P1-439: NO chimera drugs provide reversal of cognition deficits in animal models: GT 1061 an investigational new drug for Alzheimer’s

Abstract

Nitric oxide (NO) signaling is essential for normal physiological function in the CNS, including learning and memory, and is compromised in many disease states including neurodegenerative disorders. GT 1061 is an NO mimetic therapeutic agent that has received FDA regulatory approval for Alzheimer's disease (AD) clinical trials, one of a class of agents that has shown neuroprotective and cognition–enhancing properties. Data have been published showing reversal of cognition deficits by GT 1061 in two animal behavioral models. To extend the behavioral profiling of this drug to further animal models and to develop insights into mechanisms of action. Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine, most notably aging and AD. Bilateral depletion of neocortical and hippocampal acetylcholine in rats using the cholinergic toxin saporin produces deficits in spatial learning and in delayed, visual matching–to–sample tasks; thus, either saporin or scopolamine were used to induce cognition deficits. The cognition–enhancing properties of GT 1061 were assayed in a contextual memory task in young and elderly rats and the step through passive avoidance task (STPA). GT 1061 was also assayed in the forced swim test (FST), an assay routinely used for screening antidepressant drugs, alone and in combination with other agents including the NMDA receptor antagonist MK 801. GT 1061 reversed cognition deficits induced by saporin or scopolamine in the contextual fear conditioning and STPA, tasks that involve the amygdala and hippocampus. The effects of GT 1061 alone in the FST were not as profound, but co–administration did yield significant behavioral effects, in particular in attenuating the effects of NMDA receptor blockade by MK 801. The new behavioral data on GT 1061 extend the effects of this drug from previous reports of cognition enhancement in hippocampus dominated tasks, to those that also involve the amygdala. The NO mimetic, GT 1061, is not a pro–depressant in the FST, despite the fact that nitric oxide synthase (NOS) inhibitors act as antidepressants. The new data support the further development of NO mimetics and NO chimeras for AD.