Tuesday, July 3, 2007

Brain homeostasis for Niacin

Niacin and NAD levels in brain are homeostatically
regulated. In niacin-defi cient animals, levels of niacin
and NAD in the brain are much better maintained
than they are in the liver. Conversely, even massive
doses (500 mg kg–1) of nicotinamide injected intravenously
result in only a 50% increase in brain NAD
levels (Spector, 1981).
In plasma and cerebrospinal fl uid (CSF), nicotinamide
is normally the predominant if not the only
form of niacin present. In rabbits, the concentration
of nicotinamide in plasma and CSF is 0.5 μM and
0.7 μM, respectively. Phosphorylated forms of nicotinamide
or nicotinic acid cannot penetrate brain cells
without fi rst being dephosphorylated.
The choroid plexus, the anatomical locus of the
blood–CSF barrier, contains separate saturable uptake
systems for nicotinic acid and nicotinamide
(Spector & Kelley, 1979). The half-saturation concentrations
for 14C accumulation by the isolated choroid
plexus with [14C]nicotinic acid and [14C]nicotinamide
in the medium were 18.1 μM and 0.23 μM, respectively;
the respective rate maxima were 439 μmol kg–1
per 30 min and 18.6 μmol kg–1 per 30 min. Nicotinic
acid uptake appeared to depend completely on its
immediate intracellular conversion to NAD, whereas
nicotinamide uptake was thought to depend partly on
its incorporation into intracellular NAD in exchange
for the nicotinamide released from NAD by the action
of NAD glycohydrolase (EC The intracellular
concentration of [14C]nicotinamide was fi ve times the
medium concentration, so it seems that nicotinamide
is actively transported into choroid plexus before
being incorporated into NAD. The isolated choroid
plexus released predominantly [14C]nicotinamide
whether pre-incubated in [14C]nicotinic acid or
Transport studies using rabbit brain slices
(Spector & Kelley, 1979) showed that uptake of
[14C]nicotinamide by brain cells in vitro was saturable
and dependent on the production of intracellular energy;
the half-saturation concentration of the uptake
system was 0.80 μM. Spector (1979) reported that
when [14C]nicotinamide was injected into the ventricle
of the brain of conscious rabbits, some of the radioactivity
was incorporated into intracellular NAD
and some left the brain and CSF extremely rapidly
by a nonsaturable system. This rapid equilibration
of nicotinamide between CSF and plasma suggests
that there is no control of the concentration of nicotinamide
in the CSF and extracellular space of brain:
nicotinamide concentrations in these compartments
refl ect concentrations in plasma. Once within the
extracellular space, nicotinamide enters brain cells by
a concentration-dependent, saturable accumulation
system. On entry into the brain cells, much of the
nicotinamide is incorporated into NAD.
Spector (1987) measured the unidirectional infl ux
of [14C]nicotinamide across cerebral capillaries (the
anatomical locus of the blood–brain barrier) using
an in situ rat brain perfusion technique. Transport
of nicotinamide was much faster than could be
explained by simple diffusion alone and was not
saturable with 10 mM nicotinamide in the perfusate.
However, with periods of infusion longer than 30 s,
there was substantial backfl ow of [14C]nicotinamide
into the perfusate. At a concentration of 1.7 μM,
nicotinamide transport was not inhibited by 3-
acetylpyridine. The non-saturability and lack of
inhibition in the presence of a structural analogue
indicate that nicotinamide transport is not carriermediated.
The data suggested that most, if not all, of
the nicotinamide that enters brain from blood gains
access to the extracellular space of brain directly via
the blood–brain barrier.
From the above fi ndings the following inferences
can be made. The saturability seen in the brain slices
and in vivo studies is due not to saturation of carrier
(probably no carrier exists) but to saturation of the
enzymes involved in the intracellular conversion of
nicotinamide to NAD. This metabolic conversion
requires ATP and so accounts for the observed energy
dependency in these experiments. Niacin levels
in brain are controlled by the saturable system of
nicotinamide uptake by brain cells. Since CSF has a
nicotinamide concentration of ~0.7 μM, the uptake
system (with half-saturation concentration 0.8 μM)
is normally approximately half-saturated. This means
that the entry of excessive amounts of nicotinamide
into the brain is prohibited. As to the initial uptake
mechanism, it can be speculated that nicotinamide
that has entered the extracellular space of brain
mainly via the blood–brain barrier enters brain cells
by diffusion, accelerated by the favourable concentration
gradient created by metabolic trapping.

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