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

BMC Neuroscience

Gregory R. J. Thatcher⁴  David R. Pepperberg¹  Lan Yue²  Ottavio Arancio³  Mauro Fà³  Manel Ben Aissa⁴  Rezene T. Asghodom⁴  Ehsan Tavassoli⁴  Sujeewa Piyankarage⁴  Zhihui Qin⁴  Lawren VandeVrede⁴  Sue H. Lee⁴  Jia Luo⁴ 

[1] Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan St., Chicago 60607, IL, USA;Department of Ophthalmology, University of Southern California, 1441 Eastlake Ave., Los Angeles 90033, CA, USA;Department of Pathology and The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630 W 168th St., New York 10032, NY, USA;Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago 60612-7231, IL, USA

关键词: Cognitive deficits;    LTP;    pCREB;    sGC/NO/cGMP;    NMZ;    Chlormethiazole;    CMZ;    Alzheimer’s disease;   

Others  :  1230630
DOI  :  10.1186/s12868-015-0208-9

 received in 2015-06-25, accepted in 2015-10-07,  发布年份 2015

【 摘 要 】

Background

Synaptic 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.

Results

The novel compound, NMZ, was shown to retain the GABA _Apotentiating 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.

Conclusion

Our 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.

【 授权许可】

   
2015 Luo et al.

【 图 表 】

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