Last issue, I discussed the Clinton Global Initiative University, a national annual conference hosted by Bill Clinton to bring together the best and brightest new ideas from campuses all over the country. The goal of the conference is to share ideas about what your campus is doing to improve their community and the environment. ESU has been chosen to attend this conference and the Environmental Club, of which I am a member, will be representing the school.
Our project is two-fold: to implement new technology to reduce the school’s energy costs and create a comprehensive education program to inform the campus why energy conservation is important. While the technology aspect of the plan is relatively simple, smart strips that automatically shut computers off when not in use, the education portion will be more involved. It relies on making adjustments to peoples’ mindsets, which is a much more complicated process than simply plugging in a smart strip.
When most people think about the things we need to conserve energy is pretty far down on their list of priorities. Objects like trees and endangered animals are tangible: we can see them, touch them, and notice when they aren’t around anymore.
But energy is immaterial and thus harder to measure. That’s why we all rush to help save polar bears, but forget to turn off the lights when we leave a room. Many people fail to see the connection between the two acts of conservation.
Whether we use a kilowatt or ten kilowatts of energy doesn’t matter to us because we can’t see the difference. There will be a difference on our meters, and eventually on our bills, but we won’t feel the difference the same way we would with the other items we are told to conserve.
I think part of the problem is that few people have a deep understanding of where their power comes from. I willingly admit that I don’t fully know how power arrives to my apartment. I know that it involves fossil fuels, petroleum, coal and possibly nuclear power, but I know little about how that is transformed into what lights my house.
When we talk about conserving energy we really mean conserving the resources that produce the energy. We should change the mindset to involve the concrete: the material used in the first few steps, instead of seeing it as the intangible final outcome.
So how does this relate to campus? Our project relates to reducing computer energy use. We’ve all seen how the campus computers are left on constantly; over the weekends and at night. The goal of our project is to inform the campus why it is important to take that extra moment to shut off your computer when you are done for the day.
There are numerous reasons to do this. First and foremost it saves the school money. Lower energy bills are the most immediate savings. But computers will last longer if properly managed, and turning them off lengthens their shelf life. This goes for monitors, printers and projectors as well.
Secondly, and more abstractly, it’s better for the environment. It means less energy is created, less energy is transported and fewer resources are consumed.
The most challenging part of this project will not be informing people of these facts. It will be getting them to care about the facts. Just because it’s good for the Earth, or the university for that matter, why should it affect how you life your life?
Through the Clinton Global Initiative we will share the multitude of reasons why a healthier more efficient campus will positively affect you as a student or employee. To the same degree we will show why a healthy and well managed planet can benefit you. It goes beyond simply “doing what’s right.” There are clear, measurable benefits that await us, once we are willing to make the simple changes.
Synaptic plasticity and synaptic degeneration in human congenital hydrocephalus
Journal of Pediatric Neurology April 1, 2008 | Castej?n, Orlando J Abstract.
Cortical biopsies of 13 infant patients with clinical diagnosis of congenital hydrocephalus, Arnold-Chiari malformation, and postmeningitis hydrocephalus were examined with transmission electron microscopy to study the synaptic plasticity and synaptic degenerative changes in hydrocephalic edema. The immature cortical neuropil of different cortical regions showed swollen nerve cell processes separated by enlarged extracellular space. Isolated and swollen presynaptic endings with few or numerous synaptic vesicles, disruption of limiting plasma membrane, and absent postsynaptic partners were also observed. Activated flat and invaginated axodendritic and axospinodendritic asymmetric synaptic contacts showed synaptic vesicles anchored to the presynaptic membrane, and short or large synaptic active zones. The swollen and degenerated synaptic contacts, including axosomatic synapses exhibited enlargement of few synaptic vesicles and lack of pre- and postsynaptic densities. Synaptic disassembly was observed in elevated intracranial pressure- hydrocephalus. Megaspines making multiple asymmetric synaptic junctions were also distinguished. Phagocytic astrocytes engulfed the degenerated synapses. The potential role of hydrocephalic edema and ischemia, oxidative stress, increased calcium concentration, activation of N-methyl D-aspartate receptors, and disturbance of ion homeostasis are discussed in relation with the observed synaptic plasticity and synaptic degenerative changes.
1. Introduction Tsubokawaet al. [1] reported impaired hippocampal plasticity in experimental chronic hydrocephalus characterized by attenuated long-term potentiation of population spikes in hydrocephalic rats. Miyazawa and Sato [2], Miyazawa et al. [3], Suda et al. [4,5] and Miyazawa and Sato [6] found learning disability and impairment of synaptogenesis, decreased spine density, decay of synaptic vesicle protein (SVP-38 and debrins) in the affected cerebral cortex of congenitally hydrocephalic H-tX rats, and postulated the beneficial role of early shunt placement in preventing impairment of synaptogenesis. Castejon [7] briefly described some synaptic degenerative changes in a previous study of human hydrocephalic cortex. Kriebel et al. [8], Knebel and McAllister [9] described altered dendritic appendages in experimental infantile hydrocephalus in a neonate kitten model. Boillat et al. [10] reported infrequent synapses in the deep cortical pyramidal cells of infant rats with inherited hydrocephalus, and the preventing effect of early shunt treatment. Miyajima et al. [11] demonstrated a remarkable decrease of choline acetyltransferase activity, and a disturbance of uptake and transport of nerve growth factor in H-tX hydrocephalic rats. Castej??n and Arismendi [12] found decreased synaptic density of shaft synapses, dysgenesis and partial loss of dendritic spines, and edematous changes of spine apparatus in human congenital hydrocephalus. Laske et al. [13] recently reported a decrease in serum concentration of brain-derived neurotrophic factor, and endogenous protein involved in the maintenance of neuronal function and synaptic plasticity in normal pressure hydrocephalus.
The nature and role of the synaptic structural changes and their relationship to the pathophysiology of human hydrocephalus deserve further studies in order to establish a future correlation between the degree of synaptic alterations, neuropsychomotor maldevelopment and impairment of nerve synaptic transmission. This aspect is particularly important in human hydrocephalus, where neurological deficit, psychomotor disturbance, learning disability and a relatively good preservation of intellectual functions may be found despite enlargement of lateral ventricles [14-16].
In the present electron microscopic study, we report the synaptic plasticity and synaptic degenerative changes of cerebral cortex synaptic contacts in human congenital hydrocephalus. This study was performed using cortical biopsies obtained during neurosurgical treatment. To the best of our knowledge a similar study has not being carried out thus far.
2. Materials and methods Samples of cerebral cortex of 13 infant patients with clinical diagnosis of congenital hydrocephalus, Arnold-Chiari malformation, and postmeningitis hydrocephalus were used in the present study (Table 1). All patients had X-rays and magnetic resonance imaging before neurosurgical treatment. Conical biopsies were performed according to basic ethical principles of the Declaration of Helsinki. This study was approved by the ethical committee of the biological research institute and policlinica Maracaibo.
Table 1 contains the clinical data and lists the cortical regions from which the biopsies were taken. Two to five mm thick cortical biopsies were immediately fixed in the surgical room in 4% glutaraldehyde-0.1 M phosphate or cacodylate buffer, pH 7.4 at 4 ?°C. Later they were divided into 1 mm fragments and immersed in a fresh, similar solution for periods 2 to 72 h, followed by secondary fixation in 1% osmium tetroxide-0.1 M phosphate buffer, pH 7.4 for 1 h. They were then rinsed for 5 to 10 min in a buffer similar to that used in the fixative solution, dehydrated in increasing concentrations of ethanol and embedded in Araldite or Epon. For proper orientation of the electron microscope study, thick sections of approximately 0.1 to 1 ?µm were stained with toluidine blue and examined with a Zeiss photomicroscope. Ultrathin sections obtained with a Porter-Blum and LKB ultramicrotomes were stained with uranyl acetate and lead citrate and observed in a JEOL 100B electron microscope. Observations were made using intermediate magnifications ranging from 24,000 to 75,000?. go to website arnold chiari malformation
3. Results Most neuropil from different cortical regions examined from patients with congenital hydrocephalus, uncompensated congenital communicating hydrocephalus, Arnold-Chiari malformation, and congenital hydrocephalus associated with meningomyelocele (cases 1 to 7) showed few immature synaptic contacts exhibiting simultaneously features of synaptic plasticity and synaptic degeneration. In the immature neuropil, undifferentiated nerve cell processes appeared isolated and separated by the over distended extracellular space characteristic of hydrocephalic edema. Swollen, round and ellipsoidal presynaptic endings apparently without postsynaptic partners were observed; exhibiting disrupted limiting plasma membranes, and containing few scattered synaptic vesicles (Fig. 1). Few immature and activated flat asymmetric axodendritic junctions were characterized by a paucity of synaptic vesicles anchored to the presynaptic membrane (Fig. 2).
The degenerated axodendritic contacts exhibited swollen pre- and postsynaptic endings, presynaptic endings showing few or numerous synaptic vesicles, short and large active synaptic membrane complexes, and axodendritic contacts lacking synaptic vesicles and pre- and post synaptic densities (Figs 3 and 4). Activated axodendritic synapses with front vesicles attached to the presynaptic membrane also were distinguished (Fig. 5). These synapses appear separated from the perisynaptic glial ensheathment. In addition, we found isolated swollen presynaptic endings with a fragmented limiting plasma membrane, and without postsynaptic endings (Fig. 6). We observed degenerated and invaginated axospinodendritic contacts showing a curved synaptic membrane complex, few dispersed presynaptic vesicles, irregularly dilated synaptic cleft, and absence of perisynaptic glial ensheathment (Fig. 7). These curved asymmetric axodendritic synapses are featured by protrusion of postsynaptic ending into the presynaptic one.
Degenerated axosomatic synapses with few enlarged presynaptic vesicles and dense cored vesicles, fragmented limiting plasma membrane of presynaptic endings, poorly differentiated synaptic membrane complexes, and lacking pre- and postsynaptic densities were distinguished (Fig. 8).
In a 4-month-old infant patient with elevated intracranial pressure-congenital hydrocephalus and a severe hydrocephalie edema (case 11), synaptic disassembly was observed. The pre- and postsynaptic endings appeared separated by a dilated synaptic cleft, without perisynaptic glial ensheathment, and surrounded by notably enlarged extracellular spaces (Fig. 9). We also found megaspines showing asymmetric synaptic contacts with two presynaptic endings containing numerous synaptic vesicles (Fig. 10).
Axosomatic synapses on swollen pyramidal neurons showed few dispersed synaptic vesicles, presence of dense cored vesicles, and absence of pre-and postsynaptic densities (Fig. 11). Phagocytosis of degenerated presynaptic contacts of axosomatic contacts by reactive astrocytes also was found (Fig. 12).
4. Discussion We show the presence of immature synapses with coexisting ultrastructural features of synaptic plasticity and synaptic degeneration in neonatal patients with hydrocephalus from varying causes. Our overall aim was to study the induced damage of hydrocephalic edema on synaptic junctions, and to initiate a look for the neural correlates of the neurological deficit and psychomotor disturbance that are often observed in infants with hydrocephalus.
We have described activated axodendritic synapses exhibiting presynaptic endings with few or numerous synaptic vesicles anchored to the presynaptic membrane. Synaptic vesicles docked at the presynaptic membrane active zones have been correlated with activated or sensitized mature synapses [17,18]. Docked vesicles have also been considered as an index of probability of neurotransmitter release and plasticity [19].
Several types of synaptic membrane complex active zones were found, such as short and curved in asymmetric axospinous synapses, short and flat in axodendritic asymmetric, and invaginated in asymmetric axospinous synapses, which are interpreted as changes related with synaptic plasticity. In mature synapses, synaptic plasticity has been associated with curved axospinous synapses with long synaptic active zone, corresponding to the “frown” synapses of Petit [17]. The synaptic curvature and the relation to synaptic plasticity was earlier postulated by Jones and Devon [20] and Devon and Jones [21], and related with the functional state of synaptic connection [22], and with compensatory mechanisms [23,24]. A curved postsynaptic membrane implies an increased surface for postsynaptic receptor activation [17], and can be correlated with an active synaptic excitatory connection or having implication for excitation/inhibition imbalance [23]. The synaptic plasticity and synaptic degenerative features above mentioned have also been observed by the author in human mature post-traumatic edematous cerebral cortex [25,26].
The immature synapses herein described exhibit features of synaptic degeneration, such as scarcity of synaptic vesicles, enlargement and depletion of synaptic vesicles, and synaptic disassembly. The synaptic disassembly was characterized by separated and isolated pre- and postsynaptic endings, which appeared detached from the perisynaptic glial ensheathment, perhaps due to the dissecting and shear forces of elevated intracranial pressure and hydrocephalic edema. Synaptic disassembly and terminal degeneration were earlier observed by us in traumatic brain injury [26] and by Brandst?¤tten et al. [27] after illumination-induced injury of photoreceptor terminals in the fly’s optic lobe.
One of the factors presumably causing synaptic degeneration in congenital hydrocephalus is the ischemia of infant brain parenchyma due to the hydrocephalic or interstitial edema. We have observed synaptic junctions lacking pre- and postsynaptic densities. Von Lubitz and Diemer [28] earlier described cleavage and decrease in the thickness of the post-synaptic density, wrinkling of the terminal profiles and membrane discontinuities in cerebral ischemia in mature synapses of the stratum radiatum of rat hippocampus. We have also observed ischemic destruction of pre-and post-synaptic densities in mature synapses of edematous and ischemic cerebral cortex in traumatic brain injuries [26].
We have observed in the immature and degenerated presynaptic terminals the progressive disappearance of most synaptic vesicles. Enlargement, clumping and progressive disappearance of synaptic vesicles have been earlier reported in mature and degenerated presynaptic endings [26,29]. Borroni et al. [30], by means of immune electron microscopy using a proteoglycan specific antiserum, studied the rate of disappearance of vesicle proteoglycan following denervation, and compared to the rate of disappearance of other vesicular and nerve terminal associated markers. Borroni et al. [30] suggested that degeneration affects the synaptic vesicular constituents at varying rates resulting in a progressive disappearance of the entire functional capacity of the synaptic vesicles. Arvidsson [31] also observed loss of synaptic vesicles in mature synapses in transganglionic degeneration. The above-mentioned findings suggest that disappearance of synaptic vesicle is the final step in the degeneration process of immature and mature synapses either in brain edema or in hydrocephalic edema. Decreased number and lysis of synaptic vesicles were reported by Sotelo [32] in irradiated monkey cerebral cortex, and by Saavedra et al. [33] in cat degenerating lateral geniculate nucleus. Castej??n et al. [26] also reported disappearance of synaptic vesicles in traumatic human brain injuries.
Some biochemical events should be considered in relation to the synaptic plasticity and degeneration in congenital hydrocephalus. Among these are release of arachidonic acid from membrane phospholipid, release of neurotransmitters and formation of prostaglandins and thromboxanes [34], depletion of retrogradely transported trophic factors [35], oxygen radical generation and lipid peroxidative reactions [36], glutamate release during ischemia and activation of N-methyl D-aspartate receptors [37], increase in intracellular calcium concentration [38], free radical generation and increased concentration of polyamines in the brain [39], disturbance in ion homeostasis involving cellular release of potassium and massive calcium entry into the intracellular compartment as occur in brain edema [40]. Some of these processes might occur in hydrocephalie edema, and can be envisaged as leading to disturbances of synaptic function, and finally to synaptic degeneration. It is important to emphasize that the immature brain has a mute response to oxidative stress compared to the adult brain, due to inadequate expression of certain antioxidants molecules [41]. According to Potts et al. [41], the inflammatory response in the immature brain is more robust than in the adult, and characterized by greater disruption of blood-brain barrier and elaboration of cytokines. As a result, the developing brain may be more vulnerable to oxidative stress than the adult brain [42]. According to Bayir et al. [42], in the developing brain individual components of the antioxidant system are not equally expressed and not always sufficient to fulfill their tasks in a coordinate way. In the patients under study, we are dealing with an immature cerebral cortex under high pressure due to the non-circulating cerebrospinal fluid and the associated hypoxic conditions. It should also be considered that immature brain tissue appears to be more susceptible to mechanical alterations [43].
In conclusion, the synaptic plasticity and synaptic degenerative features herein reported could be related with the neuropsychomotor maldevelopment, impairment of nerve synaptic transmission, and neurological deficit observed in infant hydrocephalus.
Acknowledgement This paper has been carried out by a subvention obtained from CONDES-LUZ. The secretarial help of Laura Villamizar is greatly appreciated.
[Reference] References [1] T. Tsubokawa, Y. Katayama and T. Kawamata, Impaired hippocampal plasticity in experimental chronic hydrocephalus, Brain Inj 2 (1988), 19-30.
[2] T. Miyazawa and K. Sato, Learning disability and impairment of synaptogenesis in HTX-rats with arrested shunt-dependent hydrocephalus. Child’s Nerv Syst 7 (1991), 121-128.
[3] T. Miyazawa, H. Nishiye, K. Sato et al., Cortical synaptogenesis in congenially hydrocephalic HTX-rats using monoclonal anti-synaptic vesicle protein antibody, Brain Dev 14 (1992), 75-79.
[4] K. Suda, K. Sato, T. Miyazawa and H. Arai, Changes of synapse-related proteins (SVP-38 and drebrins) during development of brain in congenitally hydrocephalie HTX rats with and without early placement of ventriculoperitoneal shunt, Pediatr Neurasurg 20 (1994), 50-56.
[5] K. Suda, K. Sato, N. Takeda, T. Miyazawa and H. Arai, Early ventriculoperitoneal shunt-effects on learning ability and synaptogenesis of the brain in congenitally hydrocephalic HTX rats. Child’s Nerv Syst 10 (1994), 19-23.
[6] T. Miyazawa and K. Sato, Hippocampal synaptogenesis in hydrocephalic HTX-rats using a monoclonal anti-synaptic vesicle protein antibody, Brain Dev 16 (1994), 432-436.
[7] O.J. Castejon, Transmission electron microscope study of human hydrocephalic cerebral cone, J Submicrasc Cytal Pathol 26 (1994), 29-39.
[8] R.M. Kriebel, A.B. Shah and J.P. McAllister 2nd, The microstructure of cortical neuropil before and after decompression in experimental infantile hydrocephalus, Exp Neurol 119 (1993), 89-98.
[9] R.M. Kriebel and J.P. McAllister 2nd, Pathology of the hippocampus in experimental feline infantile hydrocephalus, Neural Res 22 (2000), 29-36.
[10] C.A. Boillat, H.C. Jones, G.L. Kaiser and N.G. Harris, Ultrastructural changes in the deep cortical pyramidal cells of infant rats with inherited hydrocephalus and the effect of shunt treatment, Exp Neural 147 (1997), 377-388.
[11] M. Miyajima, K. Sato and H. Arai, Choline acetyltransferase, nerve growth factor and cytokine levels are changed in congenitally hydrocephalic HTX rats, Pediatr Neurosurg 24 (19%), 1-4.
[12] O.J. Castej??n and G.J. Arismendi, Morphological changes of dendrites in the human edematous cerebral cortex. A transmission electron microscopic stuay. J Submicrosc Cytol Pathol 35 (2003), 395-413.
[13] C. Laske, E. Stransky, T. Uyhe et al., BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls, J Psychiatr Res 41 (2007), 387-394.
[14] D.B. Shurtleff, E.L. Foltz and J.D. Loeser, Hydrocephalus. A definition of its progression and relationship to intellectual function, diagnosis, and complications. Am J Dis Child 125 (1973), 688-693.
[15] B.B. Storrs, Ventricular size and intelligence in myelodysplastic children. Concepts Pediatr Neurosurg 8 ( 1988), 51 -56.
[16] H.F. Young, F.E. Nulsen, M.H. Weiss and P. Thomas, The relationship of intelligence and cerebral mantle in treated infantile hydrocephalus. (IQ potential in hydrocephalic children), Pediatrics 52 (1973), 38-44.
[17] TL. Petit, Synaptic plasticity and the structural basis of learning and memory, in: Neural Plasticity: A Lifespan Approach, TL. Petit and G.O. Ivy, eds, New York: Liss, 1988, pp. 201-234.
[18] W.T Greenough, K.E. Armstrong, TA. Comery et al., Plasticity-related changes in synapse morphology, in: Cellular and Molecular Mechanisms Underlying Higher Neural Functions, A.I. Selverston and P. Ascher, eds, New York: John Wiley & Sons, 1994, pp. 211-220. go to website arnold chiari malformation
[19] M.A. Xu-Friedman, K.M. Harris and W.G. Regehr, Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells, J Neumsci 21 (2001), 6666-6672.
[20] D.G. Jones and R.M. Devon, An ultrastructural study into the effects of pentobarbitone on synaptic organization, Brain Res 147 (1978), 47-63.
[21] R.M. Devon and D.G. Jones, Synaptic terminal parameters in unanesthetized rat cerebral cortex. Cell Tissue Res 203 ( 1979), 189-200.
[22] N.I. lakovleva, L.E. Frumkina and N.N. Bogolepov, Changes in the configuration of the synaptic membranes in the human brain in aging and vascular pathology, BMI Eksp Biol Med 116 (1993), 544-548 (in Russian).
[23] D.F. Marrone, J.C. LeBoutillier and TL. Petit, Changes in synaptic ultrastructure during reactive synaptogenesis in the rat dentate gyrus, Brain Res 1005 (2004), 124-136.
[24] D.F. Marrone, J.C. LeBoutillier and TL. Petit, Comparative analyses of synaptic densities during reactive synaptogenesis in the rat dentate gyrus, Brain Res 996 (2004), 19-30.
[25] O.J. Castej??n, Synaptic plasticity in the oedematous human cerebral cortex, J Submicmsc Cytoi Pathol 35 (2003), 177-197.
[26] O.J. Castej??n, C. Valero and M. Di? az, Synaptic degenerative changes in human traumatic brain edema. An electron microscopic study of cerebral cortical biopsies, J Neurosurg Sci 39 (1995), 47-65.
[27] J.H. Brandst?¤tter, S.R. Shaw and I.A. Meinertzhagen, Reactive synaptogenesis following degeneration of photoreceptor terminals in the fly’s optic lobe: a quantitative electron microscopic study, Proc Biol Sci 247 (1992), 1-7.
[28] O.K. von Lubitz and N.H. Diemer, Cerebral ischemia in the rat: ultrastructural and morphometric analysis of synapses in stratum radiatum of the hippocampal CA-I region, Acta Neuropathol 61 (1983), 52-60.
[29] K. Akert, M. Cu?©nod and H. Moor, Further observations on the enlargement of synaptic vesicles in degenerating optic nerve terminals of the avian tectum, Brain Res 25 (1971), 255-263.
[30] E. Borroni, P. Ferretti, W. Fiedler and G.Q. Fox, The localization and rate of disappearance of a synaptic vesicle antigen following denervation. Cell Tissue Res 241 (1985), 367-372.
[31] J. Arvidsson, Transganglionic degeneration in vibrissae innervating primary sensory neurons of the rat: a light and electron microscopic study, J Comp Neural 249 (1986), 392-403.
[32] C. Sotelo, Permanence of postsynaptic specializations in the frog sympathetic ganglion cells after denervation, Exp Brain Res 6 (1968), 294-305.
[33] J.P. Saavedra, O.L. Vaccarezza, T.A. Reader and E. Pasqualini, Synaptic transmission in the degenerating lateral geniculate nucleus. An ultrastructural and electrophysiological study, Exp Neural 26 (1970), 607-620.
[34] H.D. Pappius and L.S. Wolfe, Effects of drugs on local cerebral glucose utilization in traumatized brain: Mechanism of action of steroids revisited, in: Recent Progress in the Study and Therapy of Brain Edema, K.G. Go and A. Baethmann, eds, New York: Plenum Press, 1984, pp. 11-26.
[35] JJ. Vornov and J.T. Coyle, Glutamate neurotoxicity and the inhibition of protein synthesis in the hippocampal slice, J Neurochem 56 (1991), 996-1006.
[36] E.D. Hall, M.R. Detloff, K. Johnson and N.C. Kupina, Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury, J Neumtrauma 21 (2004), 9-20.
[37] J.Y. Koh, E. Palmer and C.W. Cotman, Activation of the metabotropic glutamate receptor attenuates N-methyl-Daspartate neurotoxicity in cortical cultures, Proc NatlAcadSci USA 88 (1991), 9431-9435.
[38] B.H. Choi, Oxygen, antioxidants and brain dysfunction, Yonsei Med J 34 (1993), 1-10.
[39] G. Lombardi, A.M. Szekely, L.A. Bristol, A. Guidotti and H. Manev, Induction of omithine decarboxylase by N-methylD-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons, J Neurochem 60 ( 1993), 1317-1324.
[40] R Nilsson, L. Hillered, Y. Olsson, MJ. Sheardown and AJ. Hansen, Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats, J Cereb Blood Flow Metab 13 (1993), 183-192.
[41] M.B. Potts, S.E. Koh, W.D. Whetstone et al., Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets, NeuroRx 3 (2006), 143-153.
[42] H. Bayir, P.M. Kochanek and V.E. Kagan, Oxidative stress in immature brain after traumatic brain injury, Dev Neurosci 28 (2006), 420-431.
[43] R. Bauer and H. Fritz, Pathophysiology of traumatic injury in the developing brain: an introduction and short update, Exp Toxicol Palhol 56 (2004), 65-73.
[Author Affiliation] Orlando J. Castej??n* Biological Research Institute: “Drs. Orlando Castej??n and Hayd?©e Viloria de Castej??n”, Faculty of Medicine, University of Zulia, Maracaibo, Venezuela Received 10 May 2007 Revised 23 July 2007 Accepted 26 November 2007 [Author Affiliation] Castej?n, Orlando J
