Rapid Ischemic Cell Death in Immature Oligodendrocytes: A Fatal Glutamate Release Feedback Loop

Abstract

Ischemic injury of immature oligodendrocytes is a major component of the brain injury associated with cerebral palsy, the most common human birth disorder. We now report that cultured immature oligodendrocytes [O4(+)/galactoceramide (GC)(-)] are exquisitely sensitive to ischemic injury (80% of cells were dead after 25.5 min of oxygen and glucose withdrawal). This rapid ischemic cell death was mediated by Ca(2+) influx via non-NMDA glutamate receptors. The receptors were gated by the release of glutamate from the immature oligodendrocytes themselves via reverse glutamate transport and included a significant element of autologous feedback of glutamate from cells onto their own receptors. High (> or = 100 microM) extracellular glutamate was protective against ischemic injury as a result of non-NMDA glutamate receptor desensitization. Other potential pathways of Ca(2+) influx, such as voltage-gated Ca(2+) channels, NMDA receptors, or the Na(+)-Ca(2+) exchanger, did not significantly contribute to ischemic Ca(2+) influx or cell injury. Release of Ca(2+) from intracellular stores was also not an important factor. In agreement with previous studies, more mature oligodendrocytes (O4(-)/GC(+)) were found to be less sensitive to ischemic injury than were the immature cells studied here.

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…These data are of particular importance, as ischemic white matter injury is less understood and may contribute substantially to neurological deficits in human stroke [120]. However, some of the previously reported effects of NCX inhibitors have to be re-evaluated because bepridil and KB-R7943 also inhibit NMDA receptors [105,106] and L-type Ca 2+ channels [107], two pathways that may also contribute to the anoxic injury of various white matter components [14,[121][122][123][124].…”

Glial activation in white matter following ischemia in the neonatal P7 rat brain

“…Glial activation in white matter following ischemia in the neonatal P7 rat brain and glutamate (Back et al, 1998;Fern & Moller, 2000;Follett et al, 2000;Volpe, 2001;Back et al, 2002) and their propensity for induction of apoptosis (Han et al, 2000;Puka-Sundvall et al, 2000). Presumed loss of oligodendrocytes is a hallmark of PVL that results in hypomyelination and neurological deficits (Rorke, 1992;Volpe, 1997).…”

Functions of optic nerve glia: axoglial signalling in physiology and pathology

“…The activity of glutamate is normally terminated by uptake into oligodendrocytes, astrocytes, and axons, 33,34 but in ischaemia, transporters operate in reverse and enhanced glutamate signalling is excitotoxic for oligodendrocytes. [35][36][37] In an experimental model, sustained activation of oligodendrocyte iGluR by injection of kainate in the optic nerve induces lesions and compromises axon conduction, which has the major features of MS and ischaemic damage. [36][37][38] It is significant, therefore, that antagonists of iGluR ameliorate the symptoms of EAE and attenuate excitotoxic injury.…”

“…[35][36][37] In an experimental model, sustained activation of oligodendrocyte iGluR by injection of kainate in the optic nerve induces lesions and compromises axon conduction, which has the major features of MS and ischaemic damage. [36][37][38] It is significant, therefore, that antagonists of iGluR ameliorate the symptoms of EAE and attenuate excitotoxic injury. 39,40 The loss of oligodendrocytes and myelin results in secondary axonal damage, 10 although axons may also express iGluR, indicating that glutamate may directly compromise axons.…”