Novel nitrates as NO mimetics directed at Alzheimer's disease

Abstract

GT 1061 is a novel therapeutic agent that is in Phase 1 clinical studies for Alzheimer's disease. GT 1061 is one of a family of novel nitrates that have demonstrated neuroprotective properties and cognition-and memory-enhancing properties in animal models. The prototype of this family, GT 715, has been reported effectively to dissociate the neuromodulatory and the systemic hypotensive effects of nitrates, the latter seriously limiting the therapeutic use of classical nitrates. Further data on the novel nitrates, GT 715 and GT 061, are presented in (a) the malonate-lesion rat model of excitotoxic neurodegeneration, and (b) the reversal of a scopolamine-induced cognition deficit in the Morris water task which tests spatial memory. These data exemplify and reinforce the combined neuroprotective and cognition enhancing properties observed in this family of NO mimetic therapeutic agents. NO mimetics, that mimic the biological activity of NO, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia. NO mimetic activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of an effective neuroprotective strategy. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia, providing a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.

Phosphodiesterase 5 Inhibition Improves Synaptic Function, Memory, and Amyloid- Load in an Alzheimer's Disease Mouse Model

“…These results are in agreement with the observation that NO-mimetic molecules may reverse the cognitive impairment caused by scopolamine (Thatcher et al, 2004), or by forebrain cholinergic depletion (Bennett et al, 2007), suggesting that stimulating the NO/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. With regard to the beneficial effect on memory, it is interesting to note that inhibition of PDE5 activity during a time window starting immediately after training for fear learning or after acquisition of the spatial task and ending at no more than 4 h after them improves learning in the transgenic animals.…”

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

“…In this model of neuronal injury [204] GT 715 was observed to significantly decrease the brain injury induced by the malonate neurotoxin at both the behavioural and neurochemical levels. Preservation of GABA levels in the striatum after malonate injection, measured as an index of the neuronal cell population, and a markedly decreased response to apomorphine in ipsolateral turning indicated that neuronal injury was significantly inhibited by GT 715 administration, and that normal function within the neostriatum was maintained [202]. These results reinforce our previous unpublished observations in a Parkinson's animal model and reported observations on the neuroprotective activity of GT 715 in the rat transient MCAO model of ischemic stroke wherein s.c. delivery of drug 2h or 4h after ischemia produced a significant reduction in infarct volume (58% reduction in total and 72%reduction in cortical infarct volumes at 4h) [190].…”

“…GT 715 supported the postulate that neuromodulatory and hypotensive effects of nitrates can be dissociated. Demonstration of the neuromodulatory effects of GT 715 was observed in a variety of models of neuroprotection: (a) in the middle cerebral artery occlusion (MCAO) rat model of focal ischemic stroke [201], (b) in the 6-hydroxydopamine-lesion rat model of Parkinson's Disease, and (c) in the malonate-lesion rat model of excitotoxic neurodegeneration [202].…”

“…Central cholinergic muscarinic receptor blockade produces profound cognitive impairments in human and animal subjects, thus the use of cholinergic muscarinic antagonists, such as scopolamine, in animal models to mimic the cognitive impairment observed in AD is well established, and has proven to be a useful model system for understanding and developing treatment strategies for neurodegenerative diseases in humans [205]. Data have been published for the novel nitrates, GT 715 and GT 061, demonstrating the reversal of cognitive deficits produced by scopolamine in rats tested in the MWT [200,202]. All members of this class tested to date in behavioural models of dementia show cognition enhancing activity, and various members manifest additional biological activity, including anticonvulsant and analgesic activity, and AMPA receptor modulation [206].…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…Other than classical nitrates or hybrid nitrates, NO donor nonsteroidal anti-inflammatory drugs [123][124][125][126][127], an additional therapeutic approach is to block the degradation of cGMP by using PDE5 inhibitors (PDE5-Is). Over the past few years, our group and others have demonstrated that treatment with PDE5-Is rescues synaptic and memory deficits in the APP/ PS1 mouse model of AD, restoring phospho-CREB levels and decreasing Aβ load [112,128].…”