adenosine production via the 5′-nucleotidase reaction ( Fig. 4 ). Fig. 3. Passive and energy-dependent ion fluxes across plasma membranes. Neuronal depolarization leads to cellular influx of Na + and Ca 2+ , and efflux of K + . Re-pumping of Na + and K + occurs at the expense of ATP. It is hypothesized that Ca 2+ efflux occurs by Na + /Ca 2+ exchange (that is, it utilizes the energy stored in the Na + gradient created by ATPase activity). This gradient is also believed to transport H + from cells to extracellular fluid. See Definitions of Abbreviations
Bo K. Siesjö
Bo K. Siesjö
of breakdown products such as lysophospholipids, diacylglycerides (DAG's), and free fatty acids, including arachidonic acid. 4–6, 119, 120, 158 However, since many of the degradation enzymes involved are activated by calcium, the breakdown of structure is due both to a loss of ATP and to a rise in calcium concentration. Linkage of Energy Metabolism to Ion Flux The coupling of energy metabolism and ion homeostasis is exemplified by Fig. 3 , which illustrates both passive and energy-driven ion flux across normally polarized cell membranes. An unequal
Bo K. Siesjö
✓ This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells “at risk,” these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis.
Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl−, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH.
In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interferes with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++.
A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.
Darell D. Bigner and Charles B. Wilson
excitable. Schubert considered his lines to be “neuronal.” A re-examination of Schubert's electrophysiologically positive cell lines with a biochemical ion-flux assay correlated well with electrophysiological data. Eight of the 35 cell lines Herschman tested by the ion-flux methods were also positive; on the basis of the sodium ion-flux data, those eight lines have been tentatively considered to be neuronal. Both Schubert's and Herschman's cell lines have been examined quantitatively for S-100 and 14-3-2 brain-specific proteins. Both laboratories concluded that these
Keasley Welch and Keith Sadler
, S. Relationship of electrical potential differences to net ion fluxes in rat proximal tubules. Nature, Lond. , 1964 , 201 : 714 – 715 . Marsh , D., and Solomon , S. Relationship of electrical potential differences to net ion fluxes in rat proximal tubules. Nature, Lond. , 1964, 201: 714–715. 20. Oken , D. E. , Whittembury , G. , Windhager , E. E. , and Solomon , A. K. Single proximal tubules of Necturus kidney. V: Unidirectional sodium movement. Amer. J. Physiol. , 1963 , 204 : 372 – 376
Marc L. Schröder, J. Paul Muizelaar, M. Ross Bullock, Jackson B. Salvant, and John T. Povlishock
of CT density below ± 50 HU and zones of abnormal attenuation on MR imaging have been shown to be linearly related to the development of edema, as measured by microgravimetry. 13 Moreover, these studies have shown that the hypoperfused edematous zones do not reperfuse significantly with the passage of time, in contrast to, for example, either nonhemorrhagic infarction as seen in human middle cerebral artery occlusion 50 or the global changes in CBF after severe head injury. 47, 48 Mechanical Deformation and Ion Flux Mechanical deformation of neuronal tissue
Min-Hsiung Chen, Ross Bullock, David I. Graham, Jimmy D. Miller, and James McCulloch
. Becker DP , Katayama Y , Tamura T , et al : Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 ( Suppl 1 ): 302 , 1989 Becker DP, Katayama Y, Tamura T, et al: Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 (Suppl 1): 302, 1989 4. Benveniste H , Drejer J , Schousboe A , et al : Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during
Ross Bullock, Steve P. Butcher, Min-Hsiung Chen, L. Kendall, and James McCulloch
: 15 – 30 , 1983 Adams JH, Graham DI, Gennarelli TA: Head injury in man and experimental animals: neuropathology. Acta Neurochir Suppl 32: 15–30, 1983 2. Becker DP , Katayama Y , Tamura T , et al : Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 (Suppl 1) : 302 , 1989 Becker DP, Katayama Y, Tamura T, et al: Excitotoxic ion fluxes and neuronal dysfunction following traumatic brain injury. J Cereb Blood Flow Metab 9 (Suppl 1): 302, 1989 3
Yoichi Katayama, Donald P. Becker, Toru Tamura, and David A. Hovda
Gen Physiol 46 : 297 – 313 , 1962 Julian FJ, Goldman DE: The effects of mechanical stimulation on some electrical properties of axons. J Gen Physiol 46: 297–313, 1962 37. Katayama Y , Cheung MK , Alves A , et al : Ion fluxes and cell swelling after experimental traumatic brain injury: the role of excitatory amino acids , in Hoff JT , Betz AL (eds): Intracranial Pressure VII. New York : Springer-Verlag , 1989 , pp 584 – 588 Katayama Y, Cheung MK, Alves A, et al: Ion fluxes and cell
Keith L. Black, Kiyonobu Ikezaki, and Arthur W. Toga
localized to the mitochondrial and nuclear subcellular fractions, 1, 2 which implies a role for the receptor in oxidative metabolism and ion fluxes. Selective high density binding by peripheral benzodiazepine ligands could be utilized clinically in several ways. First, these ligands are amenable to conjugation with potentially cytotoxic compounds. The localization of binding sites to nuclear and mitochondrial fractions could increase their therapeutic advantage compared to targets on the cell surface. The effect of modulation of the peripheral receptor itself on tumor