When you approach a Physician about
More ammunition to refute anyone who says hypoxia does not hurt neurons.
They are not looking at the whole picture.
Ask them if they have the latest neurophysiology research data.
Astrocytes enhance radical defense in capillary endothelial cells
constituting the blood-brain barrier. Schroeter ML, Mertsch K, Giese H,
Muller S, Sporbert A, Hickel B, Blasig IE Forschungsinstitut fur Molekulare
Pharmakologie, Berlin, Germany. Astrocytes induce blood- brain barrier
properties in brain endothelial cells. As antioxidative activity is assumed
to be a blood-brain barrier characteristic, we tested whether astrocyte
improve antioxidative activity of endothelial cells. Monocultivated
astrocytes showed higher antioxidative activity [manganese superoxide
dismutase, catalase, glutathione peroxidase] than endothelial cells.
Cocultivation elevated antioxidative activity in endothelial cells, and
astrocytes. Hypoxia increased radical-induced membrane lipid peroxidation
in monocultivated, but not in cocultivated endothelial cells. Thus,
endothelial cells/astrocyte cocultivation intensifies antioxidative
activity in both cell types, protects the endothelial cells, and therefore,
the blood-brain barrier against oxidative stress. The high antioxidative
activity is regarded as an essential property of the blood-brain barrier,
which is induced by astrocytes.
If anyone thinks oxygen does not impact astrocyte funtion see: Tissue oxygen
levels control astrocyte movement and differentiation in developing retina.
Zhang Y, Porat RM, Alon T, Keshet E, Stone J NSW Retinal Dystrophy
Research Centre, Department of Anatomy and Histology, University of Sydney
F13, Sydney, Australia. Astrocytes play a key role in the development of
retinal vessels by detecting hypoxia in developing retina and secreting the
hypoxia-induced angiogenic factor VEGF to induce vessel formation. The
astrocytes which play this role are themselves spreading over the retina,
just ahead of the growing vessels.
To understand the mechanisms which keep astrocytes in this strategic 'just
ahead' position we have studied the effects of hyperoxia and hypoxia on
astrocyte differentiation and movement in situ in neonatal rat retina and
in primary culture. Hyperoxia in situ inhibited the stellation of
astrocytes, so that they persisted in a relatively unbranched form, which
accumulated at the edge of their spreading population; hyperoxia permitted
but did not accelerate migration. Conversely, hypoxia induced unstellated
astrocytes to stellate within 6 h. If the hypoxia was abnormally severe, it
caused the astrocytes to hyperstellate and slowed their spread. Astrocytes in primary culture did not change morphology or motility
when challenged by hypoxia. When treated with medium conditioned by retina
however, astrocytes became mobile and, if the medium was conditioned by
hypoxic retina, became stellate. These results suggest that the oxygen
released by retinal vessels maintains the mobility of astrocytes, via a
diffusible factor released by other retinal cells. Conversely, naturally
generated hypoxia of developing retina plays a triple role, inducing
astrocytes to stellate, to end their migration and to produce VEGF, thereby
inducing vessel formation. The induction of stellation is mediated by a
diffusible factor released by other retinal cells. Thus hypoxia of the
retina generated by neural maturation induces key events in both the
differentiation of astrocytes and the formation of blood vessels.
The data show astrocytes stand as the brain's first line of support during
ischemis attacks: Neurochem Int 2000 Apr;36(4-5):369-77 Expression of
interleukin-1 alpha, tumor necrosis factor alpha and interleukin-6 genes in
astrocytes under ischemic injury. Yu AC, Lau LT Department of Biology, The
Hong Kong University of Science and Technology Astrocytes form an integral
part of the blood brain barrier and are the first cell type in the central
nervous system to encounter insult if there is an ischemic attack. The
immunologic reaction of astrocytes to an ischemic insult would be affective
to the subsequent responses of other nerve cells. We previously showed
that ischemia caused an increase in the levels of interleukin 1alpha
(IL-1alpha), tumor necrosis factor alpha (TNF alpha), and interleukin 6
(IL-6) in the culture medium of mouse cerebral cortical astrocyte.
We did not have evidence on the source of these cytokines. This study aimed
to investigate the expressions of these cytokine mRNAs in the astrocytes
under ischemia. Results demonstrated that ischemia could induce necrosis
and apoptosis in astrocytes. By using the RT-PCR method, we demonstrated
for the first time that the mRNA levels of IL- 1alpha, TNF alpha and IL-6 in
normal astrocyte was very low, but their expressions could be induced
quickly under ischemia. These cytokines might be interactive as indicated
by the difference in time course of their expressions, with IL-1alpha being
the earliest and IL- 6 being the latest. The result provided some
understanding of the induction and progression of these immunologic
responses in astrocytes under ischemia. It also supported our previous
findings that astrocytes contributed to the cytokines released under
ischemia.
Astrocytes help protect the brain in many ways, but there is a limit as to
how much hypoxia it can withstand. Here is one study: Neuroscience
2000;96(1):141-6 Extended neuronal protection induced after sublethal
ischemia adjacent to the area with delayed neuronal death. Kitagawa K,
Matsumoto M, Ohtsuki T, Kuwabara K, Mabuchi T, Yagita Y, Hori M, Yanagihara
T Division of Strokology, Department of Internal Medicine and
Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka,
Japan. In the present study, we investigated whether neurons adjacent to an
ischemic lesion acquire tolerance against subsequent ischemia or not. We
initially used unilateral hemispheric ischemia for 3 min in gerbils to
produce an ischemic lesion confined to the unilateral CA1 sector, and the
presence of tolerance was examined in the adjacent CA3 sector through
transient global ischemia by occlusion of both common carotid arteries.
Attenuation of neuronal damage was clearly observed in neurons in the CA3
sector adjacent to the ischemic lesion in the CA1 sector. The phenomenon
lasted for up to two weeks after the initial hemispheric ischemia, but was
no longer present two months later. Reactive astrocytes as identified by
the presence of glial fibrillary acidic protein were visible in the CA3
hippocampus four days and two weeks after hemispheric ischemia, but they
were scarce two months later. Expression of heat shock protein 72 in the
CA3 neurons was observed four days after hemispheric ischemia, but the
reaction returned to the control level two weeks later. In conclusion, the
present study showed that tolerance in the neurons adjacent to an ischemic
lesion could be sustained at least for two weeks, and raised the
possibility that reactive astrocytes might contribute to the extended
tolerance in neurons.
Hypoxia creates oxidative stress and releases free-radicals. Here is a
study: Neurochem Res 1999 Dec;24(12):1523-9 Taurine release is enhanced in
cell-damaging conditions in cultured cerebral cortical astrocytes.
Saransaari P, Oja SS Tampere Brain Research Center, University of Tampere
Medical School, Finland. The release of preloaded [3H]taurine from cultured
cerebral cortical astrocytes was studied under various cell-damaging
conditions, including hypoxia, ischemia, aglycemia and oxidative stress,
and in the presence of free radicals. Astrocytic taurine release was
enhanced by K+ (50 mM), veratridine (0.1 mM) and the ionotropic glutamate
receptor agonist kainate (1.0 mM). Metabotropic glutamate receptor agonists
had only weak effects on taurine release. Similarly to the swelling-induced
taurine release the efflux in normoxia seems to be mediated mainly by
DIDS-(diisothiocyanostilbene-2,2'-disulphonate) and SITS-(4-acetamido-
4'-isothiocyanostilbene-2,2'-disulphonate) sensitive CI- channels, since
these blockers were able to reduce both basal and K+ - stimulated release.
The basal release of taurine was moderately enhanced in hypoxia and
ischemia, whereas the potentiation in the presence of free radicals was
marked. The small basal release from astrocytes signifies that taurine
release from brain tissue in ischemia may originate from neurons rather
than glial cells. On the other hand, the release evoked by K+ in hypoxia
and ischemia was greater than in normoxia, with a very slow time-course.
The enhanced release of the inhibitory amino acid taurine from astrocytes
in ischemia may be beneficial to surrounding neurons, outlasting the
initial stimulus and counteracting overexcitation.
How cerebral palsy occurs. Hypoxic insult during development impacts
astrocyte function. It is not too difficult to see how this leads to brain
injury: Brain Dev 1999 Jun;21(4):248-52 Early axonal and glial pathology
in fetal sheep brains with leukomalacia induced by repeated umbilical cord
occlusion. Ohyu J, Marumo G, Ozawa H, Takashima S, Nakajima K, Kohsaka S,
Hamai Y, Machida Y, Kobayashi K, Ryo E, Baba K, Kozuma S, Okai T, Taketani
Y Department of Mental Retardation and Birth Defect Research, National
Institute of Neuroscience, NCNP, Kodaira, Tokyo, Japan. We conducted a
chronic preparation experiment involving near term fetal sheep to evaluate
the contribution of umbilical cord occlusion to fetal brain injury. In
experimental groups (n = 11), complete cord occlusion for 3 min followed by
5 min release, repeated 5 times were performed at 3 days after initial
surgery. Instrumental cases without cord occlusion (n = 3) and
uninstrumental twins (n = 6) were also examined as controls. Multiple
necrotic foci predominantly in the periventricular white matter were found
in the fetal brains examined at 1-3 days after cord occlusion.
To estimate the contribution of early axonal and glial reaction to brain
injury the following immunohistochemical study was performed. In the
lesions, coagulation necrosis, axonal swelling and microglial activation
were demonstrated with amyloid precursor protein or ionized calcium binding
adapter molecule 1 immunohistochemistry. The induction of tumor necrosis
factor alpha and inducible nitric oxide synthase were also detected
immunohistochemically in the microglia at 1 and 3 days after cord
occlusion. In contrast, the reaction of glial fibrillary acidic protein
positive astrocytes was faint at 1 day after occlusion, but the induction
of cyclooxygenase-2 was observed. These findings suggest the glial reaction
of cytokines and free radicals induced by fetal hypoxia may contribute to
the occurrence of brain injury.
It appears that astrocyte malfunction may lead to seizure activity: Lab
Anim Sci 1998 Feb;48(1):34-7 Neuropathologic findings associated with
seizures in FVB mice. Goelz MF, Mahler J, Harry J, Myers P, Clark J,
Thigpen JE, Forsythe DB National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina, USA. Observations made
during seizure presentation in 12 of 68 mice included facial grimace, chewing automatism, ptyalism with matting of the
fur of the ventral aspect of the neck and/or forelimbs, and clonic
convulsions that frequently progressed to tonic convulsions and death. Four
mice were dead at presentation, with matting of the fur of the neck and
forelimbs. The remainder of the mice had nonspecific signs of disease, such
as lethargy, moribundity, or matting of the fur. Vendor and in-house animal
health surveillance reports indicated that mice were seronegative to all
murine pathogens. Results of gross pathologic examination were
unremarkable. Microscopic findings were limited to the brain and liver. In
all mice, neuronal necrosis was present in the cerebral cortex,
hippocampus, and thalamus. Concurrent astrocyte hypertrophy, as evidenced by
an increase in glial fibrillary acidic protein staining, was detected.
How can anyone can say hypoxia does not hurt neurons?
It does not take too much digging to find data refuting that notion: Ann
Neurol 1997 Sep;42(3):335-48 Hypoxia-ischemia causes abnormalities in
glutamate transporters and death of astroglia and neurons in newborn
striatum. Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler
R, Rothstein J, Traystman RJ Department of Pathology, Johns Hopkins
University School of Medicine. The neonatal striatum degenerates after
hypoxia-ischemia (H-I). We tested the hypothesis that damage to astrocytes
and loss of glutamate transporters accompany striatal neurodegeneration
after H-I. Newborn piglets were subjected to 30 minutes of hypoxia
(arterial O2 saturation, 30%) and then 7 minutes of airway occlusion (O2
saturation, 5%), producing cardiac arrest, followed by cardiopulmonary
resuscitation. Piglets recovered for 24, 48, or 96 hours. At 24 hours, 66%
of putaminal neurons were injured, without differing significantly
thereafter, but neuronal densities were reduced progressively (21-44%). By
DNA nick- end labeling, the number of dying putaminal cells per square
millimeter was increased maximally at 24 to 48 hours. Glial fibrillary
acidic protein-positive cell body densities were reduced 48 to 55% at 24 to
48 hours but then recovered by 96 hours. Early postischemia, subsets of
astrocytes had fragmented DNA; later postischemia, subsets of astrocytes
proliferated. By immunocytochemistry, glutamate transporter 1 (GLT1) was
lost after ischemia in the astroglial compartment but gained in cells
appearing as neurons, whereas neuronal excitatory amino acid carrier 1
(EAAC1) dissipated. By immunoblotting, GLT1 and EAAC1 levels were 85% and
45% of control, respectively, at 24 hours of recovery. Thus, astroglial
and neuronal injury occurs rapidly in H-I newborn striatum, with early
gliodegeneration and glutamate transporter abnormalities possibly
contributing to neurodegeneration.
Dr James MD
Printed with Permission
