidance, memantine- treated OBX rats (both in experiment I and II) showed improved fear learning and memory. Our findings suggest that memantine has both neuroprotective and cognitive enhancing effects without antidepressant-like properties in the OBX rat. Based on our results, we propose that memantine may be more beneficial to AD patients when administered early in the disease process.
authors.affiliation: Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. yborre@gmail.com
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Borre
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Bosman
authors.forename: Susan
authors.initials: S
authors.lastname: Lemstra
authors.forename: Koen G
authors.initials: KG
authors.lastname: Westphal
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Oosting
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000523:psychology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009830:Olfactory Bulb / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine