Different patterns of axonal damage after intracerebral injection of malonate or AMPA.

White matter damage occurs following stroke and traumatic brain injury. In preclinical studies of potential therapies to reduce acute brain damage, it is important not only to understand the mechanisms by which this damage occurs, but also to employ techniques that fully quantify the extent of damage. In both respects, neurons have previously received greater attention than axons. The aim of the present study was to compare the extent of axonal damage visualised with different immunohistochemical markers following intracerebral injection of either the excitotoxin AMPA or the mitochondrial inhibitor malonate. Adult mice received intrastriatal injection of toxin and 24 h later the amount of white matter damage visualised with either amyloid precursor protein (APP) or neurofilament 200 (NF200) immunohistochemistry. Malonate induced a dose-dependent increase in the extent of axonal damage with either marker. However, AMPA induced a dose-dependent increase in the extent of axonal damage visualised by NF200 immunoreactivity but not by APP immunoreactivity. Malonate and AMPA also differed in their effects on other assessments of white matter integrity and (14)C-2-deoxyglucose autoradiography revealed the two toxins to differ in their initial effects on cerebral metabolism. These data indicate that the ability of commonly-used axonal damage markers to quantify the full extent of white matter damage differs following initial excitotoxicity or mitochondrial inhibition. We also confirmed that the markers reveal different extents of axonal damage in a rat model of focal cerebral ischaemia. Therefore, in preclinical studies designed to assess brain protecting agents, it is advisable to use more than one marker to quantify the true extent of axonal damage.