title: 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: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. jialuo@uic.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. suelee1@uic.edu.
authors.forename: Sue H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. lvandev2@uic.edu.
authors.forename: Lawren
authors.initials: L
authors.lastname: VandeVrede
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. qinzhh@uic.edu.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. spiyan2@uic.edu.
authors.forename: Sujeewa
authors.initials: S
authors.lastname: Piyankarage
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. etavas2@uic.edu.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Tavassoli
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. rasgho2@uic.edu.
authors.forename: Rezene T
authors.initials: RT
authors.lastname: Asghodom
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. benaissa@uic.edu.
authors.forename: Manel
authors.initials: M
authors.lastname: Ben Aissa
authors.affiliation: 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, NY, 10032, USA. mf2257@columbia.edu.
authors.forename: Mauro
authors.initials: M
authors.lastname: Fà
authors.affiliation: 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, NY, 10032, USA. oa1@columbia.edu.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, Lions of Illinois Eye Research Institute, University of Illinois at Chicago, 1855 W. Taylor St., Chicago, IL, 60612, USA. lyue@usc.edu.|Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan St., Chicago, IL, 60607, USA. lyue@usc.edu.|Department of Ophthalmology, University of Southern California, 1441 Eastlake Ave., Los Angeles, CA, 90033, USA. lyue@usc.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Yue
authors.affiliation: Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, Lions of Illinois Eye Research Institute, University of Illinois at Chicago, 1855 W. Taylor St., Chicago, IL, 60612, USA. davipepp@uic.edu.|Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan St., Chicago, IL, 60607, USA. davipepp@uic.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Pepperberg
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL, 60612-7231, USA. thatcher@uic.edu.
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002719:Chlormethiazole / Q000031:analogs & derivatives*; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D058492:Drug Repositioning / Q000379:methods*; D058785:GABA-A Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018697:Nootropic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D014982:Xenopus laevis
chemical_list: D058785:GABA-A Receptor Agonists; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D002719:Chlormethiazole; D009569:Nitric Oxide; D050882:CREB-Binding Protein; D006152:Cyclic GMP