PMID- 21945230
OWN - NLM
STAT- MEDLINE
DCOM- 20111220
LR  - 20211020
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 232
IP  - 2
DP  - 2011 Dec
TI  - Human nasal olfactory epithelium as a dynamic marker for CNS therapy development.
PG  - 203-11
LID - 10.1016/j.expneurol.2011.09.002 [doi]
AB  - Discovery of new central nervous system (CNS) acting therapeutics has been slowed 
      down by the lack of useful applicable biomarkers of disease or drug action often 
      due to inaccessibility of relevant human CNS tissue and cell types. In recent 
      years, non-neuronal cells, such as astrocytes, have been reported to play a 
      highly significant role in neurodegenerative diseases, CNS trauma, as well as 
      psychiatric disease and have become a target for small molecule and biologic 
      therapies. We report the development of a method for measuring pharmacodynamic 
      changes induced by potential CNS therapeutics using nasal olfactory neural tissue 
      biopsy. We validated this approach using a potential astrocyte-targeted 
      therapeutic, thiamphenicol, in a pre-clinical rodent study as well as a phase 1 
      human trial. In both settings, analysis of the olfactory epithelial tissue 
      revealed biological activity of thiamphenicol at the drug target, the excitatory 
      amino acid transporter 2 (EAAT2). Therefore, this biomarker approach may provide 
      a reliable evaluation of CNS glial-directed therapies and hopefully improve 
      throughput for nervous system drug discovery.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Sattler, Rita
AU  - Sattler R
AD  - Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
FAU - Ayukawa, Yoko
AU  - Ayukawa Y
FAU - Coddington, Luke
AU  - Coddington L
FAU - Sawa, Akira
AU  - Sawa A
FAU - Block, David
AU  - Block D
FAU - Chipkin, Richard
AU  - Chipkin R
FAU - Rothstein, Jeffrey D
AU  - Rothstein JD
LA  - eng
GR  - NS33958/NS/NINDS NIH HHS/United States
GR  - U01 NS050094-05/NS/NINDS NIH HHS/United States
GR  - R01 NS033958-17/NS/NINDS NIH HHS/United States
GR  - U01 NS050094/NS/NINDS NIH HHS/United States
GR  - R21 NS067117/NS/NINDS NIH HHS/United States
GR  - R21 NS067117-02/NS/NINDS NIH HHS/United States
GR  - R01 NS033958/NS/NINDS NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110916
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Glutamate Plasma Membrane Transport Proteins)
RN  - 0 (SLC1A2 protein, human)
RN  - EC 1.13.12.- (Luciferases)
RN  - FLQ7571NPM (Thiamphenicol)
SB  - IM
CIN - Nat Rev Neurol. 2011 Nov;7(11):596. PMID: 22009286
CIN - Exp Neurol. 2012 Jun;235(2):508-12. PMID: 22465461
MH  - Animals
MH  - Animals, Newborn
MH  - Anti-Bacterial Agents/blood/pharmacokinetics
MH  - Astrocytes/*cytology/metabolism
MH  - Biological Assay/*methods
MH  - Biomarkers/metabolism
MH  - Biopsy
MH  - Cell Line, Transformed
MH  - Central Nervous System/cytology
MH  - Drug Design
MH  - Drug Monitoring/*methods
MH  - Excitatory Amino Acid Transporter 2
MH  - Gene Expression/physiology
MH  - Glutamate Plasma Membrane Transport Proteins/genetics/metabolism
MH  - Humans
MH  - Luciferases/genetics
MH  - Mice
MH  - Olfactory Mucosa/cytology/metabolism
MH  - Olfactory Receptor Neurons/*cytology/metabolism
MH  - Primary Cell Culture
MH  - Thiamphenicol/blood/*pharmacokinetics
PMC - PMC3220936
MID - NIHMS331305
COIS- Conflict of Interest: J.D.R. and R.C. have an equity interest in Psyadon 
      Pharmaceuticals; J.D.R. and R.C. are on the Psyadon Board of Directors. D. B. has 
      equity interest and serves on the Board of Directors of Gliknik Pharma. R.S. and 
      J.D.R. are on a pending patent for the use of thiamphenicol in various 
      neurological and psychiatric disorders. No other authors have competing interests 
      to declare.
EDAT- 2011/09/29 06:00
MHDA- 2011/12/21 06:00
PMCR- 2012/12/01
CRDT- 2011/09/28 06:00
PHST- 2011/01/17 00:00 [received]
PHST- 2011/07/12 00:00 [revised]
PHST- 2011/09/04 00:00 [accepted]
PHST- 2011/09/28 06:00 [entrez]
PHST- 2011/09/29 06:00 [pubmed]
PHST- 2011/12/21 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - S0014-4886(11)00309-8 [pii]
AID - 10.1016/j.expneurol.2011.09.002 [doi]
PST - ppublish
SO  - Exp Neurol. 2011 Dec;232(2):203-11. doi: 10.1016/j.expneurol.2011.09.002. Epub 
      2011 Sep 16.