P4-417: Combination treatment of galantamine and memantine reverses behavioural deficits in the anti-NGF mouse model of Alzheimer’s disease

Abstract

Galantamine is a modest acetylcholinesterase inhibitor and an enhancer of acetylcholine action on nicotinic receptors, probably through binding to an allosteric receptor site; memantine is an uncompetitive NMDA receptor antagonist. Both are used to treat Alzheimer's disease. Using the transgenic AD11 anti–NGF mouse model exhibiting a pathology mimicking “sporadic” AD, we explored potential actions of galantamine, memantine, and the combination. AD11 mice (4.5 months) were treated with IP galantamine 3.5 mg/kg/day or memantine 30 mg/kg/day in drinking water, or with both drugs for 2.5 months. Control groups consisted of WT and AD11 mice (all groups, n = 10), treated with vehicle. Due to deaths in the galantamine (n = 5), memantine (n =1) and combination treated (n = 5) AD11 mice, doses were reduced (galantamine 3.5 mg/kg/alternate days or memantine 20 mg/kg/day) for an additional 4.5 months. AD11 mice were tested for object (OR) recognition and context (CTX), before and during treatment. Spatial deficits were determined after treatment using the Morris water maze test (MWM). Intragroup and intergroup analysis was performed. Vehicle treated AD11 mice showed significant OR (P < 0.001), CTX (P = 0.045) and MWM deficits (P < 0.05). Despite reduced samples, drug efficacy could be tested. Galantamine (n = 6) and the combination (n = 4) rescued OR deficit (P = 0.009 and P = 0.007, respectively). Galantamine and the combination rescued CTX deficit during the initial phases of the treatment, with a reduced efficacy 5 months after treatment started (P = 0.06, P = 0.29, respectively). Memantine alone rescued OR deficit but did not ameliorate the late CTX deficit. All treatment regimens ameliorated the learning deficit during the acquisition phase of MWM, but only the combination improved the performance in the retention phase of MWM (P = 3.85 E–5). These data suggest that galantamine ameliorates OR and CTX deficits in AD11 mice and that the simultaneous administration of two drugs addressing AD at two different molecular levels reduces the spatial deficits in a mouse model for sporadic AD. Study sponsored by Janssen–Cilag Medical Affairs EMEA, a division of Janssen Pharmaceutica N.V.