P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study
The AAPS Journal ( # 2016)
DOI: 10.1208/s12248
P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study
Heli Savolainen 2
Peter Meerlo 1
Philip H. Elsinga 2
Albert D. Windhorst 0
Rudi A.J.O. Dierckx 2
Nicola A. Colabufo 3 4
Aren van Waarde 2
Gert Luurtsema 2
0 Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam , De Boelelaan 1085 C, 1081 HV, Amsterdam , Netherlands
1 Groningen Institute for Evolutionary Life Sciences, University of Groningen , Nijenborgh 7, 9747 AG, Groningen , Netherlands
2 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen , Hanzeplein 1, 9713 GZ, Groningen , Netherlands
3 Biofordrug slr , via Orabona 4, 70125, Bari , Italy
4 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari , via Orabona 4, 70125, Bari , Italy
The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from harmful compounds. P-glycoprotein (P-gp) is one of the major efflux transporters at the BBB. In the present study, we assessed whether (1) P-gp function in the brain is constant or fluctuates across the day and (2) if it is affected by sleep deprivation. Four groups of rats were PET scanned with a radiolabeled P-gp substrate [18F]MC225, each at a different moment of the 12-h light-dark cycle to study diurnal variations: early sleep phase (ZT3), late sleep phase (ZT9), early active phase (ZT15), and late active phase (ZT21). In two additional groups, controls were allowed to sleep normally while experimental animals were sleep-deprived for 10 h in a slowly rotating drum during the sleep phase. Kinetic modeling with a one-tissue compartment model fit resulted for all brain regions in 1.2-1.8fold higher distribution volumes (VT) at ZT15 than at other time points. VT-values at ZT3, ZT9, and ZT21 were not significantly different from each other. Regional tracer distribution volumes in controls and sleep-deprived animals were also not significantly different. Our results indicate that P-gp function in rats displays a daily rhythm with reduced function at the beginning of the active phase. This rhythm is not dependent on sleep since acute sleep deprivation had no effect. Knowing the diurnal variation of P-gp function could be important for the design of PET studies and for choosing the correct administration time for P-gpdependent drugs.
circadian rhythm; efflux transporter; [18F]MC225; pharmacokinetic modeling; sleep deprivation
INTRODUCTION
P-glycoprotein (P-gp) is expressed on the luminal side of
endothelial cells in the blood-brain barrier (BBB) (
1, 2
). This
transporter protects the brain by pumping a wide variety of
substances back into the blood. P-gp function is not constant
but can be modulated by a wide variety of endogenous (
3, 4
)
and exogenous factors (
5–7
). However, little is known about
physiological fluctuations in P-gp function across the day in
relation to the circadian rhythm. Such fluctuations could be
important for selecting the optimal time of the day for
application of therapeutic drugs. By selecting the appropriate
hour of administration for a drug which is a (weak) substrate
for P-gp, the ratio between beneficial effect and undesired
side effects could be optimized. Many CNS drugs have some
affinity for P-gp, e.g., certain anticancer drugs,
antidepressants, and HIV-protease inhibitors (
8–11
).
Most processes in the mammalian body display a 24-h
rhythm, from molecular processes to behavior. Many of these
rhythms are coordinated by an endogenous circadian clock
that is located in the suprachiasmatic nuclei (SCN) of the
hypothalamus (
12
). Ultimately, rhythms in the regulation of
gene expression, protein synthesis, hormone levels, or
neurotransmitter release could affect P-gp expression and function.
Moreover, the endogenous circadian clock might not only
affect P-gp function through direct physiological mechanisms,
but a daily rhythm in P-gp function might also be related to
sleep, which is itself under control of the SCN (
13, 14
).
Recent data have indicated that the clearance of harmful
substances from the brain may be directly related to the sleep
state. Such substances include the neurodegenerative marker
amyloid-ß (Aß) which is a substrate for P-gp (
15,
16
). Cerebral accumulation of Aβ-plaques is a hallmark,
and probably also the major cause, of Alzheimer’s disease
(AD) (17). In humans, both a shorter duration and a reduced
quality of sleep result in increased accumulation of Aβ in the
brain (
18
). In mice, natural sleep is associated with a 60%
increase in the volume of the cerebral interstitial space,
resulting in an increase in convective exchange of
cerebrospinal fluid with interstitial fluid, which causes an increased
rate of Aß clearance during sleep (
19
). Another study showed
that acute (6 h) sleep deprivation in wild-type mice and
chronic (20 h daily during (...truncated)