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P2‐085: VCAM‐1 AS A BIOMARKER OF COGNITIVE DECLINE IN ALZHEIMER'S DISEASE
Author(s) -
Drake Jonathan D.,
Daiello Lori A.,
Chambers Alison,
Ott Brian R.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.770
Subject(s) - biomarker , dementia , confounding , cognitive decline , clinical dementia rating , vcam 1 , medicine , disease , oncology , alzheimer's disease , alzheimer's disease neuroimaging initiative , psychology , cognition , cohort , amyloid (mycology) , cell adhesion molecule , neuroscience , immunology , pathology , biology , icam 1 , genetics
CNS. To evaluate potential CNS penetrant IDO1 inhibitors, we optimized a murine pharmacokinetic-pharmacodynamic (PK/PD) model in which CNS IDO1 is upregulated by systemic LPS administration. Methods:We administered lipopolysaccharide (LPS) systemically to male CD-1 mice in order to induce IDO1 expression in brain. These LPS treated mice were then administered potential IDO1 inhibitors, and the levels of brain kynurenine:tryptophan (KT) quantified to examine the PK/PD relationship. In addition to PK/PD we can examine potential modulation of down-stream pathways relevant to neurodegeneration. To optimise this model, we first conducted a time course analysis from 4-48 hours post-LPS administration to determine the time of maximum CNS IDO1 upregulation and kynurenine concentration. We then performed a dose escalation with a tool compound to confirm the PK/PD relationship between inhibitor concentration and brainKT levels. Finally, we administered an IDO1 inhibitor that does not cross the blood brain barrier to ensure that the measured effect was due to central, not peripheral, IDO1 inhibition. Results:We determined that the optimal time of LPS administration was 20 hours before sacrifice, and the optimal window for compound administration was 1-3 hours before sacrifice, depending on the test compound PK. We confirmed the PK/PD relationship of CNS inhibitor concentration and kynurenine levels, and that the effect was due to central, not peripheral, IDO1 inhibition. Conclusions:We have demonstrated that systemically administered LPS in mice is a useful model for evaluating the PK/PD relationship of potential CNS IDO1 inhibitors in vivo, which can be used in the development of novel therapeutics for AD. This model can also be used to examine the effects of IDO1 inhibition on downstream pathways that may play a role in neurodegeneration.