Putative Neuroprotective Role for C-type Natriuretic Peptide (CNP) in Humans: Monoamine Oxidase Inhibition (MAOI) Prevents Decline in CSF NTproCNP in Parkinson's Disease (PD)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 142-166-Hypothalamus-Pituitary Development & Biology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-158
Timothy C Prickett*1, Yassar Alamri1, Timothy J Anderson1, John C Dalrymple-Alford2 and Eric A Espiner1
1University of Otago, Christchurch, New Zealand, 2University of Otago
Background: CNP is a nerve growth factor which is widely expressed in the hypothalamus, mesolimbic pathway and spinal cord. CNP peptides are some 50 fold higher in CSF than in plasma. Nothing is known of CNP's role in the human brain but in rodents CNP promotes axonal growth and branching, and by interacting with dopaminergic neurons and projection fields, affects locomotion, learning and behaviour (1). Our recent findings in 10 subjects with treated PD show low levels of CNP peptides in CSF compared to those in controls.
Objectives: Using stored samples of CSF drawn from subjects participating in the DATATOP study (2), objectives were to determine peptide levels in untreated PD at enrolment and during the course of disease progression (study 1), and to assess the effect on peptide levels of MAOI (study 2) - a treatment that delays the need for L DOPA therapy.
Methods: Amino terminal pro CNP (NTproCNP) - a stable product of CNP gene expression - was measured in CSF samples at enrolment and again after placebo treatment (mean time interval 12 months) in 59 subjects (study 1). In study 2, CSF was sampled at baseline and after treatment with MAOI (deprenyl, n=59) or Vitamin E/ placebo (n=30). In all subjects the timing of the 2nd CSF collection was dictated by the need to initiate L DOPA therapy (an end point for the DATATOP study).
Results: Mean baseline level of CSF NTproCNP at enrolment (all subjects combined, n=146) was 810±19 pM and significantly reduced compared with those of age matched control subjects (3) without neurological disorder (1045±7pM, p<0.001 n=51). In study 1, concentrations declined significantly during placebo (p=0.02). Further, there was a significant positive association between baseline NTproCNP and the time interval separating CSF sampling (r=0.31, p<0.01) - lower values at baseline qualified for earlier intervention. In contrast, in study 2, CSF NTproCNP increased in subjects receiving deprenyl (n=56), increments being positively associated with time interval (r=0.37, p<0.006). In subjects receiving either placebo or vitamin E, levels declined as found in study 1.
Conclusion: In untreated PD, CSF NTproCNP is reduced, falls with time and lower levels at baseline are associated with more rapid functional decline. Abrogation of the time dependent fall in CSF NTproCNP by deprenyl - which delays the need for L DOPA - raises the possibility that some of the neuroprotective actions of MAOI in PD are mediated by preserving tissue CNP levels.

(1) Deschatrettes E, et al. Overexpression of cyclic GMP-dependent protein kinase reduces MeCP2 and HDAC2 expression. Brain and Behavior 2012;2:732.  (2) The Parkinson’s Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The New England Journal of Medicine 1993;328:176.  (3) Schouten BJ, et al. Central and peripheral forms of C-type natriuretic peptide (CNP): evidence for differential regulation in plasma and cerebrospinal fluid. Peptides. 2011;32:797.

Nothing to Disclose: TCP, YA, TJA, JCD, EAE

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study was supported by The Michael J. Fox Foundation for Parkinson's Research.