NO Chimeras as Therapeutic Agents in Alzheimers Disease

Abstract

NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

“…GT 1061, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, is being investigated as neuroprotective in patients with Alzheimer's disease [6]. In addition, this group has synthesized the NO chimera GT-094.…”

“…Besides cancer, NO-donating compounds hold promise for the control of other diseases, including cardiovascular diseases [2], asthma [3], hypoxic-ischemic brain injury [4], glaucoma [5], and Alzheimer's disease [6]. To date, an extensive body of work including studies in preclinical models and relevant clinical trials underscores their therapeutic potential.…”

Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection: mechanistic considerations and clinical relevance

“…Interestingly, transient forebrain ischemia, which is ameliorated through NNR pathways, is associated with hyperphosphorylation of tau proteins in the hippocampus [32] . These broad neuroprotective effects following diverse insults can be recruited through several subtypes of the nicotinic receptor family of ligandgated ion channels: the α4β2 nicotinic receptor [17,[33][34][35] and the α7 nicotinic receptor [13,16,18,19,[36][37][38][39][40] . Cytisine, a partial agonist of α4β2 and a full agonist of the α7 nicotinic receptor, is protective against beta amyloid toxicity in rat cortical neurons [34] .…”

Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair

“…The NOS isoforms also have multiple functions that may be targets for therapeutic strategies including the control of blood pressure, wound healing, migraines and Alzheimer's disease (Togo et al, 2004,Thatcher, 2005,Ramadan and Buchanan, 2006,Vignini et al, 2006. This is in addition to the NO mimetic that is currently in clinical trials for Alzheimer's disease (Thatcher et al, 2006). The Human MnSOD active site.…”