When you approach physicians about using more oxygen in traumatic brain injury, give them references:
Dr James MD
- Sukoff MH, Ragatz RE. Hyperbaric oxygenation for the treatment of acute cerebral edema. Neurosurgery 1982;10:29-38.
- Rockswold GL, Ford SE, Anderson DC, et al. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygenation. J Neurosurg 1992;76:929-934.
- Neubauer RA, Gottlieb SF, Pevsner NH. Hyperbaric oxygen treatment for closed head injury. Southern Med J 1994;87:933-936.
Continuing evolution of brain damage over 22 years, the reference is;
- Courville CB, Kimball TS. Histologic observations in a case of old gunshot wound of the brain. Arch Path 1934;17: 10-21.
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 function 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 suit 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 over excitation.
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 un instrumental twins (n = 6) were 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 post-ischemia, subsets of astrocytes had fragmented DNA; later post-ischemia, subsets of astrocytes proliferated. By immuno-cytochemistry, 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
Reprinted with Permission
