Cisterna magna cannulated repeated CSF sampling rat model--effects of a gamma-secretase inhibitor on Aβ levels.
Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Aβ) lowering agent. The surgically implanted cisterna magna cannula was patent over a period of 1-2 weeks and enabled repeated sampling of CSF (volume of ∼30-50μL/sample) from each rat. CSF Aβ40 levels showed good intra-animal variability across time points and inter-animal variability within a time point. Peripheral treatment with a gamma-secretase inhibitor (GSI) led to a rapid and robust decline in CSF Aβ40 levels that returned to baseline over 24-96h after dosing. Terminal brain, CSF and plasma Aβ levels measured at 24h after dosing demonstrated robust Aβ lowering and showed excellent correlation across these compartments. These results are the first pharmacological validation of the repeated CSF sampling rat model for Aβ lowering agents. This model can have broad applicability in pharmacological evaluation for diverse CNS targets.
Merck & Co., Inc., Neuroscience, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jennifer.shapiro@merck.com
Jennifer S
JS
Shapiro
Mark
M
Stiteler
Guoxin
G
Wu
Eric A
EA
Price
Adam J
AJ
Simon
Sethu
S
Sankaranarayanan
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000032:analysis; D002404:Catheterization / Q000379:methods*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002946:Cisterna Magna / Q000502:physiology*; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D009777:Occipital Bone / Q000033:anatomy & histology; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D016229:Amyloid beta-Peptides; D000906:Antibodies; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases