Biomedical Engineering Reference
In-Depth Information
Glucose is rapidly delivered
(32)
by a variety of transporters
(33)
located at the blood-brain barrier and plasma membranes and
then broken down by non-oxidative (
∼
5% ATP) and oxidative
(
95% ATP) pathways to maintain ATP concentration (2-4 mM
(27)
). Some glucose is stored by glial cells as glycogen
(34)
.
Because astrocytes lack the enzyme to generate glucose from
glycogen, glucose-6-phosphate generated in glia may be trans-
ferred to neurons to serve as an additional energy buffer
(35)
.
Total creatine, which represents the quantities of phosphocre-
atine (PCr) and creatine (Cr), can undergo phosphorylation-
dephosphorylation reaction catalyzed by creatine kinase (i.e.,
ADP + PCr
∼
ATP + Cr). Therefore, PCr may provide an
additional energy reserve when oxidative phosphorylation can-
not maintain constant ATP supply
(36)
. These alternate energy
reserves together can provide energy support for a short time (a
couple of minutes) under ischemic conditions
(27)
. It is possi-
ble, however, that these extra non-oxidative pathways may pro-
vide faster ATP (in ms range) than from mitochondrial respiration
(35, 36)
.
To date, in spite of several decades of research, it remains
unclear by what mechanism(s) nutrient supply (of glucose and
oxygen) adjusts to changing energy demanded by neurons
and astrocytes
(37)
. Many vasoactive agents have been impli-
cated in mechanism(s) leading to functional hyperemia. Given the
extremely low and high oxygen contents, respectively, in brain
and blood (
↔
Mvs.mM
(24)
) but, at the same time, its ubiq-
uitous need for oxidation of glucose (and other carbohydrates),
should blood flow be tightly coupled to oxidative energy use,
and thereby, suggest potential mechanism(s) for functional hyper-
emia
(38)
? Although theoretical
(39)
and experimental
(40)
stud-
ies show that these parameters are indeed well coupled, oxygen
is not a candidate for a vasoactive agent because its excess has
no impact on the hemodynamic response (within 500 ms) dur-
ing sensory stimulation
(41)
. In other words, the system's use
of energy substrates is
only
based on demand
(20)
, not availabil-
ity
(42)
. Since suggestions of other agents (e.g., H
+
,K
+
,Ca
2
+
,
adenosine) have lacked clear evidence of an impartial role with
functional hyperemia
(37)
, new proposals
(43)
have shifted some
attention to astrocytes as key participants, thereby revising the
century-old neurovascular coupling idea
(44)
to include glia (i.e.,
“neurogliovascular” coupling).
Recent opinions
(5,9,12)
suggest that neuronal glutamate
release not only induces metabolic responses in glial cells but it
may also even trigger hemodynamic events through them. This
seems plausible given that astrocytes are proximal to both cere-
bral microvasculature
(4, 5)
and glutamatergic and GABAergic
neurons
(45, 46)
. Past experiments
(47)
suggested that astro-
cytes are activated by glutamate uptake (and increase glial glucose
μ
