Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia

Abstract

BackgroundSynaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property.ResultsThe novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice.ConclusionOur findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-015-0208-9) contains supplementary material, which is available to authorized users.

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

“…The results reported here provide some support for the relevance of treatment strategies in animal models of Alzheimer’s disease directed at increasing inhibitory tone [13, 26, 27, 51]. Limited evidence suggests pharmacotherapies directly targeting components of the presynaptic molecular machinery such as levetiracetam (which interacts with the vesicular protein SV2) may be of benefit in Alzheimer’s disease through modulating inhibitory tone [16, 28, 30, 39, 52].…”

A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer’s disease

“…NMZ was first tested in APP/PS1 double transgenic mice that manifest aberrant accumulation of human Aβ driven by FAD mutations in APP 695 K670N/M671L and PS1 M146L . We have previously measured NMZ brain bioavailability and correlated brain levels with efficacy in cognition enhancement in scopolamine-induced amnestic mice, demonstrating that the brain concentration of NMZ required for memory consolidation after amnestic insult is approximately 0.5–1.0 nM [ 19 ]. Our previous PK/PD studies [ 19 ] guided dose selection herein, since NMZ was effective by both i.p.…”

“…We hypothesized that a small chemical modification to CMZ, as in the novel therapeutic agent, 4-methyl-5-(2-(nitrooxy) ethyl) thiazol-3-ium chloride (NMZ), would address these contributors (Fig. 1 ) [ 19 , 20 ].

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“…Therefore NMZ, although not targeted at a specific component of Aβ accumulation, might reduce brain Aβ consequent to activation of NO/cGMP/CREB [ 27 , 28 ]. We previously demonstrated that NMZ retained attributes of CMZ including potentiation of gamma-aminobutyric acid (GABA) signaling at the GABA A receptor [ 19 , 20 ]. We also reported procognitive actions associated with NO/cGMP, including reversal of scopolamine-induced cognitive deficits, and demonstrated a high therapeutic index and efficacy at low nanomolar concentrations of NMZ in the brain [ 19 ].…”

2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate‐potentiated GABAA receptor response in hippocampal neurons

“…Excitotoxicity was a cause of neuronal dysfunction and neuron death, with features of over‐activation of glutamate receptors, excessive intracellular calcium, and mitochondrial damage. CMZ as an neuroprotective agent showed a potential therapeutic effect on neuronal injury by regulating excitatory and/or inhibitory neurotransmission balance in neurodegenerative diseases, which acts as the GABA A receptor positive allosteric modulator . As one of the CMZ derivatives, NMZ also exhibited neuroprotective effect, and it was reported to modify the symptoms and condition of AD in several animal models …”