Abstract
The involvement of anoxia/ischemia (AI) in neuropathology is more extensive than previously thought. The variety of insults extends from cardiac arrest to imperceptible microinfarcts. How these affect the nervous tissue is an arduous problem, in part due to the experimental tendency to focus on the parts instead of the whole. Over the years, this strategy taught us that white matter (WM) is far more resistant to AI than gray matter (Tekkok et al, 2003), and that astrocytes are more resistant than neurons (Sochocka et al, 1994), which work under an exquisite aerobic regime. Also, within neurons, the axon has its own energy factory and survives better than its parent soma, but peripheral axons are far more resistant than central fibers. That being said, the pieces have helped little in understanding the whole, i.e. how AI affects tissues made up of several metabolically coupled cell types, each with its own anaerobic capacity. For instance, selective disruption of the aerobic metabolism in astrocytes in intact normoxic tissue kills neurons (Largo et al, 1996). Also, different portions of the same axonal fibers travelling within central or peripheral tracts show strikingly varied resistance to AI (Utzschneider et al, 1991). Although calcium overload may be a common point in the road to irreversible injury (Kristián and Siesjö, 1998), the different cell types and elements may get there through diverse routes according to their own molecular machinery and/or the global properties of the tissue in which they are integrated. Selective vulnerability (Somjen et al, 1990) reminds us of the importance of supracellular factors in AI.
Indeed, brain energy metabolism is a case where dissecting the system for study downgrades the functions of its components. But, as is usual in life systems, this problem also has an additional dimension. There is a continuous remodeling from birth to aging (Boumezbeur et al, 2010). The article by Hamner et al (2010) brings us to a new standpoint. By using portions of the optic nerve subjected to anoxia, the authors report total loss of electrogenesis in 8-month-old mice, but only partial in 1-month specimens. They propose a reduced anaerobic capacity of WM with age. The anoxic inactivation of axons in gray matter has internal (ATP exhaustion) and external challengers (depolarization driven by external potassium flood), although the latter may not be at play in peripheral axons and to different degrees in different central nerve tracts in WM. The interesting point in Hamner's report is that it calls our attention to a poorly attended issue: axonal metabolism may also change with age. As the experiments were carried out in mice, we do not know yet how much this finding may relate to development or to aging in humans. New opportunities emerge for the clinics. In neurodegenerative brain diseases, we should start considering the possibility that axons may be as labile as cell bodies when facing AI episodes. For instance, microinfarcts might produce axonal damage, which may lead to neurological deficits as much as soma damage.
Footnotes
The authors declare no conflict of interest.